FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Heske, CM Yeung, C Mendoza, A Baumgart, JT Edessa, LD Wan, XL Helman, LJ AF Heske, Christine M. Yeung, Choh Mendoza, Arnulfo Baumgart, Joshua T. Edessa, Leah D. Wan, Xiaolin Helman, Lee J. TI The Role of PDGFR-beta Activation in Acquired Resistance to IGF-1R Blockade in Preclinical Models of Rhabdomyosarcoma SO TRANSLATIONAL ONCOLOGY LA English DT Article ID FACTOR-I RECEPTOR; SMALL-MOLECULE INHIBITOR; GROWTH-FACTOR-II; MONOCLONAL-ANTIBODY; SARCOMA ALLIANCE; MECHANISMS; PATHWAY; KINASE; TUMORS; COLLABORATION AB To determine what alternative pathways may act as mechanisms of bypass resistance to type 1 insulin-like growth factor receptor (IGF-1R) blockade in rhabdomyosarcoma (RMS), we compared expression of receptor tyrosine kinase activity in a number of IGF-1R antibody-resistant and -sensitive RMS cell lines. We found that platelet-derived growth factor receptor beta (PDGFR-beta) activity was upregulated in three xenograft-derived IGF-1R antibody-resistant cell lines that arose from a highly sensitive fusion-positive RMS cell line (Rh41). Furthermore, we identified four additional fusion-negative RMS cell lines that similarly upregulated PDGFR-beta activity when selected for IGF-1R antibody resistance in vitro. In the seven cell lines described, we observed enhanced growth inhibition when cells were treated with dual IGF-1R and PDGFR-beta inhibition in vitro. In vivo studies have confirmed the enhanced effect of targeting IGF-1R and PDGFR-beta in several mouse xenograft models of fusion-negative RMS. These findings suggest that PDGFR-beta acts as a bypass resistance pathway to IGF-1R inhibition in a subset of RMS. Therapy co-targeting these receptors may be a promising new strategy in RMS care. C1 [Heske, Christine M.; Yeung, Choh; Mendoza, Arnulfo; Baumgart, Joshua T.; Edessa, Leah D.; Wan, Xiaolin; Helman, Lee J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Heske, CM (reprint author), NIH, Pediat Oncol Branch, Bldg 10,Room 1W-3816,10 Ctr Dr, Bethesda, MD 20892 USA. EM christine.heske@nih.gov FU Intramural Research Program of National Institutes of Health, the National Cancer Institute; Intramural Research Program of National Institutes of Health, Center for Cancer Research; Conquer Cancer Foundation of ASCO Young Investigator Award - Quad W Foundation FX This work was supported by grants from the Intramural Research Program of National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research and by a Conquer Cancer Foundation of ASCO Young Investigator Award supported by the Quad W Foundation. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Society of Clinical Oncology or the Conquer Cancer Foundation. NR 22 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 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD DEC PY 2016 VL 9 IS 6 BP 540 EP 547 DI 10.1016/j.tranon.2016.09.002 PG 8 WC Oncology SC Oncology GA EK4OE UT WOS:000393905600009 PM 27835791 ER PT J AU Campbell, SM Ulrich, CM Grady, C AF Campbell, Stephen M. Ulrich, Connie M. Grady, Christine TI A Broader Understanding of Moral Distress SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE decision making; medicine; moral theory; professional ethics; professional-patient relationship ID CARE AB On the traditional view, moral distress arises only in cases where an individual believes she knows the morally right thing to do but fails to perform that action due to various constraints. We seek to motivate a broader understanding of moral distress. We begin by presenting six types of distress that fall outside the bounds of the traditional definition and explaining why they should be recognized as forms of moral distress. We then propose and defend a new and more expansive definition of moral distress and examine how it can enable the development of a taxonomy of moral distress. C1 [Campbell, Stephen M.] Bentley Univ, Waltham, MA USA. [Ulrich, Connie M.] Univ Penn, Philadelphia, PA 19104 USA. [Grady, Christine] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Campbell, SM (reprint author), Bentley Univ, Dept Philosophy, 175 Forest St, Waltham, MA 02452 USA. EM scampbell@bentley.edu NR 25 TC 14 Z9 14 U1 3 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD DEC PY 2016 VL 16 IS 12 BP 2 EP 9 DI 10.1080/15265161.2016.1239782 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EF1WN UT WOS:000390115900009 ER PT J AU Rosner, MH Edeani, A Yanagita, M Glezerman, IG Leung, N AF Rosner, Mitchell H. Edeani, Amaka Yanagita, Motoko Glezerman, Ilya G. Leung, Nelson TI Paraprotein-Related Kidney Disease: Diagnosing and Treating Monoclonal Gammopathy of Renal Significance SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHAIN DEPOSITION DISEASE; FREE LIGHT-CHAINS; STEM-CELL TRANSPLANTATION; HIGH-DOSE MELPHALAN; MULTIPLE-MYELOMA; AL AMYLOIDOSIS; FIBRILLARY GLOMERULONEPHRITIS; UNDETERMINED SIGNIFICANCE; PROLIFERATIVE GLOMERULONEPHRITIS; WALDENSTROM MACROGLOBULINEMIA AB Paraprotein-related kidney disease represents a complex group of diseases caused by an abnormal paraprotein secreted by a clone of B cells. The disease manifestations range from tubulopathies, such as the Fanconi syndrome, to a spectrum of glomerular diseases that can present with varying degrees of proteinuria and renal dysfunction. Diagnosis of these diseases can be challenging because of the wide range of manifestations as well as the relatively common finding of a serum paraprotein, especially in elderly patients. Thus, renal biopsy along with detailed hematologic workup is essential to link the presence of the paraprotein to the associated renal disease. Recent advances in treatment with more effective and targeted chemotherapies, as well as stem cell transplantation, have improved the renal and overall prognosis for many of these disorders. C1 [Rosner, Mitchell H.] Univ Virginia Hlth Syst, Div Nephrol, Charlottesville, VA USA. [Edeani, Amaka] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Yanagita, Motoko] Kyoto Univ, Grad Sch Med, Dept Nephrol, Kyoto, Japan. [Glezerman, Ilya G.] Mem Sloan Kettering Canc Ctr, Dept Med, Renal Serv, 1275 York Ave, New York, NY 10021 USA. [Glezerman, Ilya G.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Leung, Nelson] Mayo Clin, Div Nephrol & Hypertens, 200 First St SW, Rochester, MN 55905 USA. [Leung, Nelson] Mayo Clin, Div Hematol, Rochester, MN USA. RP Leung, N (reprint author), Mayo Clin, Div Nephrol & Hypertens, 200 First St SW, Rochester, MN 55905 USA. EM leung.nelson@mayo.edu FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Berrien Community Foundation Lucille Kirshenbaum Fund; Omeros Corp.; MSK Cancer Center Support Grant/Core Grant [P30 CA008748] FX The work of A.E. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The work of N.L. is supported by donations from Mr. and Mrs. Ted Kirshenbaum, Dr. Gary Kohler, and Anne Drennan; the Berrien Community Foundation Lucille Kirshenbaum Fund; the Southshore Development Company; and grants from Omeros Corp. I.G.G. is supported by MSK Cancer Center Support Grant/Core Grant (P30 CA008748). NR 68 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2016 VL 11 IS 12 BP 2280 EP 2287 DI 10.2215/CJN.02920316 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EE3OF UT WOS:000389498200026 PM 27526705 ER PT J AU Simonsen, L Gog, JR Olson, D Viboud, C AF Simonsen, Lone Gog, Julia R. Olson, Don Viboud, Cecile TI Infectious Disease Surveillance in the Big Data Era: Towards Faster and Locally Relevant Systems SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE big data; medical claims; Internet search queries; syndromic data; death certificates; electronic patient records; influenza; infectious diseases surveillance; real-time monitoring ID PUBLIC-HEALTH SURVEILLANCE; UNITED-STATES; INFLUENZA; FLU; TIME AB While big data have proven immensely useful in fields such as marketing and earth sciences, public health is still relying on more traditional surveillance systems and awaiting the fruits of a big data revolution. A new generation of big data surveillance systems is needed to achieve rapid, flexible, and local tracking of infectious diseases, especially for emerging pathogens. In this opinion piece, we reflect on the long and distinguished history of disease surveillance and discuss recent developments related to use of big data. We start with a brief review of traditional systems relying on clinical and laboratory reports. We then examine how large-volume medical claims data can, with great spatiotemporal resolution, help elucidate local disease patterns. Finally, we review efforts to develop surveillance systems based on digital and social data streams, including the recent rise and fall of Google Flu Trends. We conclude by advocating for increased use of hybrid systems combining information from traditional surveillance and big data sources, which seems the most promising option moving forward. Throughout the article, we use influenza as an exemplar of an emerging and reemerging infection which has traditionally been considered a model system for surveillance and modeling. C1 [Simonsen, Lone; Olson, Don; Viboud, Cecile] US NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Gog, Julia R.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge, England. RP Simonsen, L (reprint author), Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. EM lsimonsen2@gmail.com FU DHS RAPIDD program; European Commission; Lundbeck Foundation; Fogarty International Center, NIH FX This work was supported by the DHS RAPIDD program, maintained by the Fogarty International Center, National Institutes of Health (NIH; support to L. S. and J. R. G.); the European Commission (Marie Curie senior fellowship to L. S.); the Lundbeck Foundation (visiting professorship grant to L. S.); and the in-house research program of the Fogarty International Center, NIH (support to C. V. and D. O.). NR 48 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2016 VL 214 SU 4 BP S380 EP S385 DI 10.1093/infdis/jiw376 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RW UT WOS:000393130300002 ER PT J AU Solem, RC Ruellas, A Ricks-Oddie, JL Kelly, K Oberoi, S Lee, J Miller, A Cevidanesh, L AF Solem, R. Christian Ruellas, Antonio Ricks-Oddie, Joni L. Kelly, Katherine Oberoi, Snehlata Lee, Janice Miller, Arthur Cevidanesh, Lucia TI Congenital and acquired mandibular asymmetry: Mapping growth and remodeling in 3 dimensions (vol 150, pg 238, 2016) SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Correction C1 [Solem, R. Christian] Univ Calif Los Angeles, Sect Orthodont, Los Angeles, CA 90024 USA. [Ruellas, Antonio] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Ruellas, Antonio] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Ricks-Oddie, Joni L.] Univ Calif Los Angeles, Inst Digital Res & Educ, Los Angeles, CA USA. [Kelly, Katherine; Cevidanesh, Lucia] Univ Michigan, Sch Dent, Dept Orthodont & Pediat Dent, Ann Arbor, MI 48109 USA. [Oberoi, Snehlata] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. [Lee, Janice] Natl Inst Dent & Craniofacial Research, NIH, Bethesda, MD USA. [Miller, Arthur] Univ Calif San Francisco, Sch Dent, San Francisco, CA USA. RP Solem, RC (reprint author), Univ Calif Los Angeles, Sect Orthodont, Los Angeles, CA 90024 USA. NR 1 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 0889-5406 EI 1097-6752 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD DEC PY 2016 VL 150 IS 6 BP 911 EP 912 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EI8DH UT WOS:000392734900008 ER PT J AU Varga, TV Winters, AH Jablonski, KA Horton, ES Khare-Ranade, P Knowler, WC Marcovina, SM Renstrom, F Watson, KE Goldberg, R Florez, JC Pollin, TI Franks, PW AF Varga, Tibor V. Winters, Alexandra H. Jablonski, Kathleen A. Horton, Edward S. Khare-Ranade, Prajakta Knowler, William C. Marcovina, Santica M. Renstrom, Frida Watson, Karol E. Goldberg, Ronald Florez, Jose C. Pollin, Toni I. Franks, Paul W. CA Diabetes Prevention Program Res Gr TI Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE clinical trial; genetics; lifestyle; lipids; lipoproteins; molecular epidemiology; polymorphism, genetic ID LOW-DENSITY-LIPOPROTEIN; REACTOME PATHWAY KNOWLEDGEBASE; CARDIOVASCULAR-DISEASE RISK; CORONARY-ARTERY-DISEASE; BODY-MASS INDEX; GENETIC-VARIANTS; SATURATED-FAT; LIFE-STYLE; CHOLESTEROL; POPULATION AB Background-We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. Methods and Results-We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3x10(-4)>P>1.1x10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (beta=-0.11 mu mol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5x10(-3); P-interaction=1x10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions-Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. C1 [Varga, Tibor V.; Renstrom, Frida; Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Winters, Alexandra H.; Pollin, Toni I.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Winters, Alexandra H.; Pollin, Toni I.] Univ Maryland, Sch Med, Program Genet & Genom Med, Baltimore, MD 21201 USA. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Horton, Edward S.; Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Khare-Ranade, Prajakta] Washington Univ, St Louis, MO USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Marcovina, Santica M.] Univ Washington, Northwest Lipid Metab & Diabet Res Labs, Seattle, WA 98195 USA. [Renstrom, Frida] Umea Univ, Dept Biobank Res, Umea, Sweden. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Watson, Karol E.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Goldberg, Ronald] Univ Miami, Leonard M Miller Sch Med, Div Endocrinol Diabet & Metab, Lipid Disorders Clin,Diabet Res Inst, Coral Gables, FL 33124 USA. [Florez, Jose C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Franks, Paul W.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Franks, PW (reprint author), Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, CRC, Bldg 91,Level 10,Jan Waldenstroms Gata 35, SE-20502 Malmo, Sweden. EM Paul.Franks@med.lu.se FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; National Institutes of Health/NIDDK [R01DK072041]; Swedish Heart-Lung Foundation; Faculty of Medicine at Umea University; EPiHealth (Lund University) FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Foods, and Quaker Oats donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group, and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. A complete list of centers, investigators, and staff is shown in the Acknowledgments. The Diabetes Prevention Program Genetics Project was supported by National Institutes of Health/NIDDK grant R01DK072041; additional funding from the Swedish Heart-Lung Foundation supported the costs of data analysis (for Dr Varga). Part of the work described in this article was undertaken as part of the 2013 to 2014 BLUE ScY educational exchange program, which was supported by the Faculty of Medicine at Umea University and EPiHealth (Lund University; for Dr Varga). NR 40 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2016 VL 9 IS 6 BP 495 EP + DI 10.1161/CIRCGENETICS.116.001457 PG 169 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA EH5OZ UT WOS:000391823900005 PM 27784733 ER PT J AU Natarajan, P Bis, JC Bielak, LF Cox, AJ Dorr, M Feitosa, MF Franceschini, N Guo, X Hwang, SJ Isaacs, A Jhun, MA Kavousi, M Li-Gao, R Lyytikainen, LP Marioni, RE Schminke, U Stitziel, NO Tada, H van Setten, J Smith, AV Vojinovic, D Yanek, LR Yao, J Yerges-Armstrong, LM Amin, N Baber, U Borecki, IB Carr, JJ Chen, YDI Cupples, LA de Jong, PA de Koning, H de Vos, BD Demirkan, A Fuster, V Franco, OH Goodarzi, MO Harris, TB Heckbert, SR Heiss, G Hoffmann, U Hofman, A Isgum, I Jukema, JW Kahonen, M Kardia, SLR Kral, BG Launer, LJ Massaro, J Mehran, R Mitchell, BD Jr, THM de Mutsert, R Newman, AB Nguyen, KD North, KE O'Connell, JR Oudkerk, M Pankow, JS Peloso, GM Post, W Province, MA Raffield, LM Raitakari, OT Reilly, DF Rivadeneira, F Rosendaal, F Sartori, S Taylor, KD Teumer, A Trompet, S Turner, ST Uitterlinden, AG Vaidya, D van der Lugt, A Volker, U Wardlaw, JM Wassel, CL Weiss, S Wojczynski, MK Becker, DM Becker, LC Boerwinkle, E Bowden, DW Deary, IJ Dehghan, A Felix, SB Gudnason, V Lehtimaki, T Mathias, R Mook-Kanamori, DO Psaty, BM Rader, DJ Rotter, JI Wilson, JG van Duijn, CM Volzke, H Kathiresan, S Peyser, PA O'Donnell, CJ AF Natarajan, Pradeep Bis, Joshua C. Bielak, Lawrence F. Cox, Amanda J. Dorr, Marcus Feitosa, Mary F. Franceschini, Nora Guo, Xiuqing Hwang, Shih-Jen Isaacs, Aaron Jhun, Min A. Kavousi, Maryam Li-Gao, Ruifang Lyytikainen, Leo-Pekka Marioni, Riccardo E. Schminke, Ulf Stitziel, Nathan O. Tada, Hayato van Setten, Jessica Smith, Albert V. Vojinovic, Dina Yanek, Lisa R. Yao, Jie Yerges-Armstrong, Laura M. Amin, Najaf Baber, Usman Borecki, Ingrid B. Carr, J. Jeffrey Chen, Yii-Der Ida Cupples, L. Adrienne de Jong, Pim A. de Koning, Harry de Vos, Bob D. Demirkan, Ayse Fuster, Valentin Franco, Oscar H. Goodarzi, Mark O. Harris, Tamara B. Heckbert, Susan R. Heiss, Gerardo Hoffmann, Udo Hofman, Albert Isgum, Ivana Jukema, J. Wouter Kahonen, Mika Kardia, Sharon L. R. Kral, Brian G. Launer, Lenore J. Massaro, Joe Mehran, Roxana Mitchell, Braxton D. Jr, Thomas H. Mosley de Mutsert, Renee Newman, Anne B. Nguyen, Khanh-dung North, Kari E. O'Connell, Jeffrey R. Oudkerk, Matthijs Pankow, James S. Peloso, Gina M. Post, Wendy Province, Michael A. Raffield, Laura M. Raitakari, Olli T. Reilly, Dermot F. Rivadeneira, Fernando Rosendaal, Frits Sartori, Samantha Taylor, Kent D. Teumer, Alexander Trompet, Stella Turner, Stephen T. Uitterlinden, Andre G. Vaidya, Dhananjay van der Lugt, Aad Volker, Uwe Wardlaw, Joanna M. Wassel, Christina L. Weiss, Stefan Wojczynski, Mary K. Becker, Diane M. Becker, Lewis C. Boerwinkle, Eric Bowden, Donald W. Deary, Ian J. Dehghan, Abbas Felix, Stephan B. Gudnason, Vilmundur Lehtimaki, Terho Mathias, Rasika Mook-Kanamori, Dennis O. Psaty, Bruce M. Rader, Daniel J. Rotter, Jerome I. Wilson, James G. van Duijn, Cornelia M. Volzke, Henry Kathiresan, Sekar Peyser, Patricia A. O'Donnell, Christopher J. CA CHARGE Consortium TI Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE carotid intima-media thickness; coronary artery calcification; exome; genome-wide association study; genomics ID CORONARY-ARTERY CALCIFICATION; INTIMA-MEDIA THICKNESS; HEART-DISEASE RISK; DEFECTIVE APOLIPOPROTEIN B-100; BEAM COMPUTED-TOMOGRAPHY; OLD ORDER AMISH; CARDIOVASCULAR RISK; III HYPERLIPOPROTEINEMIA; MYOCARDIAL-INFARCTION; AORTIC CALCIFICATION AB Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease. C1 [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Natarajan, Pradeep; Peloso, Gina M.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Bielak, Lawrence F.; Jhun, Min A.; Kardia, Sharon L. R.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Cox, Amanda J.; Raffield, Laura M.; Bowden, Donald W.] Wake Forest Hlth Sci, Diabet Heart Study, Winston Salem, NC USA. [Dorr, Marcus; Felix, Stephan B.] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Schminke, Ulf] Univ Med Greifswald, Dept Neurol, Greifswald, Germany. [Teumer, Alexander; Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Volker, Uwe; Weiss, Stefan] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Dorr, Marcus; Teumer, Alexander; Volker, Uwe; Weiss, Stefan; Felix, Stephan B.; Volzke, Henry] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Feitosa, Mary F.; Stitziel, Nathan O.; Province, Michael A.; Wojczynski, Mary K.] Washington Univ, Sch Med, Dept Genet, Div Stat Genet, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, Div Cardiovasc, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Franceschini, Nora; Heiss, Gerardo; North, Kari E.] Univ N Carolina, Gilling Sch Global Publ Hlth, Epidemiol, Chapel Hill, NC USA. [Guo, Xiuqing; Yao, Jie; Chen, Yii-Der Ida; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Guo, Xiuqing; Yao, Jie; Chen, Yii-Der Ida; Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Hwang, Shih-Jen] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Kavousi, Maryam; Vojinovic, Dina; Amin, Najaf; Demirkan, Ayse; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Dehghan, Abbas; van Duijn, Cornelia M.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [van der Lugt, Aad] Univ Med Ctr Rotterdam, Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Dehghan, Abbas] Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England. [Isaacs, Aaron] Maastricht Univ, Maastricht Ctr Syst Biol MaCSBio, Maastricht, Netherlands. [Li-Gao, Ruifang; de Mutsert, Renee; Rosendaal, Frits; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Jukema, J. Wouter; Trompet, Stella] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Marioni, Riccardo E.; Wardlaw, Joanna M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Div Neuroimaging Sci, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo E.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Tada, Hayato] Kanazawa Univ, Grad Sch Med, Div Cardiovasc Med, Kanazawa, Ishikawa, Japan. [van Setten, Jessica] Univ Med Ctr Utrecht, Cardiol, Utrecht, Netherlands. [de Jong, Pim A.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [de Vos, Bob D.; Isgum, Ivana] Univ Med Ctr Utrecht, Image Sci Inst, Utrecht, Netherlands. [Smith, Albert V.; Gudnason, Vilmundur] Icelandic Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Yanek, Lisa R.; Kral, Brian G.; Post, Wendy; Vaidya, Dhananjay; Becker, Diane M.; Becker, Lewis C.; Mathias, Rasika] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Yerges-Armstrong, Laura M.; Mitchell, Braxton D.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Baber, Usman; Fuster, Valentin; Mehran, Roxana; Sartori, Samantha] Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY 10029 USA. [Borecki, Ingrid B.] Regeneron Pharmaceut Inc, Analyt Genet, Tirrytown, NY USA. [Carr, J. Jeffrey] Vanderbilt, Radiol, Cardiovasc Med & Biomed Informat, Nashville, TN USA. [Cupples, L. Adrienne; Massaro, Joe; Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [de Koning, Harry] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res, NIH, Baltimore, MD 21224 USA. [Jukema, J. Wouter] Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Netherlands Heart Inst, InterUniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Mitchell, Braxton D.] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Jr, Thomas H. Mosley] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Nguyen, Khanh-dung] Merck & Co Inc, MRL, Genet & Pharmacogen Dept, Boston, MA USA. [Reilly, Dermot F.] Merck Sharpe & Dohme Corp, Genet & Pharmacogen Dept, Boston, MA USA. [Oudkerk, Matthijs] Univ Groningen, Univ Med Ctr Groningen, Ctr Med Imaging North East Netherlands, Groningen, Netherlands. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Wassel, Christina L.] Univ Vermont, Dept Pathol & Lab Med, Colchester, Essex, England. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol, Sch Publ Hlth, Houston, TX 77030 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rader, Daniel J.] Univ Penn, Dept Med, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Volzke, Henry] German Ctr Diabet Res DZD, Greifswald, Germany. [O'Donnell, Christopher J.] Boston Vet Affairs Healthcare Syst, Div Cardiol, Boston, MA USA. RP O'Donnell, CJ (reprint author), Harvard Med Sch, Boston Vet Affairs Healthcare Syst, 1400 Vet Foreign Wars Pkwy,Bldg 1 5B-113, Boston, MA 02132 USA.; Natarajan, P (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Natarajan, P (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM pnatarajan@partners.org; odonnellc@nhlbi.nih.gov RI Fuster, Valentin/H-4319-2015; Feitosa, Mary/K-8044-2012; OI Fuster, Valentin/0000-0002-9043-9986; Feitosa, Mary/0000-0002-0933-2410; Carr, John/0000-0002-4398-8237; Mitchell, Braxton/0000-0003-4920-4744; Vaidya, Dhananjay/0000-0002-7164-1601; Pankow, James/0000-0001-7076-483X FU John S. LaDue Memorial Fellowship in Cardiology, Harvard Medical School; NWO VENI grant (VENI) [91616079]; National Heart, Lung, and Blood Institute [R01HL105756, R01HL120393]; Data Supplement FX Dr Natarajan is supported by the John S. LaDue Memorial Fellowship in Cardiology, Harvard Medical School. Dr Kavousi is supported by the NWO VENI grant (VENI, 91616079). Infrastructure for the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology) is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. Funding support for the CHARGE Consortium Exome Chip analyses is provided in part by the National Heart, Lung, and Blood Institute grant R01HL120393. Please refer to the Data Supplement regarding additional sources of funding. NR 88 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 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2016 VL 9 IS 6 BP 511 EP + DI 10.1161/CIRCGENETICS.116.001572 PG 57 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA EH5OZ UT WOS:000391823900007 PM 27872105 ER PT J AU Clayton, JA AF Clayton, Janine Austin TI Sex influences in neurological disorders: case studies and perspectives SO DIALOGUES IN CLINICAL NEUROSCIENCE LA English DT Editorial Material DE sex difference; gender; brain research; hormone; clinical trial ID TEMPORAL-LOBE EPILEPSY; PARKINSONS-DISEASE; GENDER-DIFFERENCES; MULTIPLE-SCLEROSIS; MURINE MODEL; CHROMOSOME COMPLEMENT; PROBABLE MIGRAINE; NONMOTOR SYMPTOMS; ISCHEMIC-STROKE; NITRIC-OXIDE AB Beginning in the late 1980s and early 1990s, scientists and the public alike recognized that, for too long, women had been underrepresented in clinical trials. While much progress was made in the following decades, preclinical research still often ignores sex as a fundamental biological variable. Many neurological disorders, including multiple sclerosis and migraine, show strong sex differences in incidence and disease manifestation. In this commentary, we highlight case studies of neurological disorders affecting men and women to demonstrate the need for more such studies. Research conducted in these areas so far has shed light on the underlying mechanisms of the disease and offers the promise to help develop more personalized treatments for both men and women. (C) 2016, AICH - Servier Research Group C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. RP Clayton, JA (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM janine.clayton@nih.gov FU Office of Research on Women's Health of the National Institutes of Health FX This manuscript has not been published elsewhere. There are no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was funded by the Office of Research on Women's Health of the National Institutes of Health. NR 51 TC 0 Z9 0 U1 2 U2 2 PU INST CONFERENCE HIPPOCRATE PI SURESNESS-CEDEX PA 50 RUE CARNOT, SURESNESS-CEDEX, 92284, FRANCE SN 1294-8322 EI 1958-5969 J9 DIALOGUES CLIN NEURO JI Dialogues Clin. Neurosci. PD DEC PY 2016 VL 18 IS 4 BP 357 EP 360 PG 4 WC Neurosciences SC Neurosciences & Neurology GA EJ7AQ UT WOS:000393373600002 PM 28179807 ER PT J AU Blanco, C Wall, MM Lindquist, MA Rodriguez-Fernandez, JM Franco, S Wang, S Olfson, M AF Blanco, Carlos Wall, Melanie M. Lindquist, Martin A. Rodriguez-Fernandez, Jorge Mario Franco, Silvia Wang, Shuai Olfson, Mark TI Generalizability of Neuroimaging Studies in 5 Common Psychiatric Disorders Based on the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; MAJOR DEPRESSIVE DISORDER; RESEARCH DOMAIN CRITERIA; COMMUNITY SAMPLES; MENTAL-DISORDERS; PRECISION MEDICINE; DIAGNOSTIC MODULES; ANXIETY DISORDERS AB Objective: Although neuroimaging studies have an important role in psychiatric nosology and treatment development, little is known about the representativeness of participants in neuroimaging research. We estimated the effects of commonly used study eligibility criteria on the representativeness of neuroimaging research participants in relation to the general population with the psychiatric disorders of interest. Methods: Common eligibility criteria were applied from 112 published neuroimaging studies of DSM-IV nicotine dependence (13 studies), alcohol dependence (12 studies), drug use disorders (13 studies), major depressive disorder (MDD) (37 studies), and posttraumatic stress disorder (PTSD) (36 studies) to representative US samples with these conditions from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (n = 43,093). The analyses were repeated with NESARC respondents with the disorders and substantial psychosocial impairment. Results: Most NESARC respondents with nicotine dependence (64.1%), alcohol dependence (57.7%), drug use disorders (86.6%), and PTSD (66.9%), though not with MDD (18.2%), would have been excluded by eligibility criteria used in at least half of the relevant neuroimaging studies. Across the diagnostic groups, comorbid psychiatric and general medical conditions resulted in the largest percentages of exclusions. Corresponding analyses limited to respondents with substantial impairment excluded larger percentages with nicotine dependence (77.6%), alcohol dependence (75.8%), drug use disorders (93.5%), and PTSD (76.8%), though not MDD (18.3%). Conclusions: Neuroimaging studies tend to recruit highly selected samples with the psychiatric disorders of interest that markedly underrepresent individuals with common comorbid conditions. Larger studies with less restrictive eligibility criteria may promote translation of advances in neuroimaging research to populations commonly encountered in clinical practice. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Blanco, Carlos] NIDA, Rockville, MD USA. [Wall, Melanie M.; Rodriguez-Fernandez, Jorge Mario; Franco, Silvia; Wang, Shuai; Olfson, Mark] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. [Wall, Melanie M.] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Lindquist, Martin A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Olfson, M (reprint author), Columbia Univ, Dept Psychiat, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@cumc.columbia.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Program, NIAAA, National Institutes of Health (NIH); NIH grants [DA019606, MH076051, MH082773]; Agency for Healthcare Research and Quality grant [HS02112]; New York State Psychiatric Institute FX The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health (NIH). Work on this article was supported by NIH grants DA019606, MH076051, and MH082773; Agency for Healthcare Research and Quality grant HS02112; and the New York State Psychiatric Institute (Drs Blanco, Olfson, and Wall). NR 56 TC 1 Z9 1 U1 1 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2016 VL 77 IS 12 BP E1618 EP E1625 DI 10.4088/JCP.15m10264 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EJ2EL UT WOS:000393022700010 PM 28086006 ER PT J AU Korkut, S Bastug, O Raygada, M Hatipoglu, N Kurtoglu, S Kendirci, M Lyssikatos, C Stratakis, CA AF Korkut, Sabriye Bastug, Osman Raygada, Margarita Hatipoglu, Nihal Kurtoglu, Selim Kendirci, Mustafa Lyssikatos, Charalampos Stratakis, Constantine A. TI Complex Glycerol Kinase Deficiency and Adrenocortical Insufficiency in Two Neonates SO JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY LA English DT Article DE Deletions; X-chromosome; glycerol kinase; adrenal insufficiency AB Contiguous gene deletions of chromosome Xp21 can lead to glycerol kinase deficiency and severe adrenocortical insufficiency (AI) in a male newborn among other problems. We describe our experience with two such patients who presented with dysmorphic facies, AI, and pseudo-hypertriglyceridemia. Both infants had normal serum 17-hidroxyprogesterone levels, and adrenal glands could not be observed with ultrasonography. Creatine kinase and triglyceride levels were measured to elucidate the etiology of adrenal hypoplasia and were above normal limits in both cases. Both patients required steroid and salt supplementation. They were both found to have Xp21.2 deletions (DMD, NR0B1, GK, IL1RAPL1). We conclude that AI in the context of other genetic abnormalities should prompt chromosomal investigations in the absence of another unifying explanation. C1 [Korkut, Sabriye; Bastug, Osman; Kurtoglu, Selim] Erciyes Univ, Fac Med, Dept Pediat, Div Neonatol, Kayseri, Turkey. [Raygada, Margarita; Lyssikatos, Charalampos; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Raygada, Margarita; Lyssikatos, Charalampos; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Endocrinol & Genet, Pediat Endocrinol Interinst Training Program, Bethesda, MD USA. [Hatipoglu, Nihal; Kurtoglu, Selim; Kendirci, Mustafa] Erciyes Univ, Fac Med, Dept Pediat, Div Pediat Endocrinol, Kayseri, Turkey. [Kendirci, Mustafa] Erciyes Univ, Fac Med, Dept Pediat, Div Pediat Metab, Kayseri, Turkey. RP Korkut, S (reprint author), Erciyes Univ, Fac Med, Dept Pediat, Div Neonatol, Kayseri, Turkey. EM sabriyeyaman@hotmail.com NR 11 TC 0 Z9 0 U1 0 U2 0 PU GALENOS YAYINCILIK PI FINDIKZADE PA ERKAN MOR, MOLLA GURANI CAD 21-1, FINDIKZADE, ISTANBUL 34093, TURKEY SN 1308-5727 EI 1308-5735 J9 J CLIN RES PEDIATR E JI J. Clin Res. Pediatr. Endocrinol. PD DEC PY 2016 VL 8 IS 4 BP 468 EP 471 DI 10.4274/jcrpe.2539 PG 4 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA EJ2LA UT WOS:000393040300014 PM 27087023 ER PT J AU Bansal, S Chowell, G Simonsen, L Vespignani, A Viboud, C AF Bansal, Shweta Chowell, Gerardo Simonsen, Lone Vespignani, Alessandro Viboud, Cecile TI Big Data for Infectious Disease Surveillance and Modeling SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE big data; infectious diseases; surveillance; disease models; transmission; social media; Internet search queries; electronic health records; mobility; adverse events; outbreaks AB We devote a special issue of the Journal of Infectious Diseases to review the recent advances of big data in strengthening disease surveillance, monitoring medical adverse events, informing transmission models, and tracking patient sentiments and mobility. We consider a broad definition of big data for public health, one encompassing patient information gathered from high-volume electronic health records and participatory surveillance systems, as well as mining of digital traces such as social media, Internet searches, and cell-phone logs. We introduce nine independent contributions to this special issue and highlight several cross-cutting areas that require further research, including representativeness, biases, volatility, and validation, and the need for robust statistical and hypotheses-driven analyses. Overall, we are optimistic that the big-data revolution will vastly improve the granularity and timeliness of available epidemiological information, with hybrid systems augmenting rather than supplanting traditional surveillance systems, and better prospects for accurate infectious diseases models and forecasts. C1 [Bansal, Shweta; Chowell, Gerardo; Simonsen, Lone; Viboud, Cecile] NIH, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Vespignani, Alessandro] Northeastern Univ, Network Sci Inst, Boston, MA 02115 USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Bansal, Shweta/0000-0002-1740-5421 FU RAPIDD (Research And Policy for Infectious Diseases Dynamics) Program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; European Commission; Lundbeck Foundation; Fogarty International Center; Defense Threat Reduction Agency [1-0910039]; National Institutes of Health [MIDAS-U54-GM111274] FX This work was supported by the RAPIDD (Research And Policy for Infectious Diseases Dynamics) Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (L. S. and S. B.); the European Commission (Marie Curie Senior fellowship to L. S.); the Lundbeck Foundation (visiting professorship grant to L. S.); the in-house research program of Fogarty International Center (G. C. and C. V.); the Defense Threat Reduction Agency (grant 1-0910039 to A. V.); and the National Institutes of Health (grant MIDAS-U54-GM111274 to A. V.). NR 23 TC 0 Z9 0 U1 6 U2 6 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 DEC 1 PY 2016 VL 214 SU 4 BP S375 EP S379 DI 10.1093/infdis/jiw400 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RW UT WOS:000393130300001 ER PT J AU Chowell, G Cleaton, JM Viboud, C AF Chowell, Gerardo Cleaton, Julie M. Viboud, Cecile TI Elucidating Transmission Patterns From Internet Reports: Ebola and Middle East Respiratory Syndrome as Case Studies SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE transmission chain; cluster; Internet data stream; big data; transmission patterns; exposure setting; contact network; reproduction number; Ebola; MERS ID VIRUS DISEASE EVD; SYNDROME CORONAVIRUS; PUBLIC-HEALTH; HEMORRHAGIC-FEVER; RISK-FACTORS; DYNAMICS; OUTBREAK; SURVEILLANCE; MODELS; UGANDA AB The paucity of traditional epidemiological data during epidemic emergencies calls for alternative data streams to characterize the key features of an outbreak, including the nature of risky exposures, the reproduction number, and transmission heterogeneities. We illustrate the potential of Internet data streams to improve preparedness and response in outbreak situations by drawing from recent work on the 2014-2015 Ebola epidemic in West Africa and the 2015 Middle East respiratory syndrome (MERS) outbreak in South Korea. We show that Internet reports providing detailed accounts of epidemiological clusters are particularly useful to characterize time trends in the reproduction number. Moreover, exposure patterns based on Internet reports align with those derived from epidemiological surveillance data on MERS and Ebola, underscoring the importance of disease amplification in hospitals and during funeral rituals (associated with Ebola), prior to the implementation of control interventions. Finally, we discuss future developments needed to generalize Internet-based approaches to study transmission dynamics. C1 [Chowell, Gerardo; Cleaton, Julie M.] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. EM gchowell@gsu.edu FU Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health (NIH); RAPIDD Program, Science and Technology Directorate, Department of Homeland Security; National Science Foundation (NDF) [1414374]; United Kingdom Biotechnology and Biological Sciences Research Council [BB/M008894/1] FX This work was supported by the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health (NIH; support to G. C. and C. V.); the RAPIDD Program, Science and Technology Directorate, Department of Homeland Security (support to G. C. and C. V.); the National Science Foundation (NDF; grant 1414374 to G. C.), as part of the joint NSF-NIH-US Department of Agriculture Ecology and Evolution of Infectious Diseases program; and the United Kingdom Biotechnology and Biological Sciences Research Council (grant BB/M008894/1). NR 42 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2016 VL 214 SU 4 BP S421 EP S426 DI 10.1093/infdis/jiw356 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RW UT WOS:000393130300009 ER PT J AU Lee, EC Asher, JM Goldlust, S Kraemer, JD Lawson, AB Bansal, S AF Lee, Elizabeth C. Asher, Jason M. Goldlust, Sandra Kraemer, John D. Lawson, Andrew B. Bansal, Shweta TI Mind the Scales: Harnessing Spatial Big Data for Infectious Disease Surveillance and Inference SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE spatial big data; spatial epidemiology; disease mapping; infectious diseases; digital epidemiology; statistical bias AB Spatial big data have the velocity, volume, and variety of big data sources and contain additional geographic information. Digital data sources, such as medical claims, mobile phone call data records, and geographically tagged tweets, have entered infectious diseases epidemiology as novel sources of data to complement traditional infectious disease surveillance. In this work, we provide examples of how spatial big data have been used thus far in epidemiological analyses and describe opportunities for these sources to improve disease-mitigation strategies and public health coordination. In addition, we consider the technical, practical, and ethical challenges with the use of spatial big data in infectious disease surveillance and inference. Finally, we discuss the implications of the rising use of spatial big data in epidemiology to health risk communication, and public health policy recommendations and coordination across scales. C1 [Lee, Elizabeth C.; Goldlust, Sandra; Bansal, Shweta] Georgetown Univ, Dept Biol, 408 Reiss Sci Bldg, Washington, DC 20057 USA. [Kraemer, John D.] Georgetown Univ, Dept Hlth Syst Adm, Washington, DC USA. [Asher, Jason M.] Leidos, Washington, DC USA. [Lawson, Andrew B.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Bansal, S (reprint author), Georgetown Univ, Dept Biol, 408 Reiss Sci Bldg, Washington, DC 20057 USA. EM shweta.bansal@georgetown.edu OI Lee, Elizabeth/0000-0002-4156-9637; Bansal, Shweta/0000-0002-1740-5421 FU Jayne Koskinas Ted Giovanis Foundation for Health and Policy; National Cancer Institute [R01CA172805]; RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the Jayne Koskinas Ted Giovanis Foundation for Health and Policy (dissertation support grant to E. C. L.); the National Cancer Institute (grant R01CA172805 to A. B. L.); and the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 31 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2016 VL 214 SU 4 BP S409 EP S413 DI 10.1093/infdis/jiw344 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RW UT WOS:000393130300007 ER PT J AU Jenkins, DE Sreenivasan, D Carman, F Samal, B Eiden, LE Bunn, SJ AF Jenkins, Danielle E. Sreenivasan, Dharshini Carman, Fiona Samal, Babru Eiden, Lee E. Bunn, Stephen J. TI Interleukin-6-mediated signaling in adrenal medullary chromaffin cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE chromaffin cell; cytokine; inflammation; interleukin-6; STAT3; tyrosine hydroxylase ID TUMOR-NECROSIS-FACTOR; NEUROPEPTIDE GENE-EXPRESSION; HORMONE-RELATED PROTEIN; TYROSINE-HYDROXYLASE; CATECHOLAMINE RELEASE; GLUCOCORTICOID SECRETION; ADRENOCHROMAFFIN CELLS; TRANSCRIPTION FACTORS; ADRENOCORTICAL-CELLS; CA2+ CHANNELS AB The pro-inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-1 beta/alpha modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine-31) and activity, as well as up-regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin-releasing peptide, and parathyroid hormone-like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G-protein-coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase-activating polypeptide) and the cytokine receptor agonists (interferon-a and tumor necrosis factor-a). Of 90 genes up-regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6-dependent genes activated by IL6-induced transcription factors, such as hypoxia-inducible factor 1 alpha. Notably, genes induced by IL6 include both neuroen-docrine-specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine-tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge. C1 [Jenkins, Danielle E.; Carman, Fiona; Bunn, Stephen J.] Univ Otago, Otago Sch Med Sci, Ctr Neuroendocrinol, Dept Anat, POB 913, Dunedin, New Zealand. [Sreenivasan, Dharshini] Univ Auckland, Auckland Bioengn Inst, Auckland, New Zealand. [Samal, Babru; Eiden, Lee E.] NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Bunn, SJ (reprint author), Univ Otago, Otago Sch Med Sci, Ctr Neuroendocrinol, Dept Anat, POB 913, Dunedin, New Zealand. EM stephen.bunn@anatomy.otago.ac.nz FU NIMH Intramural Research Program [Z01 MH002386-21]; University of Otago Research Grant FX We thank Chang-Mei Hsu and Shirley Douglas for their expert technical assistance in preparation of adrenal medullary cell cultures, RNA for microarray, and qRT-PCR analysis. Djida Ait-Ali is thanked for substantive intellectual and technical contributions to this project, which cannot be acknowledged by authorship solely because she could not be contacted and therefore her assent to authorship could not be obtained. This work was supported by NIMH Intramural Research Program Project Z01 MH002386-21 and a University of Otago Research Grant. The authors declare no conflicts of interest. NR 78 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 139 IS 6 BP 1138 EP 1150 DI 10.1111/jnc.13870 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EJ2KK UT WOS:000393038700015 PM 27770433 ER PT J AU Feng, LR Dickinson, K Kline, N Saligan, LN AF Feng, Li Rebekah Dickinson, Kristin Kline, Neila Saligan, Leorey N. TI Different Phenotyping Approaches Lead to Dissimilar Biologic Profiles in Men With Chronic Fatigue After Radiation Therapy SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Cancer-related fatigue; radiation therapy; prostate cancer; transcriptome profiles; fatigue phenotypes ID CANCER-RELATED FATIGUE; NEUROPATHIC PAIN; FUNCTIONAL ASSESSMENT; SYSTEM; POPULATION; BIOGENESIS; DIAGNOSIS; DEPRESSION; EXOSOMES; ANEMIA AB Context. Cancer-related fatigue (CRF) persists months after treatment completion. Although a CRF biomarker has not yet been identified, validated self-report questionnaires are used to define and phenotype CRF in the discovery of potential biomarkers. Objectives. The purposes of this study are to identify CRF subjects using three well-known CRF phenotyping approaches using validated self-report questionnaires and to compare the biologic profiles that are associated with each CRF phenotype. Methods. Fatigue in men with nonmetastatic prostate cancer receiving external beam radiation therapy was measured at baseline (T1), midpoint (T2), end point (T3), and one-year post-external beam radiation therapy (T4) using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and Patient Reported Outcomes Measurement Information System-Fatigue. Chronic fatigue (CF) and nonfatigue subjects were grouped based on three commonly used phenotyping approaches: 1) T4 FACTF < 43; 2) T1-T4 decline in FACT-F score >= 3 points; 3) T4 Patient Reported Outcomes Measurement Information System-Fatigue T-score > 50. Differential gene expressions using whole-genome microarray analysis were compared in each of the phenotyping criterion. Results. The study enrolled 43 men, where 34% -38% had CF based on the three phenotyping approaches. Distinct gene expression patterns were observed between CF and nonfatigue subjects in each of the three CRF phenotyping approaches: 1) Approach 1 had the largest number of differentially expressed genes and 2) Approaches 2 and 3 had 40 and 21 differentially expressed genes between the fatigue groups, respectively. Conclusion. The variation in genetic profiles for CRF suggests that phenotypic profiling for CRF should be carefully considered because it directly influences biomarker discovery investigations. Published by Elsevier Inc. on behalf of American Academy of Hospice and Palliative Medicine. C1 [Feng, Li Rebekah; Dickinson, Kristin; Saligan, Leorey N.] NINR, NIH, 9000 Rockville Pike,Bldg 3, Bethesda, MD 20892 USA. [Kline, Neila] Vassar Coll, Poughkeepsie, NY 12601 USA. RP Saligan, LN (reprint author), NINR, NIH, 9000 Rockville Pike,Bldg 3, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov OI Saligan, Leorey/0000-0001-9481-7836 FU Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health FX This study is fully supported by the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health. NR 36 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 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 BP 832 EP 840 DI 10.1016/j.jpainsymman.2016.07.007 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800320 PM 27521284 ER PT J AU Berger, A Sloan, DH AF Berger, Ann Sloan, Danetta Hendricks TI Development of an instrument to Assess Psycho-social Spiritual Healing: The NIH HEALS SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Berger, Ann; Sloan, Danetta Hendricks] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA B11-A BP E21 EP E22 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800037 ER PT J AU Sloan, D Berger, A AF Sloan, Danetta Berger, Ann TI Development of the HEALS: Healing Experience in All Life Stressors SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Sloan, Danetta; Berger, Ann] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA P295 BP E144 EP E144 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800285 ER PT J AU Weaver, M October, T Hinds, P AF Weaver, Meaghann October, Tessie Hinds, Pamela TI Incorporating Good Patient, Parent, and Provider Definitions to Improve Care Interactions and Psychosocial Outcomes for Children with Cancer, Their Families, and Their Care Teams SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Meeting Abstract C1 [Weaver, Meaghann] NIH, Bldg 10, Bethesda, MD 20892 USA. [October, Tessie; Hinds, Pamela] Childrens Natl Hlth Syst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2016 VL 52 IS 6 MA D03-A BP E30 EP E31 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EJ4KE UT WOS:000393184800054 ER PT J AU Kubota, Y London, SJ Cushman, M Chamberlain, AM Rosamond, WD Heckbert, SR Zakai, N Folsom, AR AF Kubota, Y. London, S. J. Cushman, M. Chamberlain, A. M. Rosamond, W. D. Heckbert, S. R. Zakai, N. Folsom, A. R. TI Lung function, respiratory symptoms and venous thromboembolism risk: the Atherosclerosis Risk in Communities Study SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE chronic obstructive pulmonary disease; lung function; respiratory symptoms; restrictive lung disease; venous thromboembolism ID OBSTRUCTIVE PULMONARY-DISEASE; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; AIRWAY-OBSTRUCTION; COPD; POPULATION; MORTALITY; EXACERBATIONS; EPIDEMIOLOGY; ASSOCIATIONS AB Background: The evidence for the association between chronic obstructive pulmonary disease (COPD) and venous thromboembolism (VTE) is limited. There is no study investigating the association between restrictive lung disease (RLD) and respiratory symptoms with VTE. Objectives: To investigate prospectively the association of lung function and respiratory symptoms with VTE. Patients/Methods: In 1987-1989, we assessed lung function by using spirometry, and obtained information on respiratory symptoms (cough, phlegm, and dyspnea) in 14 654 participants aged 45-64 years, without a history of VTE or anticoagulant use, and followed them through 2011. Participants were classified into four mutually exclusive groups: 'COPD' (forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] below the lower limit of normal [LLN]), 'RLD' (FEV1/FVC >= LLN and FVC < LLN), `respiratory symptoms with normal spirometic results' (without RLD or COPD), and 'normal' (without respiratory symptoms, RLD, or COPD). Results: We documented 639 VTEs (238 unprovoked and 401 provoked VTEs). After adjustment for VTE risk factors, VTE risk was increased for individuals with either respiratory symptoms with normal spirometric results (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.73) or COPD (HR 1.33, 95% CI 1.07-1.67) but not for those with RLD (HR 1.15, 95% CI 0.82-1.60). These elevated risks of VTE were derived from both unprovoked and provoked VTE. Moreover, FEV1 and FEV1/FVC showed dose-response relationships with VTE. COPD was more strongly associated with pulmonary embolism than with deep vein thrombosis. Conclusions: Obstructive spirometric patterns were associated with an increased risk of VTE, suggesting that COPD may increase the risk of VTE. Respiratory symptoms may represent a novel risk marker for VTE. C1 [Kubota, Y.; Folsom, A. R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 South 2nd St,Suite 300, Minneapolis, MN 55454 USA. [Kubota, Y.] Osaka Univ, Grad Sch Med, Publ Hlth, Dept Social Med, Osaka, Japan. [London, S. J.] NIEHS, US Dept HHS, Epidemiol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Cushman, M.; Zakai, N.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Cushman, M.; Zakai, N.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Chamberlain, A. M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Rosamond, W. D.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Heckbert, S. R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Folsom, AR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 South 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM folso001@umn.edu OI London, Stephanie/0000-0003-4911-5290 FU Nippon Foundation; National Institute of Environmental Health Sciences (NIH). National Heart, Lung, and Blood Institute (NHLBI) [R01-HL0597367, HHSN268201100005C, HHSN26820 1100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, HHSN268201100012C] FX The authors thank the staff and participants of the ARIC Study for their important contributions. Y. Kubota's fellowship at the School of Public Health, University of Minnesota is supported by grants from the Nippon Foundation. S. J. London is supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIH). National Heart, Lung, and Blood Institute (NHLBI) support: R01-HL0597367 and contracts HHSN268201100005C, HHSN26820 1100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, and HHSN268201100012C. NR 35 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 14 IS 12 BP 2394 EP 2401 DI 10.1111/jth.13525 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EJ2OX UT WOS:000393051000011 PM 27696765 ER PT J AU Poston, L Caleyachetty, R Cnattingius, S Corvalan, C Uauy, R Herring, S Gillman, MW AF Poston, Lucilla Caleyachetty, Rishi Cnattingius, Sven Corvalan, Camila Uauy, Ricardo Herring, Sharron Gillman, Matthew W. TI Preconceptional and maternal obesity: epidemiology and health consequences SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID BODY-MASS INDEX; MIDDLE-INCOME COUNTRIES; GESTATIONAL DIABETES-MELLITUS; INTERPREGNANCY WEIGHT CHANGE; ADVERSE PREGNANCY OUTCOMES; INDEPENDENT RISK-FACTOR; LOW-BIRTH-WEIGHT; CESAREAN DELIVERY; UNITED-STATES; PREPREGNANCY WEIGHT AB Obesity in women of reproductive age is increasing in prevelance worldwide. Obesity reduces fertility and increases time taken to conceive, and obesity-related comorbidities (such as type 2 diabetes and chronic hypertension) heighten the risk of adverse outcomes for mother and child if the woman becomes pregnant. Pregnant women who are obese are more likely to have early pregnancy loss, and have increased risk of congenital fetal malformations, delivery of large for gestational age infants, shoulder dystocia, spontaneous and medically indicated premature birth, and stillbirth. Late pregnancy complications include gestational diabetes and pre-eclampsia, both of which are associated with long-term morbidities post partum. Women with obesity can also experience difficulties during labour and delivery, and are more at risk of post-partum haemorrhage. Long-term health risks are associated with weight retention after delivery, and inherent complications for the next pregnancy. The wellbeing of the next generation is also compromised. All these health issues could be avoided by prevention of obesity among women of reproductive age, which should be viewed as a global public health priority. For women who are already obese, renewed efforts should be made towards improved management during pregnancy, especially of blood glucose, and increased attention to postpartum weight management. Effective interventions, tailored to ethnicity and culture, are needed at each of these stages to improve the health of women and their children in the context of the global obesity epidemic. C1 [Poston, Lucilla] Kings Coll London, Fac Life Sci & Med, Div Womens Hlth, London, England. [Caleyachetty, Rishi] Univ Birmingham, Inst Appl Hlth Res, Birmingham, W Midlands, England. [Cnattingius, Sven] Karolinska Univ Sjukhuset, Dept Med Solna, Stockholm, Sweden. [Corvalan, Camila] Univ Chile, Inst Nutr & Food Technol, Santiago, Chile. [Uauy, Ricardo] Pontificia Univ Catolica Chile, Div Pediat, Fac Med, Santiago, Chile. [Uauy, Ricardo; Herring, Sharron] Temple Univ, Ctr Obes Res & Educ, Dept Med, Philadelphia, PA 19122 USA. [Uauy, Ricardo; Herring, Sharron] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Gillman, Matthew W.] NIH, Off Director, Environm Influences Child Hlth Outcomes ECHO, Rockville, MD USA. RP Poston, L (reprint author), St Thomas Hosp, KCL Div Womens Hlth, London SE1 7EH, England. EM lucilla.poston@kcl.ac.uk FU US National Institutes of Health; Doris Duke Charitable Foundation; Health Resources and Services Administration FX LP reports grants from Abbott Nutrition and NESTEC, outside the submitted work. SH reports grants from the US National Institutes of Health, Doris Duke Charitable Foundation, and Health Resources and Services Administration during the conduct of the study. NR 119 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD DEC PY 2016 VL 4 IS 12 BP 1025 EP 1036 DI 10.1016/S2213-8587(16)30217-0 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EJ2FO UT WOS:000393025700029 PM 27743975 ER PT J AU Pettifor, A MacPhail, C Hughes, JP Selin, A Wang, J Gomez-Olive, FX Eshleman, SH Wagner, RG Mabuza, W Khoza, N Suchindran, C Mokoena, I Twine, R Andrew, P Townley, E Laeyendecker, O Agyei, Y Tollman, S Kahn, K AF Pettifor, Audrey MacPhail, Catherine Hughes, James P. Selin, Amanda Wang, Jing Gomez-Olive, F. Xavier Eshleman, Susan H. Wagner, Ryan G. Mabuza, Wonderful Khoza, Nomhle Suchindran, Chirayath Mokoena, Immitrude Twine, Rhian Andrew, Philip Townley, Ellen Laeyendecker, Oliver Agyei, Yaw Tollman, Stephen Kahn, Kathleen TI The effect of a conditional cash transfer on HIV incidence in young women in rural South Africa (HPTN 068): a phase 3, randomised controlled trial SO LANCET GLOBAL HEALTH LA English DT Article ID TRANSACTIONAL SEX; PREVALENCE; INFECTION; RISK; ASSOCIATION; HEALTH AB Background Cash transfers have been proposed as an intervention to reduce HIV-infection risk for young women in sub-Saharan Africa. However, scarce evidence is available about their effect on reducing HIV acquisition. We aimed to assess the effect of a conditional cash transfer on HIV incidence among young women in rural South Africa. Methods We did a phase 3, randomised controlled trial (HPTN 068) in the rural Bushbuckridge subdistrict in Mpumalanga province, South Africa. We included girls aged 13-20 years if they were enrolled in school grades 8-11, not married or pregnant, able to read, they and their parent or guardian both had the necessary documentation necessary to open a bank account, and were residing in the study area and intending to remain until trial completion. Young women (and their parents or guardians) were randomly assigned (1:1), by use of numbered sealed envelopes containing a randomisation assignment card which were numerically ordered with block randomisation, to receive a monthly cash transfer conditional on school attendance (>= 80% of school days per month) versus no cash transfer. Participants completed an Audio Computer-Assisted Self-Interview (ACASI), before test HIV counselling, HIV and herpes simplex virus (HSV)-2 testing, and post-test counselling at baseline, then at annual follow-up visits at 12, 24, and 36 months. Parents or guardians completed a Computer-Assisted Personal Interview at baseline and each follow-up visit. A stratified proportional hazards model was used in an intention-to-treat analysis of the primary outcome, HIV incidence, to compare the intervention and control groups. This study is registered at ClinicalTrials. gov (NCT01233531). Findings Between March 5, 2011, and Dec 17, 2012, we recruited 10 134 young women and enrolled 2537 and their parents or guardians to receive a cash transfer programme (n=1225) or not (control group; n=1223). At baseline, the median age of girls was 15 years (IQR 14-17) and 672 (27%) had reported to have ever had sex. 107 incident HIV infections were recorded during the study: 59 cases in 3048 person-years in the intervention group and 48 cases in 2830 person-years in the control group. HIV incidence was not significantly different between those who received a cash transfer (1.94% per person-years) and those who did not (1.70% per person-years; hazard ratio 1.17, 95% CI 0.80-1.72, p=0.42). Interpretation Cash transfers conditional on school attendance did not reduce HIV incidence in young women. School attendance significantly reduced risk of HIV acquisition, irrespective of study group. Keeping girls in school is important to reduce their HIV-infection risk. C1 [Pettifor, Audrey] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Pettifor, Audrey; Selin, Amanda; Suchindran, Chirayath] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Suchindran, Chirayath] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Pettifor, Audrey; MacPhail, Catherine; Gomez-Olive, F. Xavier; Wagner, Ryan G.; Mabuza, Wonderful; Mokoena, Immitrude; Twine, Rhian; Tollman, Stephen; Kahn, Kathleen] Univ Witwatersrand, Med Res Council Wits Rural Publ Hlth & Hlth Trans, Sch Publ Hlth, Fac Hlth Sci, Johannesburg, South Africa. [Pettifor, Audrey; MacPhail, Catherine; Khoza, Nomhle] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [MacPhail, Catherine] Univ New England, Sch Hlth, Armidale, NSW, Australia. [Hughes, James P.; Wang, Jing] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hughes, James P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Eshleman, Susan H.; Agyei, Yaw] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Andrew, Philip] FHI 360, Durham, NC USA. [Townley, Ellen] NIAID, Div AIDS Henry M Jackson Fdn, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Wagner, Ryan G.; Tollman, Stephen; Kahn, Kathleen] Umea Ctr Global Hlth Res, Umea, Sweden. [Wagner, Ryan G.; Tollman, Stephen; Kahn, Kathleen] INDEPTH Network, Accra, Ghana. RP Pettifor, A (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM apettif@email.unc.edu FU National Institute of Allergy and Infectious Diseases, National Institute of Mental Health of the National Institutes of Health FX National Institute of Allergy and Infectious Diseases, National Institute of Mental Health of the National Institutes of Health. NR 31 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-109X J9 LANCET GLOB HEALTH JI Lancet Glob. Health PD DEC PY 2016 VL 4 IS 12 BP E978 EP E988 DI 10.1016/S2214-109X(16)30253-4 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ2FV UT WOS:000393026400031 PM 27815148 ER PT J AU Meissner, EG McLaughlin, M Matthews, L Gharib, AM Wood, BJ Levy, E Sinkus, R Virtaneva, K Sturdevant, D Martens, C Porcella, SF Goodman, ZD Kanwar, B Myers, RP Subramanian, M Hadigan, C Masur, H Kleiner, DE Heller, T Kottilil, S Kovacs, JA Morse, CG AF Meissner, Eric G. McLaughlin, Mary Matthews, Lindsay Gharib, Ahmed M. Wood, Bradford J. Levy, Elliot Sinkus, Ralph Virtaneva, Kimmo Sturdevant, Dan Martens, Craig Porcella, Stephen F. Goodman, Zachary D. Kanwar, Bittoo Myers, Robert P. Subramanian, Mani Hadigan, Colleen Masur, Henry Kleiner, David E. Heller, Theo Kottilil, Shyam Kovacs, Joseph A. Morse, Caryn G. TI Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial SO LIVER INTERNATIONAL LA English DT Article DE hepatic venous pressure gradient; lysyl oxidases; magnetic resonance elastography; transforming growth factor beta-3 ID HEPATITIS-C VIRUS; MAGNETIC-RESONANCE ELASTOGRAPHY; SIMPLE NONINVASIVE INDEX; OXIDASE-LIKE 2; LYSYL OXIDASE; NONALCOHOLIC STEATOHEPATITIS; CIRRHOSIS; DISEASE; THERAPY; MICROENVIRONMENT AB Background: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. Aim: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. Methods: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. Results: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-beta 3 and IL-10 pathways with treatment. Conclusion: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-beta 3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials. C1 [Meissner, Eric G.; McLaughlin, Mary; Hadigan, Colleen; Kottilil, Shyam] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Meissner, Eric G.] Med Univ South Carolina, Dept Microbiol & Immunol, Div Infect Dis, Charleston, SC 29425 USA. [Meissner, Eric G.; Matthews, Lindsay; Masur, Henry; Kovacs, Joseph A.; Morse, Caryn G.] NIH, Ctr Clin, Dept Crit Care Med, AIDS Sect, Bethesda, MD 20892 USA. [Gharib, Ahmed M.] NIDDK, Biomed & Metab Imaging Branch, Bethesda, MD 20892 USA. [Wood, Bradford J.; Levy, Elliot] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Sinkus, Ralph] Kings Coll London, Biomed Engn Imaging Sci & Biomed Engn Div, London, England. [Virtaneva, Kimmo; Sturdevant, Dan; Martens, Craig; Porcella, Stephen F.] NIAID, Rocky Mt Lab, Genom Unit, Res Technol Sect, Hamilton, MT 59840 USA. [Goodman, Zachary D.] Inova Fairfax Hosp, Ctr Liver Dis, Falls Church, VA USA. [Kanwar, Bittoo; Myers, Robert P.; Subramanian, Mani] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Kleiner, David E.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. RP Morse, CG (reprint author), NIH, Ctr Clin, Bldg 10,2C145, Bethesda, MD 20892 USA. EM cmorse@cc.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU United States National Institutes of Health (NIH) Intramural Research Program; NIH Bench to Bedside Award - Office of AIDS Research; National Cancer Institute [HHSN261200800001E]; NIH; Gilead Sciences; NIH Clinical Center, NIAID; NIDDK FX Supported by the United States National Institutes of Health (NIH) Intramural Research Program, NIH Clinical Center, NIAID, NIDDK and, in part, by an NIH Bench to Bedside Award funded by the Office of AIDS Research. Funded in part with federal funds from the National Cancer Institute, under contract HHSN261200800001E. This study was partially funded by a Collaborative Research and Development Agreement between NIH and Gilead Sciences. NR 33 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD DEC PY 2016 VL 36 IS 12 BP 1783 EP 1792 DI 10.1111/liv.13177 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EJ3HS UT WOS:000393103800010 PM 27232579 ER PT J AU Bao, R Liu, Y Savarino, SJ Xia, D AF Bao, Rui Liu, Yang Savarino, Stephen J. Xia, Di TI Off-pathway assembly of fimbria subunits is prevented by chaperone CfaA of CFA/I fimbriae from enterotoxigenic E. coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID UROPATHOGENIC ESCHERICHIA-COLI; FACTOR ANTIGEN-I; PILUS BIOGENESIS; STRUCTURAL BASIS; FOLDING ENERGY; USHER PATHWAY; PROTEIN; RECOGNITION; MECHANISM; BACTERIA AB The assembly of the class 5 colonization factor antigen I (CFA/I) fimbriae of enterotoxigenic E. coli was proposed to proceed via the alternate chaperoneusher pathway. Here, we show that in the absence of the chaperone CfaA, CfaB, the major pilin subunit of CFA/I fimbriae, is able to spontaneously refold and polymerize into cyclic trimers. CfaA kinetically traps CfaB to form a metastable complex that can be stabilized by mutations. Crystal structure of the stabilized complex reveals distinctive interactions provided by CfaA to trap CfaB in an assembly competent state through donor-strand complementation (DSC) and cleft-mediated anchorage. Mutagenesis indicated that DSC controls the stability of the chaperonesubunit complex and the cleft-mediated anchorage of the subunit C-terminus additionally assist in subunit refolding. Surprisingly, over-stabilization of the chaperone-subunit complex led to delayed fimbria assembly, whereas destabilizing the complex resulted in no fimbriation. Thus, CfaA acts predominantly as a kinetic trap by stabilizing subunit to avoid its off-pathway self-polymerization that results in energetically favorable trimers and could serve as a driving force for CFA/I pilus assembly, representing an energetic landscape unique to class 5 fimbria assembly. C1 [Bao, Rui] Sichuan Univ, Div Infect Dis, Collaborat Innovat Ctr Biotherapy, Natl Key Lab Biotherapy,West China Hosp, Chengdu 610041, Peoples R China. [Bao, Rui; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, Yang; Savarino, Stephen J.] Naval Med Res Ctr, Enter Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. [Savarino, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Trans NIH/FDA Intramural Biodefense Program; National Natural Science Foundation of China [81501787]; U.S. Army Military Infectious Diseases Research Program Work Unit [A0307]; Henry M. Jackson Foundation for the Advancement of Military Medicine FX The authors wish to thank the beam line staff of the SER-CAT at APS, ANL for assistance in data collection and George Leiman for editorial assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by a grant from the Trans NIH/FDA Intramural Biodefense Program (to D.X.) and by the National Natural Science Foundation of China (Programs 81501787 to R.B.). The research was also supported by the U.S. Army Military Infectious Diseases Research Program Work Unit Number A0307 (to S.J.S.), and by the Henry M. Jackson Foundation for the Advancement of Military Medicine (S.J.S.). NR 40 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2016 VL 102 IS 6 BP 975 EP 991 DI 10.1111/mmi.13530 PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA EJ3XK UT WOS:000393145300002 PM 27627030 ER PT J AU Norris, SA Jinnah, HA Espay, AJ Klein, C Bruggemann, N Barbano, RL Malaty, IAC Rodriguez, RL Vidailhet, M Roze, E Reich, SG Berman, BD LeDoux, MS Richardson, SP Agarwal, P Mari, Z Ondo, WG Shih, LC Fox, SH Berardelli, A Testa, CM Cheng, FCF Truong, D Nahab, FB Xie, T Hallett, M Rosen, AR Wright, LJ Perlmutter, JS AF Norris, Scott A. Jinnah, H. A. Espay, Alberto J. Klein, Christine Brueggemann, Norbert Barbano, Richard L. Malaty, Irene Andonia C. Rodriguez, Ramon L. Vidailhet, Marie Roze, Emmanuel Reich, Stephen G. Berman, Brian D. LeDoux, Mark S. Richardson, Sarah Pirio Agarwal, Pinky Mari, Zoltan Ondo, William G. Shih, Ludy C. Fox, Susan H. Berardelli, Alfredo Testa, Claudia M. Cheng, Florence Ching-Fen Truong, Daniel Nahab, Fatta B. Xie, Tao Hallett, Mark Rosen, Ami R. Wright, Laura J. Perlmutter, Joel S. TI Clinical and Demographic Characteristics Related to Onset Site and Spread of Cervical Dystonia SO MOVEMENT DISORDERS LA English DT Article DE spasmodic torticollis; focal; segmental; geste antagoniste; neck ID IDIOPATHIC TORSION DYSTONIA; MOVEMENT-DISORDERS; FOCAL DYSTONIA; TREMOR; BLEPHAROSPASM; RISK; TORTICOLLIS; MULTICENTER; SYMPTOMS; FEATURES AB Background: Clinical characteristics of isolated idiopathic cervical dystonia such as onset site and spread to and from additional body regions have been addressed in single-site studies with limited data and incomplete or variable dissociation of focal and segmental subtypes. The objectives of this study were to characterize the clinical characteristics and demographics of isolated idiopathic cervical dystonia in the largest standardized multicenter cohort. Methods: The Dystonia Coalition, through a consortium of 37 recruiting sites in North America, Europe, and Australia, recruited 1477 participants with focal (60.7%) or segmental (39.3%) cervical dystonia on examination. Clinical and demographic characteristics were evaluated in terms of the body region of dystonia onset and spread. Results: Site of dystonia onset was: (1) focal neck only (78.5%), (2) focal onset elsewhere with later segmental spread to neck (13.3%), and (3) segmental onset with initial neck involvement (8.2%). Frequency of spread from focal cervical to segmental dystonia (22.8%) was consistent with prior reports, but frequency of segmental onset with initial neck involvement was substantially higher than the 3% previously reported. Cervical dystonia with focal neck onset, more than other subtypes, was associated with spread and tremor of any type. Sensory tricks were less frequent in cervical dystonia with segmental components, and segmental cervical onset occurred at an older age. Conclusions: Subgroups had modest but significant differences in the clinical characteristics that may represent different clinical entities or pathophysiologic subtypes. These findings are critical for design and implementation of studies to describe, treat, or modify disease progression in idiopathic isolated cervical dystonia. (C) 2016 International Parkinson and Movement Disorder Society. C1 [Norris, Scott A.; Wright, Laura J.; Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurol, Campus Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. [Jinnah, H. A.; Rosen, Ami R.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Jinnah, H. A.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Espay, Alberto J.] Univ Cincinnati, Dept Neurol, James J & Joan A Gardner Family Ctr Parkinsons Di, Cincinnati, OH USA. [Klein, Christine; Brueggemann, Norbert] Univ Lubeck, Inst Neurogenet, Lubeck, Germany. [Klein, Christine; Brueggemann, Norbert] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Barbano, Richard L.] Univ Rochester, Dept Neurol, Rochester, NY USA. [Malaty, Irene Andonia C.; Rodriguez, Ramon L.] Univ Florida, Dept Neurol, Gainesville, FL USA. [Vidailhet, Marie; Roze, Emmanuel] Sorbonne Univ, Hop Univ Pitie Salpetriere, Paris, France. [Reich, Stephen G.] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Berman, Brian D.] Univ Colorado Denver, Sch Med, Dept Neurol, Aurora, CO USA. [LeDoux, Mark S.] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Memphis, TN 38163 USA. [LeDoux, Mark S.] Univ Tennessee, Ctr Hlth Sci, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Richardson, Sarah Pirio] Univ New Mexico, Dept Neurol, Albuquerque, NM 87131 USA. [Agarwal, Pinky] Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Mari, Zoltan] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Ondo, William G.] Houston Methodist, Dept Neurol, Houston, TX USA. [Shih, Ludy C.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Fox, Susan H.] Univ Toronto, Univ Hlth Network, Dept Med, Div Neurol, Toronto, ON, Canada. [Berardelli, Alfredo] Sapienza Univ Rome, Dept Neurol & Psychiat, Rome, Italy. [Berardelli, Alfredo] IRCCS Neuromed, Rome, Italy. [Testa, Claudia M.] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Cheng, Florence Ching-Fen] West Mead Hosp, Dept Neurol, Westmead, NSW, Australia. [Truong, Daniel] Parkinson & Movement Disorder Inst, Fountain Valley, CA USA. [Nahab, Fatta B.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Xie, Tao] Univ Chicago, Med Ctr, Dept Neurol, Chicago, IL 60637 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurobiol, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Phys Therapy, St Louis, MO USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Occupat Therapy, St Louis, MO USA. RP Norris, SA (reprint author), Washington Univ, Sch Med, Dept Neurol, Campus Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. EM norriss@npg.wustl.edu FU Dystonia Coalition, a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS [U54NS065701, U54TR001456]; NCATS; National Institute of Neurological Diseases and Stroke (NINDS); NIH NINDS [NS065701, NS058714, NS41509, NS075321]; Murphy Fund; American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA, McDonnell Center for Higher Brain Function; Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund); Barnes-Jewish Hospital Foundation (Parkinson Disease Research Fund) FX Dystonia Coalition (U54NS065701 and U54TR001456), a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. The Dystonia Coalition is funded through collaboration between NCATS and the National Institute of Neurological Diseases and Stroke (NINDS). The study was also supported by grants from the NIH NINDS (NS065701, NS058714, NS41509, NS075321), Murphy Fund, American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA, McDonnell Center for Higher Brain Function; and the Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and the Parkinson Disease Research Fund). NR 40 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 31 IS 12 BP 1874 EP 1882 DI 10.1002/mds.26817 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EJ3PD UT WOS:000393123200018 PM 27753188 ER PT J AU Neveu, MA De Preter, G Marchand, V Bol, A Brender, JR Saito, K Kishimoto, S Porporato, PE Sonveaux, P Gregoire, V Feron, O Jordan, BF Krishna, MC Gallez, B AF Neveu, Marie-Aline De Preter, Geraldine Marchand, Valerie Bol, Anne Brender, Jeffery R. Saito, Keita Kishimoto, Shun Porporato, Paolo E. Sonveaux, Pierre Gregoire, Vincent Feron, Olivier Jordan, Benedicte F. Krishna, Murali C. Gallez, Bernard TI Multimodality Imaging Identifies Distinct Metabolic Profiles In Vitro and In Vivo SO NEOPLASIA LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; CANCER-CELLS; AEROBIC GLYCOLYSIS; ENERGY-METABOLISM; TUMOR-CELLS; OXYGEN; PROLIFERATION; THERAPY; MICE; LINK AB The study of alterations of tumor metabolism should allow the identification of new targets for innovative anticancer strategies. Metabolic alterations are generally established in vitro, and conclusions are often extrapolated to the in vivo situation without further tumor metabolic phenotyping. To highlight the key role of microenvironment on tumor metabolism, we studied the response of glycolytic and oxidative tumor models to metabolic modulations in vitro and in vivo. MDA-MB-231 and SiHa tumor models, characterized in vitro as glycolytic and oxidative, respectively, were studied. Theoretically, when passing from a hypoxic state to an oxygenated state, a Warburg phenotype should conserve a glycolytic metabolism, whereas an oxidative phenotype should switch from glycolytic to oxidative metabolism (Pasteur effect). This challenge was applied in vitro and in vivo to evaluate the impact of different oxic conditions on glucose metabolism. F-18-fluorodeoxyglucose uptake, lactate production, tumor oxygenation, and metabolic fluxes were monitored in vivo using positron emission tomography, microdialysis, electron paramagnetic resonance imaging, and C-13-hyperpolarizated magnetic resonance spectroscopy, respectively. In vitro, MDA-MB-231 cells were glycolytic under both hypoxic and oxygenated conditions, whereas SiHa cells underwent a metabolic shift after reoxygenation. On the contrary, in vivo, the increase in tumor oxygenation (induced by carbogen challenge) led to a similar metabolic shift in glucose metabolism in both tumor models. The major discordance in metabolic patterns observed in vitro and in vivo highlights that any extrapolation of in vitro metabolic profiling to the in vivo situation should be taken cautiously and that metabolic phenotyping using molecular imaging is mandatory in vivo. C1 [Neveu, Marie-Aline; De Preter, Geraldine; Marchand, Valerie; Jordan, Benedicte F.; Gallez, Bernard] Catholic Univ Louvain, LDRI, Biomed Magnet Resonance Res Grp, Brussels, Belgium. [Bol, Anne; Gregoire, Vincent] Catholic Univ Louvain, Dept Radiat Oncol, Brussels, Belgium. [Bol, Anne; Gregoire, Vincent] Catholic Univ Louvain, Inst Expt & Clin Res IREC, Ctr Mol Imaging Radiotherapy & Oncol, Brussels, Belgium. [Brender, Jeffery R.; Saito, Keita; Kishimoto, Shun; Krishna, Murali C.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Porporato, Paolo E.; Sonveaux, Pierre; Feron, Olivier] Catholic Univ Louvain, Inst Expt & Clin Res IREC, Pole Pharmacol & Therapeut, Brussels, Belgium. RP Gallez, B (reprint author), Catholic Univ Louvain, LDRI, Biomed Magnet Resonance Unit, REMA, Ave Mounier 73-08, B-1200 Brussels, Belgium. EM bernard.gallez@uclouvain.be FU Belgian National Fund for Scientific Research (F.S.R.-FNRS) [PDR T.0107.13]; Fonds Joseph Maisin; Action de Recherches Concertees [ARC 14/19-058]; Belgian Science Policy Office Interuniversity Attraction Pole IUAP [P7/03]; National Institute of Health FX This study was funded by grants from the Belgian National Fund for Scientific Research (F.S.R.-FNRS; PDR T.0107.13), the Fonds Joseph Maisin, the Action de Recherches Concertees ARC 14/19-058, Belgian Science Policy Office Interuniversity Attraction Pole IUAP #P7/03, and intramural National Institute of Health funds. M.A.N. is a Research Fellow and P.E.P. a Senior Postdoctoral Fellow of F.R.S.-FNRS. P.S. and B.F.J. are Research Associates of F.R.S.-FNRS. NR 31 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 1476-5586 J9 NEOPLASIA JI Neoplasia PD DEC PY 2016 VL 18 IS 12 BP 742 EP 752 DI 10.1016/j.neo.2016.10.010 PG 11 WC Oncology SC Oncology GA EJ2RF UT WOS:000393057700004 PM 27889643 ER PT J AU Rodriquez, EJ Oh, SS Perez-Stable, EJ Schroeder, SA AF Rodriquez, Erik J. Oh, Sam S. Perez-Stable, Eliseo J. Schroeder, Steven A. TI Changes in Smoking Intensity Over Time by Birth Cohort and by Latino National Background, 1997-2014 SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CIGARETTE-SMOKING; MEXICAN-AMERICANS; ASIAN-AMERICANS; UNITED-STATES; ACCULTURATION; HISPANICS; BEHAVIOR; CALIFORNIA; TOBACCO; ADULTS AB Introduction: The purpose of the study was to describe changes in smoking intensity among US Latinos and non-Latinos from 1997 to 2014. Methods: National Health Interview Survey data between 1997 and 2014 were used to determine the number of cigarettes smoked per day (CPD) among Latino and non-Latino adults who had smoked at least 100 cigarettes in their lifetime and were currently smoking every day or some days (ie, current smokers). Results: CPD declined steadily throughout the observation period and were consistently lower for Latino than for non-Latino smokers. However, decreases were not equal across birth cohorts, genders, or among Latino national background groups. CPD declined most among Mexican men and least among younger generations, Cuban women, and acculturated Latina women. Additionally, declines in smoking intensity seemed to slow over time among low CPD consumers. Conclusions: Although smoking intensity has decreased substantially since the late 1990s, CPD data suggest that declines are slowing among younger generations and certain Latina women. Effective tobacco control strategies should be developed to discourage even very light and non-daily smoking. Implications: Few studies have been conducted on how smoking intensity has changed since the late 1990s. Between 2004 and 2011, when the decline in smoking prevalence slowed, it is unknown how smoking intensity (ie, CPD) changed by age. Additionally, no research has assessed differences and changes in smoking intensity over time among Latinos. From this study we learned that smoking intensity declined significantly since the late 1990s, but this decline slowed among younger generations of smokers and certain Latina women. Findings suggest that future patterns of smoking intensity may only marginally decline in the near future. C1 [Rodriquez, Erik J.; Perez-Stable, Eliseo J.] Univ Calif San Francisco, Dept Med, Multiethn Hlth Equ Res Ctr, San Francisco, CA USA. [Rodriquez, Erik J.; Perez-Stable, Eliseo J.; Schroeder, Steven A.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Rodriquez, Erik J.; Perez-Stable, Eliseo J.; Schroeder, Steven A.] Univ Calif San Francisco, Dept Med, Ctr Tobacco Control Res & Educ, San Francisco, CA USA. [Rodriquez, Erik J.; Oh, Sam S.; Perez-Stable, Eliseo J.; Schroeder, Steven A.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Schroeder, Steven A.] Univ Calif San Francisco, Dept Med, Smoking Cessat Leadership Ctr, San Francisco, CA USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Rodriquez, EJ (reprint author), Univ Calif San Francisco, Dept Med, 3333 Calif St,Suite 335,Box 0856, San Francisco, CA 94143 USA. EM erikr@ucsf.edu FU Clinical and Translational Science Institute at the University of California, San Francisco [K19683L]; Resource Centers for Minority Aging Research of the National Institute on Aging, National Institutes of Health (Center for Aging in Diverse Communities) [P30 AG15272]; Cancer Education and Control Development Program in Tobacco Control of the National Cancer Institute, National Institutes of Health (Center for Tobacco Control Research and Education) [R25 CA113710]; National Latino Cancer Research Network of the National Cancer Institute, National Institutes of Health (Redes En Accion) [U01 CA86117, U54 CA153511] FX This study was funded in part by grants from the Clinical and Translational Science Institute at the University of California, San Francisco (Strategic Opportunities Support, K19683L); Resource Centers for Minority Aging Research of the National Institute on Aging, National Institutes of Health (Center for Aging in Diverse Communities, P30 AG15272); Cancer Education and Control Development Program in Tobacco Control of the National Cancer Institute, National Institutes of Health (Center for Tobacco Control Research and Education, R25 CA113710); and the National Latino Cancer Research Network of the National Cancer Institute, National Institutes of Health (Redes En Accion, U01 CA86117 and U54 CA153511). The study sponsors played no role in the design of the study, writing of the manuscript, or decision to submit the manuscript for publication. NR 47 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD DEC PY 2016 VL 18 IS 12 BP 2225 EP 2233 DI 10.1093/ntr/ntw203 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EJ4NF UT WOS:000393193300008 PM 27613930 ER PT J AU Young, WC Nadarajah, SR Berger, AM AF Young, William C. Nadarajah, Sheeba R. Berger, Ann M. TI Supportive medical care in life-threatening illness: A pilot study SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE Medical care; Cancer; Cardiac illness; Life-transforming change; Qualitative research ID POSTTRAUMATIC GROWTH; CANCER; PAIN AB Objective: The goal of this pilot study was to identify the processes by which healing occurs in patients who experience a life-threatening illness. Method: Healing was examined by using two qualitative studies that employed a semistructured interview process (interviews lasted between 30 and 115 minutes). There were 10 cardiac event survivors and 9 cancer survivors. These participants came from a community hospital setting (cardiac), nonmedical holistic services organization (cancer), and a research hospital (cancer). Before participants could take part in the study, they were administered preliminary screening measurements, the first of which was an instrument similar to the Distress Thermometer. Participants then self-reported their positive life-transforming changes. If one to three changes were reported six months after onset of the illness, participants were deemed to have passed the screening. Finally, participants were tested for speaking volume and clarity. Results: An overall theme that was prevalent throughout the interviews wasmedical support. Participants found that their positive, life-transforming changes were typically connected with supportive caregivers who helped to create a culture of care. They also indicated that an absence of this medical supportive care hindered development of such life-transforming changes. Significance of Results: Our results indicate that a medical care team will be more effective if a positive culture of care is created. This can be implemented if the team provides comfort, which involves being more engaged in the treatment of patients aswell as being more attentive to their psychosocial needs. C1 [Young, William C.; Berger, Ann M.] NIH, Pain & Palliat Care Serv, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 2-1733, Bethesda, MD 20892 USA. [Nadarajah, Sheeba R.] Bowie State Univ, Dept Nursing, Bowie, MD USA. RP Berger, AM (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 2-1733, Bethesda, MD 20892 USA. EM aberger@cc.nih.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 EI 1478-9523 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD DEC PY 2016 VL 14 IS 6 BP 680 EP 685 DI 10.1017/S147895151600033X PG 6 WC Health Policy & Services SC Health Care Sciences & Services GA EJ4IX UT WOS:000393181400011 PM 27215292 ER PT J AU Coleman, CN Koerner, JF AF Coleman, C. Norman Koerner, John F. TI BIODOSIMETRY: MEDICINE, SCIENCE, AND SYSTEMS TO SUPPORT THE MEDICAL DECISION-MAKER FOLLOWING A LARGE SCALE NUCLEAR OR RADIATION INCIDENT SO RADIATION PROTECTION DOSIMETRY LA English DT Article; Proceedings Paper CT 4th EPR BioDose Meeting CY OCT 04-08, 2015 CL Hanover, NH SP Int Assoc Biol & EPR Radiat Dosimetry ID SCARCE RESOURCES; MASS-CASUALTY; DETONATION; MANAGEMENT; ALLOCATION; STANDARDS; TOOLS AB The public health and medical response to a radiological or nuclear incident requires the capability to sort, assess, treat, triage and to ultimately discharge, refer or transport people to their next step in medical care. The size of the incident and scarcity of resources at the location of each medical decision point will determine how patients are triaged and treated. This will be a rapidly evolving situation impacting medical responders at regional, national and international levels. As capabilities, diagnostics and medical countermeasures improve, a dynamic system-based approach is needed to plan for and manage the incident, and to adapt effectively in real time. In that the concepts and terms can be unfamiliar and possibly confusing, resources and a concept of operations must be considered well in advance. An essential underlying tenet is that medical evaluation and care will be managed by healthcare professionals with biodosimetry assays providing critical supporting data. C1 [Coleman, C. Norman; Koerner, John F.] Dept Hlth & Human Serv, Chem Biol Radiol Nucl & Explos Branch, Off Emergency Management, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Coleman, C. Norman] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Koerner, JF (reprint author), Dept Hlth & Human Serv, Chem Biol Radiol Nucl & Explos Branch, Off Emergency Management, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. EM john.koerner@hhs.gov NR 19 TC 1 Z9 1 U1 2 U2 2 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 DEC 1 PY 2016 VL 172 IS 1-3 BP 38 EP 46 DI 10.1093/rpd/ncw155 PG 9 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 EJ4HX UT WOS:000393178600004 PM 27473694 ER PT J AU Simon, SL Bouville, A AF Simon, Steven L. Bouville, Andre TI LONG-TERM BIODOSIMETRY REDUX SO RADIATION PROTECTION DOSIMETRY LA English DT Article; Proceedings Paper CT 4th EPR BioDose Meeting CY OCT 04-08, 2015 CL Hanover, NH SP Int Assoc Biol & EPR Radiat Dosimetry ID RADIATION; EXPOSURE AB This paper revisits and reiterates the needs, purposes and requirements of biodosimetric assays for long-term dose and health risk assessments. While the most crucial need for biodosimetric assays is to guide medical response for radiation accidents, the value of such techniques for improving our understanding of radiation health risk by supporting epidemiological (long-term health risk) studies is significant. As new cohorts of exposed persons are identified and new health risk studies are undertaken with the hopes that studying the exposed will result in a deeper understanding of radiation risk, the value of reliable dose reconstruction is underscored. The ultimate application of biodosimetry in long-term health risk studies would be to completely replace model-based dose reconstruction-a complex suite of methods for retrospectively estimating dose that is commonly fraught with large uncertainties due to the absence of important exposure-related information, as well as imperfect models. While biodosimetry could potentially supplant model-based doses, there are numerous limitations of presently available techniques that constrain their widespread application in health risk research, including limited ability to assess doses received far in the past, high cost, great inter-individual variability, invasiveness, higher than preferred detection limits and the inability to assess internal dose (for the most part). These limitations prevent the extensive application of biodosimetry to large cohorts and should be considered a challenge to researchers to develop new and more flexible techniques that meet the demands of long-term health risk research. Events in recent years, e.g. the Fukushima reactor accident and the increased threat of nuclear terrorism, underscore that any event that results in significant radiation exposures of a group of people will also produce a much larger population, exposed at lower levels, but that likewise needs (or demands) an exposure assessment. Hence, the needs for retrospective dose estimation are likely to be greater in the future. The value of biodosimetry can be considerably enhanced with the development of new or improved methods, particularly with suitability for application at long periods of time after exposure. C1 [Simon, Steven L.; Bouville, Andre] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Simon, SL (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIAID [Y2-Al-5077]; NCI [Y3-CO-5117] FX This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute and the Intra-Agency agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement # Y2-Al-5077 and NCI agreement # Y3-CO-5117. NR 14 TC 0 Z9 0 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 DEC 1 PY 2016 VL 172 IS 1-3 BP 244 EP 247 DI 10.1093/rpd/ncw156 PG 4 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 EJ4HX UT WOS:000393178600028 PM 27412511 ER PT J AU Symons, R Morris, JZ Wu, CO Pourmorteza, A Ahlman, MA Lima, JAC Chen, MY Mallek, M Sandfort, V Bluemke, DA AF Symons, Rolf Morris, Justin Z. Wu, Colin O. Pourmorteza, Amir Ahlman, Mark A. Lima, Joao A. C. Chen, Marcus Y. Mallek, Marissa Sandfort, Veit Bluemke, David A. TI Coronary CT Angiography: Variability of CT Scanners and Readers in Measurement of Plaque Volume SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; ARTERY CALCIFICATION; DIAGNOSTIC-ACCURACY; STATIN THERAPY; DUAL-SOURCE; QUANTIFICATION; BURDEN; TRIAL AB Purpose: To determine reader and computed tomography (CT) scan variability for measurement of coronary plaque volume. Materials and Methods: This HIPAA-compliant study followed Standards for Reporting of Diagnostic Accuracy guidelines. Baseline coronary CT angiography was performed in 40 prospectively enrolled subjects (mean age, 67 years +/- 6 [standard deviation]) with asymptomatic hyperlipidemia by using a 320-detector row scanner (Aquilion One Vision; Toshiba, Otawara, Japan). Twenty of these subjects underwent coronary CT angiography repeated on a separate day with the same CT scanner (Toshiba, group 1); 20 subjects underwent repeat CT performed with a different CT scanner (Somatom Force; Siemens, Forchheim, Germany [group 2]). Intraclass correlation coefficients (ICCs) and BlandAltman analysis were used to assess interreader, intrareader, and interstudy reproducibility. Results: Baseline and repeat coronary CT angiography scans were acquired within 19 days +/- 6. Interreader and intrareader agreement rates were high for total, calcified, and noncalcified plaques for both CT scanners (all ICCs >= 0.96) without bias. Scanner variability was 618.4% (coefficient of variation) with same-vendor follow-up. However, scanner variability increased to 629.9% with different-vendor follow-up. The sample size to detect a 5% change in noncalcified plaque volume with 90% power and an a error of.05 was 286 subjects for same-CT scanner follow-up and 753 subjects with different-vendor follow-up. Conclusion: State-of-the-art coronary CT angiography with same-vendor follow-up has good scan-rescan reproducibility, suggesting a role of coronary CT angiography in monitoring coronary artery plaque response to therapy. Differences between coronary CT angiography vendors resulted in lower scanre-scan reproducibility. (C) RSNA, 2016 C1 [Symons, Rolf; Morris, Justin Z.; Pourmorteza, Amir; Ahlman, Mark A.; Mallek, Marissa; Sandfort, Veit; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Marcus Y.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. RP Bluemke, DA (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM david.bluemke@nih.gov OI Symons, Rolf/0000-0001-7889-6773 FU National Institutes of Health Intramural Research program [ZIACL090019, ZIAEB000072] FX Supported by National Institutes of Health Intramural Research program (ZIACL090019, ZIAEB000072). NR 39 TC 0 Z9 0 U1 2 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2016 VL 281 IS 3 BP 737 EP 748 DI 10.1148/radiol.2016161670 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4QI UT WOS:000393201500008 PM 27636027 ER PT J AU de Gonzalez, AB Ntowe, E Kitahara, CM Gilbert, E Miller, DL Kleinerman, RA Linet, MS AF de Gonzalez, Amy Berrington Ntowe, Estelle Kitahara, Cari M. Gilbert, Ethel Miller, Donald L. Kleinerman, Ruth A. Linet, Martha S. TI Long-term Mortality in 43 763 US Radiologists Compared with 64 990 US Psychiatrists SO RADIOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; RADIATION-EXPOSURE; PHYSICIAN SPECIALISTS; BRITISH RADIOLOGISTS; CIRCULATORY DISEASE; IONIZING-RADIATION; CANCER INCIDENCE; UNITED-STATES; RISK; WORKERS AB Purpose: To compare mortality rates from all causes, specific causes, total cancers, and specific cancers to assess whether differences between radiologists and psychiatrists are consistent with known risks of radiation exposure and the changes in radiation exposure to radiologists over time. Materials and Methods: The authors used the American Medical Association Physician Masterfile to construct a cohort of 43 763 radiologists (20% women) and 64 990 psychiatrists (27% women) (comparison group) who graduated from medical school in 1916-2006. Vital status was obtained from record linkages with the Social Security Administration and commercial databases, and cause of death was obtained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for all causes and specific causes of death. Results: During the follow-up period (1979-2008), 4260 male radiologists and 7815 male psychiatrists died. The male radiologists had lower death rates (all causes) compared with the psychiatrists (RR = 0.94; 95% CI: 0.90, 0.97), similar cancer death rates overall (RR = 1.00; 95% CI: 0.93, 1.07), but increased acute myeloid leukemia and/or myelodysplastic syndrome death rates (RR = 1.62; 95% CI: 1.05, 2.50); these rates were driven by those who graduated before 1940 (RR = 4.68; 95% CI: 0.91, 24.18). In these earliest workers (before 1940) there were also increased death rates from melanoma (RR = 8.75; 95% CI: 1.89, 40.53), non-Hodgkin lymphoma (NHL) (RR = 2.69; 95% CI: 1.33, 5.45), and cerebrovascular disease (RR = 1.49; 95% CI: 1.11, 2.01). The 208 deaths in female radiologists precluded detailed investigation, and the number of female radiologists who graduated before 1940 was very small (n = 47). Conclusion: The excess risk of acute myeloid leukemia and/or myelodysplastic syndrome mortality in radiologists who graduated before 1940 is likely due to occupational radiation exposure. The melanoma, NHL, and cerebrovascular disease mortality risks are possibly due to radiation. The authors found no evidence of excess mortality in radiologists who graduated more recently, possibly because of increased radiation protection and/or lifestyle changes. (C) RSNA, 2016 C1 [de Gonzalez, Amy Berrington; Ntowe, Estelle; Kitahara, Cari M.; Gilbert, Ethel; Kleinerman, Ruth A.; Linet, Martha S.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Miller, Donald L.] FDA Off In Vitro Diagnost & Radiol Hlth, White Oak Campus, Silver Spring, MD USA. RP de Gonzalez, AB (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM berringtona@mail.nih.gov FU National Institutes of Health Intramural Research Program [Z01 CP010133-21] FX Supported by National Institutes of Health Intramural Research Program (grant Z01 CP010133-21). NR 34 TC 1 Z9 1 U1 2 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2016 VL 281 IS 3 BP 847 EP 857 DI 10.1148/radiol.2016152472 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EJ4QI UT WOS:000393201500018 ER PT J AU Behl, M Rice, JR Smith, MV Co, CA Bridge, MF Hsieh, JH Freedman, JH Boyd, WA AF Behl, Mamta Rice, Julie R. Smith, Marjo V. Co, Caroll A. Bridge, Matthew F. Hsieh, Jui-Hua Freedman, Jonathan H. Boyd, Windy A. TI Comparative Toxicity of Organophosphate Flame Retardants and Polybrominated Diphenyl Ethers to Caenorhabditis elegans SO TOXICOLOGICAL SCIENCES LA English DT Article DE Caenorhabditis elegans; flame retardants; mitochondrial toxicity ID MESSENGER-RNA EXPRESSION; THYROID-HORMONE LEVELS; C. ELEGANS; HOUSE-DUST; TRIS(1,3-DICHLORO-2-PROPYL) PHOSPHATE; DEVELOPMENTAL EXPOSURE; CHICKEN EMBRYOS; NEURONAL CELLS; PBDE MIXTURE; LIFE-SPAN AB With the phasing-out of the polybrominated diphenyl ether (PBDE) flame retardants due to concerns regarding their potential developmental toxicity, the use of replacement compounds such as organophosphate flame retardants (OPFRs) has increased. Limited toxicity data are currently available to estimate the potential adverse health effects of the OPFRs. The toxicological effects of 4 brominated flame retardants, including 3 PBDEs and 3,3', 5,5'-tetrabromobisphenol A, were compared with 6 aromatic OPFRs and 2 aliphatic OPFRs. The effects of these chemicals were determined using 3 biological endpoints in the nematode Caenorhabditis elegans (feeding, larval development, and reproduction). Because C. elegans development was previously reported to be sensitive to mitochondrial function, results were compared with those from an in vitro mitochondrial membrane permeabilization (MMP) assay. Overall 11 of the 12 flame retardants were active in 1 or more C. elegans biological endpoints, with only tris(2-chloroethyl) phosphate inactive across all endpoints including the in vitro MMP assay. For 2 of the C. elegans endpoints, at least 1 OPFR had similar toxicity to the PBDEs: triphenyl phosphate (TPHP) inhibited larval development at levels comparable to the 3 PBDEs; whereas TPHP and isopropylated phenol phosphate (IPP) affected C. elegans reproduction at levels similar to the PBDE commercial mixture, DE-71. The PBDEs reduced C. elegans feeding at lower concentrations than any OPFR. In addition, 9 of the 11 chemicals that inhibited C. elegans larval development also caused significant mitochondrial toxicity. These results suggest that some of the replacement aromatic OPFRs may have levels of toxicity comparable to PBDEs. C1 [Behl, Mamta; Rice, Julie R.; Hsieh, Jui-Hua; Boyd, Windy A.] NIEHS, Div Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Smith, Marjo V.; Co, Caroll A.; Bridge, Matthew F.] Social Sci Syst Inc, Durham, NC USA. [Freedman, Jonathan H.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. RP Boyd, WA (reprint author), NIEHS, Div Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Boyd, WA (reprint author), NIEHS, Div Natl Toxicol Program, Mail Drop K2-04,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM boydw@niehs.nih.gov FU National Toxicology Program Division; Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS)/National Institutes of Health (NIH) [Z01ES102045, Z01ES102046] FX This work was supported in part by the National Toxicology Program Division and by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS)/National Institutes of Health (NIH) (Z01ES102045 and Z01ES102046). NR 70 TC 0 Z9 0 U1 14 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2016 VL 154 IS 2 BP 241 EP 252 DI 10.1093/toxsci/kfw162 PG 12 WC Toxicology SC Toxicology GA EJ5VJ UT WOS:000393286500007 PM 27566445 ER PT J AU Knudsen, GA Sanders, JM Birnbaum, LS AF Knudsen, Gabriel A. Sanders, J. Michael Birnbaum, Linda S. TI Disposition of the Emerging Brominated Flame Retardant, 2-Ethylhexyl 2,3,4,5-Tetrabromobenzoate, in Female SD Rats and Male B6C3F1 Mice: Effects of Dose, Route, and Repeated Administration SO TOXICOLOGICAL SCIENCES LA English DT Article DE 2-Ethylhexyl 2,3,4,5-Tetrabromobenzoate; disposition; metabolism ID MIXTURE FIREMASTER(R) 550; IN-VITRO METABOLISM; HUMAN EXPOSURE; HOUSE-DUST; INDOOR DUST; PHASE-OUT; ACCUMULATION; ESTERASES; CHINA; LIVER AB 2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB; MW549.92 g/mol; CAS 183658-27-7) is a brominated component of flame retardant mixtures used as substitutes for some PBDEs. EH-TBB is added to various consumer products, including polyurethane foams, and has been detected in humans. The present study characterized the fate of EH-TBB in rodents. [C-14]-labeled EH-TBB was absorbed, metabolized, and eliminated via the urine and feces following single administrations of 0.1-100 mu mol/kg (similar to 0.05-55 mg/kg) or repeated administration (0.1 mu mol/kg/day x 5-10 days) by gavage to female Hsd: Sprague DawleySD (SD) rats. Cumulative excretion via feces increased (39-60%) with dose (0.1-10 mu mol/kg) with corresponding decreases in urinary excretion (54 to 37%) after 72 h. Delayed excretion of [C-14]-radioactivity in urine and feces of a 100 mu mol/kg oral dose was noted. Recovery was complete for all doses by 72 h. IV-injected rats excreted more of the 0.1 mu mol/kg dose in urine and less in feces than did gavaged rats, indicating partial biliary elimination of systemically available compound. No tissue bioaccumulation was found for rats given 5 oral daily doses of EH-TBB. Parent molecule was not detected in urine whereas 2 metabolites, tetrabromobenzoic acid (TBBA), a TBBA-sulfate conjugate, and a TBBA-glycine conjugate were identified. EH-TBB and TBBA were identified in extracts from feces. Data from gavaged male B6C3F1/Tac mice indicated minimal sex-or species differences are likely for the disposition of EH-TBB. Approximately 85% of a 0.1 mu mol/kg dose was absorbed from the gut. Overall absorption of EH-TBB is expected to be even greater at lower levels. C1 [Knudsen, Gabriel A.; Sanders, J. Michael; Birnbaum, Linda S.] NCI, Lab Toxicol & Toxicokinet, Res Triangle Pk, NC USA. RP Knudsen, GA (reprint author), 111 TW Alexander Dr,BG 101,Rm C202A, Res Triangle Pk, NC 27709 USA. EM gabriel.knudsen@nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health [ZIA BC 011476] FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health [Project ZIA BC 011476]. NR 49 TC 0 Z9 0 U1 3 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2016 VL 154 IS 2 BP 392 EP 402 DI 10.1093/toxsci/kfw176 PG 11 WC Toxicology SC Toxicology GA EJ5VJ UT WOS:000393286500020 PM 27613714 ER PT J AU Riley, WT Martin, CA Rivera, DE Hekler, EB Adams, MA Buman, MP Pavel, M King, AC AF Riley, William T. Martin, Cesar A. Rivera, Daniel E. Hekler, Eric B. Adams, Marc A. Buman, Matthew P. Pavel, Misha King, Abby C. TI Development of a dynamic computational model of social cognitive theory SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Dynamical system modeling; Computational modeling; Control systems engineering; Health behavior theory; Social cognitive theory ID PHYSICAL-ACTIVITY RESEARCH; SELF-EFFICACY; ADAPTIVE INTERVENTIONS; HEALTH-PROMOTION; BEHAVIOR-CHANGE; SUPPORT; SYSTEMS; ADULTS; GIRLS AB Social cognitive theory (SCT) is among the most influential theories of behavior change and has been used as the conceptual basis of health behavior interventions for smoking cessation, weight management, and other health behaviors. SCT and other behavior theories were developed primarily to explain differences between individuals, but explanatory theories of within-person behavioral variability are increasingly needed as new technologies allow for intensive longitudinal measures and interventions adapted from these inputs. These within-person explanatory theoretical applications can be modeled as dynamical systems. SCT constructs, such as reciprocal determinism, are inherently dynamical in nature, but SCT has not been modeled as a dynamical system. This paper describes the development of a dynamical system model of SCT using fluid analogies and control systems principles drawn from engineering. Simulations of this model were performed to assess if the model performed as predicted based on theory and empirical studies of SCT. This initial model generates precise and testable quantitative predictions for future intensive longitudinal research. Dynamic modeling approaches provide a rigorous method for advancing health behavior theory development and refinement and for guiding the development of more potent and efficient interventions. C1 [Riley, William T.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Martin, Cesar A.; Rivera, Daniel E.] Arizona State Univ, CSEL, Sch Engn Matter Transport & Energy, Tempe, AZ USA. [Hekler, Eric B.; Adams, Marc A.; Buman, Matthew P.] Arizona State Univ, Sch Nutr & Hlth Promot, Tempe, AZ USA. [Pavel, Misha] Northeastern Univ, Boston, MA 02115 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [King, Abby C.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA. RP Riley, WT (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. EM wiriley@mail.nih.gov RI Adams, Marc/C-3513-2013 OI Adams, Marc/0000-0001-6310-1472 FU National Science Foundation [IIS-1449751]; National Institute on Drug Abuse [K25DA021173]; National Institute of Nursing Research [P20NR015320]; National Heart, Lung, and Blood Institute [R01HL116448]; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK102016]; National Institute of Biomedical Imaging and Bioengineering [U54EB020405] FX DR and EH were supported by a grant from National Science Foundation (IIS-1449751). DR also was supported by a grant from the National Institute on Drug Abuse (K25DA021173). MP was supported by a grant from the National Institute of Nursing Research (P20NR015320). AK was supported by grants from National Heart, Lung, and Blood Institute (R01HL116448), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102016), and National Institute of Biomedical Imaging and Bioengineering (U54EB020405). This paper represents the views and perspectives of the authors, not the funders or the National Institutes of Health. All authors participated in this article and take responsibility for the integrity of the conceptualizations and models described. NR 47 TC 1 Z9 1 U1 2 U2 2 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 DEC PY 2016 VL 6 IS 4 BP 483 EP 495 DI 10.1007/s13142-015-0356-6 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ5YU UT WOS:000393296000001 PM 27848208 ER PT J AU Jackson, DN Chou, WYS Coa, KI Oh, A Hesse, B AF Jackson, Devlon N. Chou, Wen-Ying Sylvia Coa, Kisha I. Oh, April Hesse, Bradford TI Implications of social media use on health information technology engagement: Data from HINTS 4 cycle 3 SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Internet access; Social media use; Health information technology engagement; Communication inequalities ID NATIONAL TRENDS SURVEY; CONSUMERS PERCEPTIONS; INTERNET; COMMUNICATION; COMPLEMENTARITY; OUTCOMES; RECORDS; ADULTS AB Little is known about the association between Internet/social media use and health information technology (HIT) engagement. This study examines patterns of social media use and HIT engagement in the U.S.A. using data from the 2013 Health Information National Trends Survey (N = 3,164). Specifically, predictors of two HIT activities (i.e., communicating with a healthcare provider using the Internet or email and tracking personal health information electronically) are examined. Persons who were females, higher education, non-Hispanic others, having a regular healthcare provider, and ages 35-44 were more likely to participate in HIT activities. After controlling for sociode-mographics and health correlates, social media use was significantly associated with HIT engagement. To our knowledge, this is one of the first studies to systematically examine the use and relationships across multiple types of health-related online media. C1 [Jackson, Devlon N.; Chou, Wen-Ying Sylvia; Coa, Kisha I.; Oh, April; Hesse, Bradford] NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Jackson, Devlon N.] Univ Maryland, Maryland Ctr Hlth Equ, College Pk, MD 20742 USA. RP Jackson, DN (reprint author), NCI, Div Canc Control & Populat Sci, Rockville, MD 20850 USA.; Jackson, DN (reprint author), Univ Maryland, Maryland Ctr Hlth Equ, College Pk, MD 20742 USA. EM djacks04@umd.edu FU National Institutes of Health, National Cancer Institute; Westat FX The first author of this manuscript did not receive any funding support to conduct this research. The National Institutes of Health, National Cancer Institute and funding partner, Westat, provided funding support for the development of this publicly accessible secondary data set. NR 42 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 DEC PY 2016 VL 6 IS 4 BP 566 EP 576 DI 10.1007/s13142-016-0437-1 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ5YU UT WOS:000393296000008 PM 27628436 ER PT J AU Madan, RA Gulley, JL AF Madan, Ravi A. Gulley, James L. TI Personalized peptide vaccine in prostate cancer: capitalizing on existing immunity SO TRANSLATIONAL CANCER RESEARCH LA English DT Editorial Material ID SIPULEUCEL-T; IMMUNOTHERAPY; CHEMOTHERAPY; SURVIVAL; TRIAL; MEN C1 [Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), NCI, Genitourinary Malignancies Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM madanr@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, NIH FX The authors would like to acknowledge the support of the Center for Cancer Research, National Cancer Institute, NIH. NR 9 TC 0 Z9 0 U1 3 U2 3 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD DEC PY 2016 VL 5 SU 7 BP S1333 EP S1335 DI 10.21037/tcr.2016.12.27 PG 3 WC Oncology SC Oncology GA EJ6KY UT WOS:000393329400007 ER PT J AU Hua, ZY Gu, X Dong, YD Tan, F Liu, ZH Thiele, CJ Li, ZJ AF Hua, Zhongyan Gu, Xiao Dong, Yudi Tan, Fei Liu, Zhihui Thiele, Carol J. Li, Zhijie TI PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma SO TUMOR BIOLOGY LA English DT Article DE Neuroblastoma; BDNF; TrkB; Metastasis ID TO-MESENCHYMAL TRANSITION; NEUROTROPHIC FACTOR; RECEPTOR TRKB; HEPATOCELLULAR-CARCINOMA; MOLECULAR-BIOLOGY; INDUCED APOPTOSIS; POOR-PROGNOSIS; LUNG-CANCER; IN-VITRO; EXPRESSION AB Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells. A tumor xenograft model using SCID-Beige mice was utilized to detect the metastasis of NB tumors in vivo. Inhibitors of PI3K, MAPK, Akt, and mTOR were used. Western blotting was performed to study the expressions of P-Akt, P-Erk, and P-mTOR. Our results showed that in TrkB-expressing NB cells, BDNF treatment significantly increased gap closing (P < 0.01) in scratch wound healing assay, also significantly enhanced the numbers of migrating cells (P < 0.01) and invading cells (P < 0.01) in the Boyden chamber migration and invasion assays. In vivo, NB distant metastases were significantly increased in mice with TrkB-expressing xenograft tumors compared to those with non-TrkB-expressing tumors (P < 0.05). Pre-treatment with any of the inhibitors for PI3K (LY294002), MAPK (PD98059), Akt (perifosine), or mTOR (rapamycin) blocked the BDNF/TrkB-induced increases of cell migration and invasion in TB3 cells, and also blocked the BDNF/TrkB-induced expressions of P-Akt, P-Erk, and P-mTOR. These data indicated that BDNF/TrkB increased metastasis in NB via PI3K/Akt/mTOR and MAPK pathways, and BDNF/TrkB and the downstream targets may be potential targets for the treatment of NB metastasis. C1 [Hua, Zhongyan; Gu, Xiao; Dong, Yudi; Li, Zhijie] China Med Univ, Shengjing Hosp, Med Res Ctr, 36 Sanhao St, Shenyang 110004, Peoples R China. [Gu, Xiao] China Med Univ, Shengjing Hosp, Dept Oncol, Shenyang, Peoples R China. [Tan, Fei] China Med Univ, Shengjing Hosp, Dept Neurol, Shenyang, Peoples R China. [Liu, Zhihui; Thiele, Carol J.] NCI, Cellular & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Li, ZJ (reprint author), China Med Univ, Shengjing Hosp, Med Res Ctr, 36 Sanhao St, Shenyang 110004, Peoples R China. EM lizhijie68@hotmail.com FU National Natural Science Foundation of China [81272538, 81472359]; Liaoning Climbing Scholar Foundation; Society Development Foundation of Liaoning Province [2012225016]; NCI Intramural Research Program at National Cancer Institute at the National Institutes of Health FX This work was supported by the National Natural Science Foundation of China (Nos. 81272538 and 81472359), 2013 Liaoning Climbing Scholar Foundation, Society Development Foundation of Liaoning Province (No. 2012225016), and NCI Intramural Research Program at National Cancer Institute at the National Institutes of Health. NR 43 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD DEC PY 2016 VL 37 IS 12 BP 16227 EP 16236 DI 10.1007/s13277-016-5433-z PG 10 WC Oncology SC Oncology GA EJ0ZX UT WOS:000392941000087 ER PT J AU Jenkins, RA AF Jenkins, Richard A. TI Clinical Community Psychology: Reflections on the Decades Following Swampscott SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Editorial Material DE Swampscott conference; Clinical-community ID MENTAL-HEALTH POLICY; CHRONIC-PATIENT; DEINSTITUTIONALIZATION; STATES; CARE AB The Swampscott report was foundational, but in some ways reflected divisions within community psychology that have continued into the present. Community psychologists trained in the 1970s and, especially, the 1980s confronted a period where the original focus of community mental health began to have less influence in the mental health field due to a variety of public policies, and the growth of third party payments as a significant source of health care funding. Programs that engaged communities and provided a base for prevention interventions were greatly curtailed because of changes in federal legislation and limited opportunities for state and local funding, although prevention interventions found growing interest from research funders. Clinical and community psychologists who trained in this period increasingly looked to a variety of areas outside of mental health. Consequently, the field of community psychology has become more applied and less academic, with increased attention to advocacy, theory, and global perspectives. The sweep of these changes and their implications for the future of the field are discussed here. C1 [Jenkins, Richard A.] NIDA, Bethesda, MD 20892 USA. EM jenkinsri@mail.nih.gov NR 34 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-0562 EI 1573-2770 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD DEC PY 2016 VL 58 IS 3-4 BP 269 EP 275 DI 10.1002/ajcp.12040 PG 7 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA EI6QW UT WOS:000392621900006 ER PT J AU Lowe, SR Kwok, RK Payne, J Engel, LS Galea, S Sandler, DP AF Lowe, Sarah R. Kwok, Richard K. Payne, Julianne Engel, Lawrence S. Galea, Sandro Sandler, Dale P. TI Why Does Disaster Recovery Work Influence Mental Health?: Pathways through Physical Health and Household Income SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Disaster recovery work; Deepwater Horizon oil spill; Post-traumatic stress; Major depression; Generalized anxiety; Physical health; Income; Path analysis ID SOCIAL SUPPORT; EXXON-VALDEZ; OIL-SPILL; DISORDERS; ASSOCIATION; DEPRESSION; DISTRESS; EXPOSURE; PTSD; LIFE AB Disaster recovery work increases risk for mental health problems, yet the mechanisms underlying this association are unclear. We explored links from recovery work to post-traumatic stress (PTS), major depression (MD), and generalized anxiety disorder (GAD) symptoms through physical health symptoms and household income in the aftermath of the Deepwater Horizon oil spill. As part of the NIEHS GuLF STUDY, participants (N=10,141) reported on cleanup work activities, spill-related physical health symptoms, and household income at baseline, and mental health symptoms an average of 14.69weeks (SD=16.79) thereafter. Cleanup work participation was associated with higher physical health symptoms, which in turn were associated with higher PTS, MD, and GAD symptoms. Similar pattern of results were found in models including workers only and investigating the influence of longer work duration and higher work-related oil exposure on mental health symptoms. In addition, longer worker duration and higher work-related oil exposure were associated with higher household income, which in turn was associated with lower MD and GAD symptoms. These findings suggest that physical health symptoms contribute to workers' risk for mental health symptoms, while higher household income, potentially from more extensive work, might mitigate risk. C1 [Lowe, Sarah R.] Montclair State Univ, Dept Psychol, Montclair, NJ 07043 USA. [Kwok, Richard K.; Engel, Lawrence S.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Payne, Julianne] RTI Int, Res Triangle Pk, NC USA. [Engel, Lawrence S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Galea, Sandro] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM lowes@mail.montclair.edu OI Kwok, Richard/0000-0002-6794-8360; Sandler, Dale/0000-0002-6776-0018 FU NIH Common Fund; NIH, National Institute of Environmental Sciences [ZO1 ES 102945] FX This study was funded by the NIH Common Fund and the Intramural Program of the NIH, National Institute of Environmental Sciences (ZO1 ES 102945). NR 35 TC 0 Z9 0 U1 11 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-0562 EI 1573-2770 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD DEC PY 2016 VL 58 IS 3-4 BP 354 EP 364 DI 10.1002/ajcp.12091 PG 11 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA EI6QW UT WOS:000392621900017 PM 27704561 ER PT J AU Newman, JD Navas-Acien, A Kuo, CC Guallar, E Howard, BV Fabsitz, RR Devereux, RB Umans, JG Francesconi, KA Goessler, W Best, LT Tellez-Plaza, M AF Newman, Jonathan D. Navas-Acien, Ana Kuo, Chin-Chi Guallar, Eliseo Howard, Barbara V. Fabsitz, Richard R. Devereux, Richard B. Umans, Jason G. Francesconi, Kevin A. Goessler, Walter Best, Lyle T. Tellez-Plaza, Maria TI Peripheral Arterial Disease and Its Association With Arsenic Exposure and Metabolism in the Strong Heart Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arsenic; metabolism; peripheral vascular disease ID ANKLE-BRACHIAL INDEX; INCIDENT CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; DRINKING-WATER; RISK-FACTORS; CAROTID ATHEROSCLEROSIS; BLACKFOOT DISEASE; VASCULAR-DISEASE; UNITED-STATES; DIABETES-MELLITUS AB At high levels, inorganic arsenic exposure is linked to peripheral arterial disease (PAD) and cardiovascular disease. To our knowledge, no prior study has evaluated the association between low-to-moderate arsenic exposure and incident PAD by ankle brachial index (ABI). We evaluated this relationship in the Strong Heart Study, a large population-based cohort study of American Indian communities. A total of 2,977 and 2,966 PAD-free participants who were aged 45-74 years in 1989-1991 were reexamined in 1993-1995 and 1997-1999, respectively, for incident PAD defined as either ABI < 0.9 or ABI > 1.4. A total of 286 and 206 incident PAD cases were identified for ABI < 0.9 and ABI > 1.4, respectively. The sum of inorganic and methylated urinary arsenic species (SAs) at baseline was used as a biomarker of long-term exposure. Comparing the highest tertile of SAs with the lowest, the adjusted hazard ratios were 0.57 (95% confidence interval (CI): 0.32, 1.01) for ABI < 0.9 and 2.24 (95% CI: 1.01, 4.32) for ABI > 1.4. Increased arsenic methylation (as percent dimethylarsinate) was associated with a 2-fold increased risk of ABI > 1.4 (hazard ratio = 2.04, 95% CI: 1.02, 3.41). Long-term low-to-moderate SAs and increased arsenic methylation were associated with ABI > 1.4 but not with ABI < 0.9. Further studies are needed to clarify whether diabetes and enhanced arsenic metabolism increase susceptibility to the vasculotoxic effects of arsenic exposure. C1 [Newman, Jonathan D.] NYU Med Ctr, Div Cardiol, New York, NY 10016 USA. [Newman, Jonathan D.] NYU Med Ctr, Dept Med, Ctr Prevent Cardiovasc Dis, New York, NY 10016 USA. [Navas-Acien, Ana; Kuo, Chin-Chi; Tellez-Plaza, Maria] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Navas-Acien, Ana; Kuo, Chin-Chi; Guallar, Eliseo] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Navas-Acien, Ana; Kuo, Chin-Chi; Guallar, Eliseo] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kuo, Chin-Chi] China Med Univ, Kidney Inst, Taichung, Taiwan. [Kuo, Chin-Chi] China Med Univ, Div Nephrol, Dept Internal Med, China Med Univ Hosp, Taichung, Taiwan. [Kuo, Chin-Chi] China Med Univ, Coll Med, Taichung, Taiwan. [Guallar, Eliseo] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Howard, Barbara V.; Umans, Jason G.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Howard, Barbara V.; Umans, Jason G.] Georgetown Univ, Hyattsville, MD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol Branch, Bldg 10, Bethesda, MD 20892 USA. [Devereux, Richard B.] Cornell Univ, Div Cardiol, Dept Med, Weill Cornell Med Coll, New York, NY 10021 USA. [Francesconi, Kevin A.; Goessler, Walter] Karl Franzens Univ Graz, Inst Chem Analyt Chem, Graz, Austria. [Best, Lyle T.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Tellez-Plaza, Maria] Hosp Clin Valencia, INCLIVA Biomed Res Inst, Valencia, Spain. RP Newman, JD (reprint author), NYU, Sch Med, Div Cardiol, Translat Res Bldg,Room 853, New York, NY 10016 USA.; Newman, JD (reprint author), NYU, Sch Med, Dept Med, Ctr Prevent Cardiovasc Dis, Translat Res Bldg,Room 853, New York, NY 10016 USA. EM Jonathan.Newman@nyumc.org OI Newman, Jonathan/0000-0001-6855-7305 FU National Heart, Lung, and Blood Institute [HL090863, K23HL125991, 5T32HL007024, HL41642, HL41652, HL41654, HL65521]; National Institute of Environmental Health Sciences [P42ES10349, R01ES021367, R01ES025216]; American Heart Association [15MCPRP24480132]; National Institute of Diabetes and Digestive and Kidney Diseases [U24DK076169-09, 25732-60]; Strategic Action for Research in Health Sciences Program from Spanish Ministry of Economy and Competitiveness [CP12/ 03080]; European Funds for Regional Development FX This work was supported by grants from the National Heart, Lung, and Blood Institute (grants HL090863, K23HL125991, and 5T32HL007024; Strong Heart Study grants HL41642, HL41652, HL41654, and HL65521), the National Institute of Environmental Health Sciences (grants P42ES10349, R01ES021367, and R01ES025216), the American Heart Association (grant 15MCPRP24480132), and the National Institute of Diabetes and Digestive and Kidney Diseases (grant U24DK076169-09, subcontract 25732-60). M.T.-P. was supported by the Strategic Action for Research in Health Sciences Program (grant CP12/ 03080) from the Spanish Ministry of Economy and Competitiveness and the European Funds for Regional Development. NR 70 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 2016 VL 184 IS 11 BP 806 EP 817 DI 10.1093/aje/kww002 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI8AC UT WOS:000392725400004 PM 27810857 ER PT J AU Xu, J Khincha, PP Giri, N Alter, BP Savage, SA Wong, JMY AF Xu, Jialin Khincha, Payal P. Giri, Neelam Alter, Blanche P. Savage, Sharon A. Wong, Judy M. Y. TI Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID LINKED DYSKERATOSIS-CONGENITA; TELOMERE BIOLOGY DISORDERS; RIBOSOMAL-RNA; IN-SITU; MESSENGER-RNA; DISEASE; PSEUDOURIDINE; MAINTENANCE; DEFICIENCY; LENGTH AB Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer susceptibility syndrome caused by germline mutations in telomere biology genes. Germline mutations in DKC1, which encodes the protein dyskerin, cause X-linked recessive DC. Because of skewed X-chromosome inactivation, female DKC1 mutation carriers do not typically develop clinical features of DC. This study evaluated female DKC1 mutation carriers with DC-associated phenotypes to elucidate the molecular features of their mutations, in comparison with unaffected carriers and mutation-negative female controls. All female DKC1 mutation carriers had normal leukocyte subset telomere lengths and similarly skewed X-inactivation in multiple tissue types, regardless of phenotype. We observed dyskerin expression, telomerase RNA accumulation, and pseudouridylation present in all mutation carriers at levels comparable to healthy wild-type controls. Our study suggests that mechanisms in addition to X chromosome inactivation, such as germline mosaicism or epigenetics, may contribute to DC-like phenotypes present in female DKC1 mutation carriers. Future studies are warranted to understand the molecular mechanisms associated with the phenotypic variability in female DKC1 mutation carriers, and to identify those at risk of disease. (C) 2016 Wiley Periodicals, Inc. C1 [Xu, Jialin; Wong, Judy M. Y.] Univ British Columbia, Fac Pharmaceut Sci, Mol & Cellular Pharmacol Grp, Vancouver, BC, Canada. [Khincha, Payal P.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Wong, JMY (reprint author), Univ British Columbia, Fac Pharmaceut Sci, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.; Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E454, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov; judy.wong@ubc.ca FU Westat, Inc [HHSN261201100018C]; Natural Sciences and Engineering Research Council of Canada; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Contract grant sponsor: Westat, Inc; Contract grant number: HHSN261201100018C.; Contract grant sponsor: Natural Sciences and Engineering Research Council of Canada; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 32 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2016 VL 91 IS 12 BP 1215 EP 1220 DI 10.1002/ajh.24545 PG 6 WC Hematology SC Hematology GA EI8BY UT WOS:000392730900021 PM 27570172 ER PT J AU Salem, D Stetler-Stevenson, M Yuan, C Landgren, O AF Salem, Dalia Stetler-Stevenson, Maryalice Yuan, Constance Landgren, Ola TI Myeloma minimal residual disease testing in the United States: Evidence of improved standardization SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID MULTIPLE-MYELOMA; FLOW-CYTOMETRY; CONSENSUS GUIDELINES C1 [Salem, Dalia; Stetler-Stevenson, Maryalice; Yuan, Constance] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org RI Salem, Dalia/R-9314-2016 OI Salem, Dalia/0000-0002-4209-2260 FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health FX Contract grant sponsor: Intramural Research Program of the National Cancer Institute of the National Institutes of Health. 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 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2016 VL 91 IS 12 BP E502 EP E503 DI 10.1002/ajh.24540 PG 3 WC Hematology SC Hematology GA EI8BY UT WOS:000392730900008 PM 27556705 ER PT J AU Rodgers, GP AF Rodgers, Griffin P. TI First Lecture to New Doctors: 5 Lessons Learned SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article C1 [Rodgers, Griffin P.] NIDDK, NIH, Bldg 31,Room 9A52,31 Ctr Dr, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIDDK, NIH, Bldg 31,Room 9A52,31 Ctr Dr, Bethesda, MD 20892 USA. EM Rebecca.Cerio@nih.gov NR 7 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 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD DEC PY 2016 VL 352 IS 6 BP 615 EP 617 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EI8DX UT WOS:000392736700011 PM 27916217 ER PT J AU Pomann, GM Staicu, AM Lobaton, EJ Mejia, AF Dewey, BE Reich, DS Sweeney, EM Shinohara, RT AF Pomann, Gina-Maria Staicu, Ana-Maria Lobaton, Edgar J. Mejia, Amanda F. Dewey, Blake E. Reich, Daniel S. Sweeney, Elizabeth M. Shinohara, Russell T. TI A LAG FUNCTIONAL LINEAR MODEL FOR PREDICTION OF MAGNETIZATION TRANSFER RATIO IN MULTIPLE SCLEROSIS LESIONS SO Annals of Applied Statistics LA English DT Article DE Functional data analysis; functional linear model; magnetization transfer ratio; image analysis ID SPARSE LONGITUDINAL DATA; DIAGNOSTIC-CRITERIA; REGRESSION-ANALYSIS; CONTRAST SYNTHESIS; MRI; BRAIN; REMYELINATION; DEMYELINATION; EVOLUTION; CURVES AB We propose a lag functional linear model to predict a response using multiple functional predictors observed at discrete grids with noise. Two procedures are proposed to estimate the regression parameter functions: (1) an approach that ensures smoothness for each value of time using generalized cross-validation; and (2) a global smoothing approach using a restricted maximum likelihood framework. Numerical studies are presented to analyze predictive accuracy in many realistic scenarios. The methods are employed to estimate a magnetic resonance imaging (MRI)-based measure of tissue damage (the magnetization transfer ratio, or MTR) in multiple sclerosis (MS) lesions, a disease that causes damage to the myelin sheaths around axons in the central nervous system. Our method of estimation of MTR within lesions is useful retrospectively in research applications where MTR was not acquired, as well as in clinical practice settings where acquiring MTR is not currently part of the standard of care. The model facilitates the use of commonly acquired imaging modalities to estimate MTR within lesions, and outperforms cross-sectional models that do not account for temporal patterns of lesion development and repair. C1 [Pomann, Gina-Maria] Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Staicu, Ana-Maria] North Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Lobaton, Edgar J.] North Carolina State Univ, Dept Elect & Comp Engn, Raleigh, NC 27695 USA. [Mejia, Amanda F.] Indiana Univ, Dept Stat, Bloomington, IN 47405 USA. [Dewey, Blake E.; Reich, Daniel S.] NINDS, NIH, Bethesda, MD 20892 USA. [Sweeney, Elizabeth M.] Rice Univ, Dept Stat, Houston, TX 77005 USA. [Shinohara, Russell T.] Univ Penn, Ctr Clin Epidemiol, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Shinohara, Russell T.] Univ Penn, Biostat Perelman Sch Med, Philadelphia, PA 19104 USA. RP Pomann, GM (reprint author), Duke Univ, Dept Biostat & Bioinformat, Durham, NC 27710 USA. EM gp43@duke.edu; astaicu@ncsu.edu; edgar.lobaton@ncsu.edu; mandy.mejia@gmail.com; blake.dewey@nih.gov; reichds@ninds.nih.gov; esweene6@jhu.edu; rshi@mail.med.upenn.edu FU Intramural Research Program of NINDS FX We would like to acknowledge the conscientious efforts of the hard-working Associate Editor, whose clear guidance led to this publication. The study was supported in part by the Intramural Research Program of NINDS. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the granting organizations. NR 53 TC 0 Z9 0 U1 0 U2 0 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD DEC PY 2016 VL 10 IS 4 BP 2325 EP 2348 DI 10.1214/16-AOAS981 PG 24 WC Statistics & Probability SC Mathematics GA EI9HR UT WOS:000392819100028 ER PT J AU Ferris, RL Geiger, JL Trivedi, S Schmitt, NC Heron, DE Johnson, JT Kim, S Duvvuri, U Clump, DA Bauman, JE Ohr, JP Gooding, WE Argiris, A AF Ferris, R. L. Geiger, J. L. Trivedi, S. Schmitt, N. C. Heron, D. E. Johnson, J. T. Kim, S. Duvvuri, U. Clump, D. A. Bauman, J. E. Ohr, J. P. Gooding, W. E. Argiris, A. TI Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer SO ANNALS OF ONCOLOGY LA English DT Article DE panitumumab; head and neck squamous cell carcinoma; clinical trial; cisplatin chemoradiotherapy ID SQUAMOUS-CELL CARCINOMA; LOCALLY ADVANCED HEAD; STAT1 ACTIVATION; CHEMOTHERAPY; CETUXIMAB; CHEMORADIOTHERAPY; THERAPY AB Background: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. Patients and methods: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or >= 2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30mg/m(2) and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). Results: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). Conclusions: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. C1 [Ferris, R. L.; Heron, D. E.; Clump, D. A.; Bauman, J. E.; Ohr, J. P.; Gooding, W. E.] Univ Pittsburgh, Canc Immunol Program, Inst Canc, Pittsburgh, PA USA. [Ferris, R. L.; Trivedi, S.; Heron, D. E.; Johnson, J. T.; Kim, S.; Duvvuri, U.] Univ Pittsburgh, Dept Otolaryngol, Div Head & Neck Surg, Pittsburgh, PA USA. [Ferris, R. L.] Univ Pittsburgh, Div Hematol Oncol, Immunol, Pittsburgh, PA USA. [Geiger, J. L.; Bauman, J. E.; Ohr, J. P.] Univ Pittsburgh, Div Hematol Oncol, Internal Med, Pittsburgh, PA USA. [Schmitt, N. C.; Clump, D. A.] Johns Hopkins Univ, Dept Otolaryngol, Baltimore, MD USA. [Schmitt, N. C.] NIDCD, Tumor Biol Sect, NIH, Bethesda, MD USA. [Heron, D. E.] Univ Pittsburgh, Dept Radiat Oncol, Pittsburgh, PA USA. [Argiris, A.] Hygeia Hosp, Dept Med Oncol, Athens, Greece. [Argiris, A.] Thomas Jefferson Univ, Dept Med Oncol, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. RP Ferris, RL (reprint author), Hillman Canc Ctr Res Pavilion,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM ferrrl@upmc.edu FU National Institute of Health [R01 DE 019727, P50 CA097190, T32 CA060397]; University of Pittsburgh Cancer Institute [P30 CA047904] FX This work was supported by National Institute of Health (grants R01 DE 019727, P50 CA097190, T32 CA060397) and used the University of Pittsburgh Cancer Institute award P30 CA047904. NR 21 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2016 VL 27 IS 12 BP 2257 EP 2262 DI 10.1093/annonc/mdw428 PG 7 WC Oncology SC Oncology GA EI9JW UT WOS:000392825100018 PM 27733374 ER PT J AU Hagelstein, V Ortland, I Wilmer, A Mitchell, SA Jaehde, U AF Hagelstein, V. Ortland, I. Wilmer, A. Mitchell, S. A. Jaehde, U. TI Validation of the German patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE (TM)) SO ANNALS OF ONCOLOGY LA English DT Article DE cancer; German; patient-reported outcomes; PRO-CTCAE; questionnaire; validation ID STEM-CELL TRANSPLANTATION; CANCER; RELIABILITY; INSTRUMENT; VALIDITY; ONCOLOGY AB Background: Integrating the patient's perspective has become an increasingly important component of adverse event reporting. The National Cancer Institute has developed a Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE (TM)). This instrument has been translated into German and linguistically validated; however, its quantitative measurement properties have not been evaluated. Patients and methods: A German language survey that included 31 PRO-CTCAE items, as well as the EORTC QLQ-C30 and the Oral Mucositis Daily Questionnaire (OMDQ), was distributed at 10 cancer treatment settings in Germany and Austria. Item quality was assessed by analysis of acceptability and comprehensibility. Reliability was evaluated by using Cronbach's' alpha and validity by principal components analysis (PCA), multitrait-multimethod matrix (MTMM) and known groups validity techniques. Results: Of 660 surveys distributed to the study centres, 271 were returned (return rate 41%), and data from 262 were available for analysis. Participants' median age was 59.7 years, and 69.5% of the patients were female. Analysis of item quality supported the comprehensibility of the 31 PRO-CTCAE items. Reliability was very good; Cronbach's' alpha correlation coefficients were >0.9 for almost all item clusters. Construct validity of the PRO-CTCAE core item set was shown by identifying 10 conceptually meaningful item clusters via PCA. Moreover, construct validity was confirmed by the MTMM: monotrait-heteromethod comparison showed 100% high correlation, whereas heterotrait-monomethod comparison indicated 0% high correlation. Known groups validity was supported; PRO-CTCAE scores were significantly lower for those with impaired versus preserved health-related quality of life. Conclusion: A set of 31 items drawn from the German PRO-CTCAE item library demonstrated favourable measurement properties. These findings add to the body of evidence that PRO-CTCAE provides a rigorous method to capture patient self-reports of symptomatic toxicity for use in cancer clinical trials. C1 [Hagelstein, V.; Ortland, I.; Wilmer, A.; Jaehde, U.] Univ Bonn, Inst Pharm, Clin Pharm, Immenburg 4, D-53121 Bonn, Germany. [Mitchell, S. A.] NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Rockville, MD USA. RP Jaehde, U (reprint author), Univ Bonn, Inst Pharm, Clin Pharm, Immenburg 4, D-53121 Bonn, Germany. EM u.jaehde@uni-bonn.de NR 21 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2016 VL 27 IS 12 BP 2294 EP 2299 DI 10.1093/annonc/mdw422 PG 7 WC Oncology SC Oncology GA EI9JW UT WOS:000392825100024 PM 27681863 ER PT J AU Hirsch, D Ried, T AF Hirsch, Daniela Ried, Thomas TI Targeting colorectal cancer (stem-like) cells using LGR5 directed antibody drug conjugates SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID STEM/PROGENITOR CELLS; SMALL-INTESTINE; OVEREXPRESSION; IDENTIFICATION; REGENERATION; RECEPTORS; MARKER; TUMORS; COLON C1 [Hirsch, Daniela] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, Mannheim, Germany. [Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov NR 26 TC 0 Z9 0 U1 2 U2 2 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD DEC PY 2016 VL 4 IS 24 AR 508 DI 10.21037/atm.2016.11.78 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI7DE UT WOS:000392656900030 PM 28149870 ER PT J AU Kim, C Giaccone, G AF Kim, Chul Giaccone, Giuseppe TI Lessons learned from BATTLE-2 in the war on cancer: the use of Bayesian method in clinical trial design SO ANNALS OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; ADAPTIVE RANDOMIZATION; KRAS MUTATION; PHASE-II; BREAST-CANCER; THERAPY; CHEMOTHERAPY; PREDICTOR; MUTANT C1 [Kim, Chul] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 24 TC 0 Z9 0 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2305-5839 EI 2305-5847 J9 ANN TRANSL MED JI ANN. TRANSL. MED. PD DEC PY 2016 VL 4 IS 23 AR 466 DI 10.21037/atm.2016.11.48 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI7CA UT WOS:000392653700015 PM 28090522 ER PT J AU Xu, ZL Taylor, JA Leung, YK Ho, SM Niu, L AF Xu, Zongli Taylor, Jack A. Leung, Yuet-Kin Ho, Shuk-Mei Niu, Liang TI oxBS-MLE: an efficient method to estimate 5-methylcytosine and 5-hydroxymethylcytosine in paired bisulfite and oxidative bisulfite treated DNA SO BIOINFORMATICS LA English DT Article ID CONVERSION AB Motivation: 5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are important epigenetic regulators of gene expression. 5mC and 5hmC levels can be computationally inferred at single base resolution using sequencing or array data from paired DNA samples that have undergone bisulfite and oxidative bisulfite conversion. Current estimation methods have been shown to produce irregular estimates of 5hmC level or are extremely computation intensive. Results: We developed an efficient method oxBS-MLE based on binomial modeling of paired bisulfite and oxidative bisulfite data from sequencing or array analysis. Evaluation in several datasets showed that it outperformed alternative methods in estimate accuracy and computation speed. C1 [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. [Leung, Yuet-Kin; Ho, Shuk-Mei; Niu, Liang] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. RP Niu, L (reprint author), Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. EM niulg@ucmail.uc.edu OI xu, zongli/0000-0002-9034-8902 FU Center for Environmental Genetics grant (NIEHS award) [P30ES00606]; NIEHS [ES022071]; NIH (NIEHS) [Z01 ES049033, Z01 ES049032] FX This research was supported by the Center for Environmental Genetics grant (NIEHS award P30ES00606), NIEHS grant (ES022071), and Intramural Research Program of the NIH (NIEHS Z01 ES049033 and Z01 ES049032). NR 10 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 DEC 1 PY 2016 VL 32 IS 23 BP 3667 EP 3669 DI 10.1093/bioinformatics/btw527 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA EI8IM UT WOS:000392749500018 PM 27522082 ER PT J AU Zarate, CA Machado-Vieira, R AF Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI GSK-3: A key regulatory target for ketamine's rapid antidepressant effects mediated by enhanced AMPA to NMDA throughput SO BIPOLAR DISORDERS LA English DT Editorial Material DE alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA); glycogen synthase kinase 3 (GSK-3); ketamine ID GLYCOGEN-SYNTHASE KINASE-3; RECEPTOR ANTAGONISTS; BIPOLAR DISORDER; MOOD DISORDERS; DOUBLE-BLIND; DEPRESSION; INHIBITION; PHOSPHORYLATION; MECHANISMS; INCREASES C1 [Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD Independent Investigator Award; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator Award to CAZ, and by a Brain and Behavior Mood Disorders Research Award to CAZ. CAZ is listed as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CAZ is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders; he has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. RM-V has no conflicts of interest to disclose, financial or otherwise. NR 32 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD DEC PY 2016 VL 18 IS 8 BP 702 EP 705 DI 10.1111/bdi.12452 PG 4 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EI9GX UT WOS:000392817000010 PM 27900801 ER PT J AU Psachoulia, K Chamberlain, KA Heo, D Davis, SE Paskus, JD Nanescu, SE Dupree, JL Wynn, TA Huang, JK AF Psachoulia, Konstantina Chamberlain, Kelly A. Heo, Dongeun Davis, Stephanie E. Paskus, Jeremiah D. Nanescu, Sonia E. Dupree, Jeffrey L. Wynn, Thomas A. Huang, Jeffrey K. TI IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation SO BRAIN LA English DT Article DE inflammation; remyelination; macrophages; interleukin-4 induced 1 (IL4I1); experimental autoimmune encephalomyelitis (EAE) ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PROGRESSIVE MULTIPLE-SCLEROSIS; MATRIX METALLOPROTEINASE-12; THERAPEUTIC STRATEGIES; MACROPHAGE ACTIVATION; INDUCED DEMYELINATION; SPINAL-CORD; MICROGLIA; DISEASE; DIFFERENTIATION AB Myelin regeneration (remyelination) is a spontaneous process that occurs following central nervous system demyelination. However, for reasons that remain poorly understood, remyelination fails in the progressive phase of multiple sclerosis. Emerging evidence indicates that alternatively activated macrophages in central nervous system lesions are required for oligodendrocyte progenitor differentiation into remyelinating oligodendrocytes. Here, we show that an alternatively activated macrophage secreted enzyme, interleukin-four induced one (IL4I1), is upregulated at the onset of inflammation resolution and remyelination in mouse central nervous system lesions after lysolecithin-induced focal demyelination. Focal demyelination in mice lacking IL4I1 or interleukin 4 receptor alpha (IL4R alpha) results in increased proinflammatory macrophage density, remyelination impairment, and axonal injury in central nervous system lesions. Conversely, recombinant IL4I1 administration into central nervous system lesions reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment in IL4R alpha deficient mice. We find that IL4I1 does not directly affect oligodendrocyte differentiation, but modulates inflammation by reducing interferon gamma and IL17 expression in lesioned central nervous system tissues, and in activated T cells from splenocyte cultures. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis at disease onset significantly reversed disease severity, resulting in recovery from hindlimb paralysis. Analysis of post-mortem tissues reveals reduced axonal dystrophy in spinal cord, and decreased CD4(+) T cell populations in spinal cord and spleen tissues. These results indicate that IL4I1 modulates inflammation by regulating T cell expansion, thereby permitting the formation of a favourable environment in the central nervous system tissue for remyelination. Therefore, IL4I1 is a potentially novel therapeutic for promoting central nervous system repair in multiple sclerosis. C1 [Psachoulia, Konstantina; Chamberlain, Kelly A.; Heo, Dongeun; Davis, Stephanie E.; Paskus, Jeremiah D.; Nanescu, Sonia E.; Huang, Jeffrey K.] Georgetown Univ, Dept Biol, 37th & O St,NW, Washington, DC 20057 USA. [Dupree, Jeffrey L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Huang, JK (reprint author), Georgetown Univ, Dept Biol, 37th & O St,NW, Washington, DC 20057 USA. EM jeffrey.huang@georgetown.edu OI Huang, Jeffrey/0000-0003-0996-9451 FU NIH-NINDS [1R21NS091890-01, 5T32NS041218]; National Multiple Sclerosis Society [PP2159]; Georgetown University; Georgetown College; TurnFirst RDS Scholarship; NIH-NCATS [TL1TR001431]; NIH-NINDS Center [5P30 NS047463]; NIH-NCI Cancer Center [P30 CAO16059] FX This project was supported, in part, by funding from the NIH-NINDS grant 1R21NS091890-01 (J.K.H.), National Multiple Sclerosis Society grant PP2159 (J.K.H.), Georgetown University Music for the Mind Award (J.K.H.), Georgetown University Partners in Research Award (J.K.H.), Georgetown College (J.K.H.), NIH-NINDS Training Award 5T32NS041218 (K.A.C), TurnFirst RDS Scholarship (S.E.D), and NIH-NCATS Training Award TL1TR001431 (S.E.D). Transmission electron microscopy was performed at the VCU - Dept. of Anatomy and Neurobiology Microscopy Facility, supported, in part, by funding from NIH-NINDS Center Core grant 5P30 NS047463 and NIH-NCI Cancer Center grant P30 CAO16059 (J.L.D). NR 63 TC 1 Z9 1 U1 2 U2 2 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 DEC PY 2016 VL 139 BP 3121 EP 3136 DI 10.1093/brain/aww254 PN 12 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI7US UT WOS:000392709800015 PM 27797811 ER PT J AU Muller, SH Girard, SL Hopfner, F Merner, ND Bourassa, CV Lorenz, D Clark, LN Tittmann, L Soto-Ortolaza, AI Klebe, S Hallett, M Schneider, SA Hodgkinson, CA Lieb, W Wszolek, ZK Pendziwiat, M Lorenzo-Betancor, O Poewe, W Ortega-Cubero, S Seppi, K Rajput, A Hussl, A Rajput, AH Berg, D Dion, PA Wurster, I Shulman, JM Srulijes, K Haubenberger, D Pastor, P Vilarino-Guell, C Postuma, RB Bernard, G Ladwig, KH Dupre, N Jankovic, J Strauch, K Panisset, M Winkelmann, J Testa, CM Zeuner, KE Reischl, E Ross, OA Arzberger, T Chouinard, S Deuschl, G Louis, ED Kuhlenbaumer, G Rouleau, GA AF Mueller, Stefanie H. Girard, Simon L. Hopfner, Franziska Merner, Nancy D. Bourassa, Cynthia V. Lorenz, Delia Clark, Lorraine N. Tittmann, Lukas Soto-Ortolaza, Alexandra I. Klebe, Stephan Hallett, Mark Schneider, Susanne A. Hodgkinson, Colin A. Lieb, Wolfgang Wszolek, Zbigniew K. Pendziwiat, Manuela Lorenzo-Betancor, Oswaldo Poewe, Werner Ortega-Cubero, Sara Seppi, Klaus Rajput, Alex Hussl, Anna Rajput, Ali H. Berg, Daniela Dion, Patrick A. Wurster, Isabel Shulman, Joshua M. Srulijes, Karin Haubenberger, Dietrich Pastor, Pau Vilarino-Guell, Carles Postuma, Ronald B. Bernard, Genevieve Ladwig, Karl-Heinz Dupre, Nicolas Jankovic, Joseph Strauch, Konstantin Panisset, Michel Winkelmann, Juliane Testa, Claudia M. Zeuner, Kirsten E. Reischl, Eva Ross, Owen A. Arzberger, Thomas Chouinard, Sylvain Deuschl, Guenther Louis, Elan D. Kuhlenbaeumer, Gregor Rouleau, Guy A. TI Genome-wide association study in essential tremor identifies three new loci SO BRAIN LA English DT Article DE genome-wide association study; movement disorders; tremor; genetics; essential tremor ID QUALITY-CONTROL; DISEASE; GENETICS; TOOL AB We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor. C1 [Mueller, Stefanie H.; Hopfner, Franziska; Schneider, Susanne A.; Berg, Daniela; Zeuner, Kirsten E.; Deuschl, Guenther; Kuhlenbaeumer, Gregor] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Dept Neurol, Kiel, Germany. [Girard, Simon L.] Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada. [Girard, Simon L.; Merner, Nancy D.; Bourassa, Cynthia V.; Dion, Patrick A.; Postuma, Ronald B.; Bernard, Genevieve; Rouleau, Guy A.] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ, Canada. [Merner, Nancy D.] Auburn Univ, Dept Drug Discovery & Dev, Harrison Sch Pharm, Auburn, AL 36849 USA. [Lorenz, Delia] Univ Wurzburg, Univ Childrens Hosp, Wurzburg, Germany. [Clark, Lorraine N.] Columbia Univ, Taub Inst, Dept Pathol & Cell Biol, New York, NY USA. [Tittmann, Lukas] Christian Albrechts Univ Kiel, Inst Epidemiol, Kiel, Germany. [Tittmann, Lukas; Lieb, Wolfgang] Biobank POPGEN, Kiel, Germany. [Soto-Ortolaza, Alexandra I.; Wszolek, Zbigniew K.; Ross, Owen A.] Mayo Clin, Dept Neurosci & Neurol, Jacksonville, FL USA. [Klebe, Stephan] Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany. [Klebe, Stephan] Univ Hosp Freiburg, Dept Neurol, Freiburg, Germany. [Hallett, Mark; Haubenberger, Dietrich] NINDS, Intramural Res Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Schneider, Susanne A.] Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany. [Hodgkinson, Colin A.] NIAAA, NIH, Bethesda, MD USA. [Pendziwiat, Manuela] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Dept Paediat Neurol, Kiel, Germany. [Lorenzo-Betancor, Oswaldo; Ortega-Cubero, Sara; Pastor, Pau] Univ Navarra, CIBERNED, Ctr Investi Biomed Red Enfermedades Neurodegenera, Neurogenet,Div Neurosci,Ctr Appl Med Res CIMA, E-31080 Pamplona, Spain. [Lorenzo-Betancor, Oswaldo; Ortega-Cubero, Sara; Pastor, Pau] Univ Barcelona, Hosp Univ Mutua Terrassa, Dept Neurol, Barcelona, Spain. [Poewe, Werner; Seppi, Klaus; Hussl, Anna] Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria. [Rajput, Alex; Rajput, Ali H.] Univ Saskatchewan, Saskatoon, SK, Canada. [Rajput, Alex; Rajput, Ali H.] Saskatoon Hlth Reg, Saskatoon, SK, Canada. [Wurster, Isabel; Srulijes, Karin] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Wurster, Isabel; Srulijes, Karin] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Shulman, Joshua M.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Vilarino-Guell, Carles] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Postuma, Ronald B.] Montreal Gen Hosp, Dept Neurol, Montreal, PQ, Canada. [Bernard, Genevieve] Montreal Childrens Hosp, Div Pediat Neurol, Dept Pediat, Montreal, PQ, Canada. [Bernard, Genevieve] Montreal Childrens Hosp, Div Pediat Neurol, Dept Neurol, Montreal, PQ, Canada. [Bernard, Genevieve] Montreal Childrens Hosp, Div Pediat Neurol, Dept Neurosurg, Montreal, PQ, Canada. [Ladwig, Karl-Heinz; Reischl, Eva] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Ladwig, Karl-Heinz] Tech Univ Munich, Klinikum Rechts Isar, Dept Psychosomat Med & Psychotherapy, Munich, Germany. [Dupre, Nicolas] Univ Laval, CHU Quebec Enfant Jesus, Fac Med, Quebec City, PQ, Canada. [Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Strauch, Konstantin] Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Jankovic, Joseph; Panisset, Michel; Chouinard, Sylvain] Ctr Hosp Univ Montreal, Unite Troubles mouvement Andre Barbeau, Montreal, PQ, Canada. [Winkelmann, Juliane] Helmholtz Zentrum Munchen, Inst Neurogen, Munich, Germany. [Winkelmann, Juliane] Tech Univ Munich, Klinikum Rechts Isar, Neurol Klin & Poliklin, Munich, Germany. [Winkelmann, Juliane] Munich Cluster Syst Neurol Synergy, Munich, Germany. [Testa, Claudia M.] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Parkinsons & Movement Disorders Ctr, Richmond, VA USA. [Reischl, Eva] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Arzberger, Thomas] Univ Munich, Ctr Neuropathol & Prion Res, D-80539MU Munich, Germany. [Arzberger, Thomas] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany. [Louis, Elan D.] Yale Univ, Yale Sch Med, Dept Neurol, New Haven, CT USA. RP Rouleau, GA (reprint author), McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ, Canada. EM guy.rouleau@mcgill.ca RI Pastor, Pau/C-9834-2009; Lieb, Wolfgang/C-1990-2012; Vilarino-Guell, Carles/D-8628-2011 OI Pastor, Pau/0000-0002-7493-8777; Vilarino-Guell, Carles/0000-0002-5612-5940 FU CIHR; Canada Research Chair in genetics of the nervous system; DFG [KU1194/9-1]; National Institutes of Health [NIH R01 NS073872]; FRQS; NIH [R01 NS073872]; Munich Center of Health Sciences (MC-Health); Ludwig-Maximilians-Universitat as part of LMUinnovativ; Mayo Clinic Florida Research Committee [NS072187] FX This study was made possible by funding from the CIHR, Canada Research Chair in genetics of the nervous system and from the DFG (KU1194/9-1) and from the National Institutes of Health (NIH R01 NS073872). S.L.G. is grateful to FRQS for financial support. G.A.R. is grateful to CIHR and to the Canada Research Chair in genetics of the nervous system. G.K., G.D. and F.H. are grateful to the DFG for financial support (KU1194/9-1). E.D.L. and L.N.C. were supported by NIH R01 NS073872. KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. The Mayo Clinic Florida is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187), and this work was supported by the Mayo Clinic Florida Research Committee. This research was supported by a donation of the Rhein-Taunus-Krematorium. C.M.T. is grateful to the Emory ADRC and National Institute of Aging (P50 AG025688). NR 19 TC 1 Z9 1 U1 3 U2 3 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 DEC PY 2016 VL 139 BP 3163 EP 3169 DI 10.1093/brain/aww242 PN 12 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EI7US UT WOS:000392709800018 PM 27797806 ER PT J AU Uhde, M Ajamian, M Li, XT Wormser, GP Marques, A Alaedini, A AF Uhde, Melanie Ajamian, Mary Li, Xueting Wormser, Gary P. Marques, Adriana Alaedini, Armin TI Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Lyme disease; Borrelia burgdorferi; acute-phase response; inflammation; post-treatment Lyme disease syndrome ID BODY-FAT; ARTHRITIS; CHILDREN; SAA; CRP AB Background. Infection with Borrelia burgdorferi, the causative agent of Lyme disease, triggers host immune responses that affect the clinical outcome and are a source of biomarkers with diagnostic utility. Although adaptive immunity to B. burgdorferi has been extensively characterized, considerably less information is available about the development of innate acute-phase responses in Lyme disease. Our aim in this study was to evaluate the expression of C-reactive protein (CRP) and serum amyloid A (SAA), the prototype acute-phase response proteins, in the context of the varying manifestations associated with Lyme borreliosis. Methods. Circulating concentrations of CRP and SAA in patients with a range of early to late objective manifestations of Lyme disease and in individuals with post-treatment Lyme disease syndrome were compared with those in healthy control groups. Results. CRP and SAA levels were significantly elevated in early localized and early disseminated Lyme disease but not in the later stages of active infection. Levels of CRP, but not SAA, were also found to be significantly increased in patients with antibiotic-refractory Lyme arthritis and in those with post-treatment Lyme disease syndrome. Conclusions. These findings indicate that circulating CRP and SAA levels are highest when the concentration of spirochetes is greatest in skin and/or blood and that levels decline after the dissemination of the organism to extracutaneous sites in subsequent stages of infection. The data also suggest that antibiotic-refractory Lyme arthritis and post-treatment Lyme disease syndrome are associated with elevated CRP responses that are driven by inflammatory mechanisms distinct from those in active infection. C1 [Uhde, Melanie; Ajamian, Mary; Li, Xueting; Alaedini, Armin] Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,9th Flr, New York, NY 10032 USA. [Wormser, Gary P.] New York Med Coll, Dept Med, Div Infect Dis, Valhalla, NY 10595 USA. [Marques, Adriana] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Alaedini, A (reprint author), Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,9th Flr, New York, NY 10032 USA. EM aa819@columbia.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of NIH [R56AI093763, U54AI057158]; National Institute of Allergy and Infectious Diseases (NIAID) of NIH (Center of Excellence); Global Lyme Alliance; Intramural Research Program of NIAID FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of NIH (grants R56AI093763 to A. A., and U54AI057158 to A. A.; principal investigator of the Center of Excellence Grant, W. I. Lipkin), the Global Lyme Alliance (A. A.), and the Intramural Research Program of NIAID (A. R. M.). NR 25 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2016 VL 63 IS 11 BP 1399 EP 1404 DI 10.1093/cid/ciw599 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EI7WA UT WOS:000392713900001 PM 27585799 ER PT J AU Playford, EG Lipman, J Jones, M Lau, AF Kabir, M Chen, SCA Marriott, DJ Seppelt, I Gottlieb, T Cheung, W Iredell, JR McBryde, ES Sorrell, TC AF Playford, E. Geoffrey Lipman, Jeffrey Jones, Michael Lau, Anna F. Kabir, Masrura Chen, Sharon C. -A. Marriott, Deborah J. Seppelt, Ian Gottlieb, Thomas Cheung, Winston Iredell, Jonathan R. McBryde, Emma S. Sorrell, Tania C. TI Problematic Dichotomization of Risk for Intensive Care Unit (ICU)-Acquired Invasive Candidiasis: Results Using a Risk-Predictive Model to Categorize 3 Levels of Risk From a Multicenter Prospective Cohort of Australian ICU Patients SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE invasive candidiasis; risk prediction; critical care; prophylaxis; candidemia ID CRITICALLY-ILL; FUNGAL-INFECTIONS; SURGICAL-PATIENTS; COLONIZATION; VALIDATION; BLOOD; METAANALYSIS; PROPHYLAXIS; INITIATION; MORTALITY AB Background. Delayed antifungal therapy for invasive candidiasis (IC) contributes to poor outcomes. Predictive risk models may allow targeted antifungal prophylaxis to those at greatest risk. Methods. A prospective cohort study of 6685 consecutive nonneutropenic patients admitted to 7 Australian intensive care units (ICUs) for >= 72 hours was performed. Clinical risk factors for IC occurring prior to and following ICU admission, colonization with Candida species on surveillance cultures from 3 sites assessed twice weekly, and the occurrence of IC >= 72 hours following ICU admission or <= 72 hours following ICU discharge were measured. From these parameters, a risk-predictive model for the development of ICU-acquired IC was then derived. Results. Ninety-six patients (1.43%) developed ICU-acquired IC. A simple summation risk-predictive model using the 10 independently significant variables associated with IC demonstrated overall moderate accuracy (area under the receiver operating characteristic curve = 0.82). No single threshold score could categorize patients into clinically useful high-and low-risk groups. However, using 2 threshold scores, 3 patient cohorts could be identified: those at high risk (score >= 6, 4.8% of total cohort, positive predictive value [PPV] 11.7%), those at low risk (score <= 2, 43.1% of total cohort, PPV 0.24%), and those at intermediate risk (score 3-5, 52.1% of total cohort, PPV 1.46%). Conclusions. Dichotomization of ICU patients into high-and low-risk groups for IC risk is problematic. Categorizing patients into high-, intermediate-, and low-risk groups may more efficiently target early antifungal strategies and utilization of newer diagnostic tests. C1 [Playford, E. Geoffrey] Princess Alexandra Hosp, Infect Management Serv, Brisbane, Qld, Australia. [Playford, E. Geoffrey] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Lipman, Jeffrey] Royal Brisbane & Womens Hosp, Dept Intens Care, Brisbane, Qld, Australia. [Lipman, Jeffrey] Univ Queensland, Brisbane, Qld, Australia. [Jones, Michael] Macquarie Univ, Dept Psychol, Sydney, NSW, Australia. [Lau, Anna F.; Kabir, Masrura; Iredell, Jonathan R.; Sorrell, Tania C.] Westmead Inst Med Res, Ctr Infect Dis & Microbiol, Westmead, NSW, Australia. [Chen, Sharon C. -A.] Westmead Hosp, Inst Clin Pathol & Med Res, Ctr Infect Dis & Microbiol Lab Serv, Westmead, NSW, Australia. [Chen, Sharon C. -A.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Marriott, Deborah J.] St Vincent Hosp, Dept Microbiol & Infect Dis, Worcester, MA 01604 USA. [Seppelt, Ian] Univ Sydney, Dept Intens Care Med, Nepean Hosp, Sydney, NSW 2006, Australia. [Gottlieb, Thomas] Concord Hosp, Dept Microbiol & Infect Dis, Concord, NSW, Australia. [Cheung, Winston] Concord Hosp, Dept Intens Care Med, Concord, NSW, Australia. [Iredell, Jonathan R.; Sorrell, Tania C.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [McBryde, Emma S.] Univ Melbourne, Royal Melbourne Hosp, Victorian Infect Dis Serv, Melbourne, Vic 3010, Australia. [Lau, Anna F.] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [McBryde, Emma S.] James Cook Univ, Australian Inst Trop Med & Hyg, Townsville, Qld, Australia. RP Sorrell, TC (reprint author), Westmead Inst Med Res, Marie Bashir Inst, Level 4,196 Hawkesbury Rd, Westmead, NSW 2145, Australia. EM tania.sorrell@sydney.edu.au FU National Health and Medical Research Council of Australia [512307]; National Health and Medical Research Council of Australia (Centre for Research Excellence) [264625]; Australian Universities Postgraduate award; Pfizer Pharmaceuticals FX This work was supported by the National Health and Medical Research Council of Australia (project grant number 512307, Centre for Research Excellence grant number 264625); an Australian Universities Postgraduate award to A. F. L.; and an investigator-initiated grant from Pfizer Pharmaceuticals. T. C. S. is a Sydney Medical Foundation Fellow. NR 29 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 1 PY 2016 VL 63 IS 11 BP 1463 EP 1469 DI 10.1093/cid/ciw610 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EI7WA UT WOS:000392713900010 PM 27601224 ER PT J AU Alvarado, MC Malkova, L Bachevalier, J AF Alvarado, Maria C. Malkova, Ludise Bachevalier, Jocelyne TI Development of relational memory processes in monkeys SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Relational memory; Development; Medial temporal lobe; Prefrontal; Macaque ID TRANSVERSE-PATTERNING PROBLEM; OBJECT RECOGNITION MEMORY; RHESUS MACAQUES; HIPPOCAMPAL-FORMATION; PERIRHINAL CORTEX; LOCATION MEMORY; DAMAGE; LESIONS; TASK; ASSOCIATIONS AB The present study tested whether relational memory processes, as measured by the transverse patterning problem, are late-developing in nonhuman primates as they are in humans. Eighteen macaques ranging from 3 to 36 months of age, were trained to solve a set of visual discriminations that formed the transverse patterning problem. Subjects were trained at 3, 4-6, 12, 15-24 or 36 months of age to solve three discriminations as follows: 1) A+ vs. B-; 2) B+ vs. C-; 3) C+ vs. A. When trained concurrently, subjects must adopt a relational strategy to perform accurately on all three problems. All 36 month old monkeys reached the criterion of 90% correct, but only one 24-month-old and one 15-month-old did, initially. Three-month old infants performed at chance on all problems. Six and 12-month-olds performed at 75-80% correct but used a linear' or elemental solution (e.g. A > B > C), which only yields correct performance on two problems. Retraining the younger subjects at 12, 24 or 36 months yielded a quantitative improvement on speed of learning, and a qualitative improvement in 24-36 month old monkeys for learning strategy. The results suggest that nonspatial relational memory develops late in macaques (as in humans), maturing between 15 and 24 months of age. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Alvarado, Maria C.; Bachevalier, Jocelyne] Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd NE, Atlanta, GA 30329 USA. [Malkova, Ludise] Georgetown Univ, Washington, DC 20057 USA. [Malkova, Ludise] NIMH, Bethesda, MD 20892 USA. RP Alvarado, MC (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd NE, Atlanta, GA 30329 USA. EM malvara@emory.edu FU Intramural Research Program of the National Institute of Mental Health/National Institutes of Health/Department of Health and Human Services; NIMH [MH58846]; NICHD [HD35471]; ORIP/OD [P51OD011132] FX This project was funded in part by the Intramural Research Program of the National Institute of Mental Health/National Institutes of Health/Department of Health and Human Services; and by NIMH grantMH58846 and NICHD grant HD35471 to JB. Writing of this manuscript was supported in part by ORIP/OD P51OD011132 (formerly NCRR P51RR000165). NR 36 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 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD DEC PY 2016 VL 22 BP 27 EP 35 DI 10.1016/j.dcn.2016.10.007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EI7XD UT WOS:000392716900004 PM 27833046 ER PT J AU Stern, ST Martinez, MN Stevens, DM AF Stern, Stephan T. Martinez, Marilyn N. Stevens, David M. TI When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics? SO DRUG METABOLISM AND DISPOSITION LA English DT Editorial Material ID PLASMA-PROTEIN BINDING; ALBUMIN-BOUND PACLITAXEL; IN-VIVO; NONLINEAR PHARMACOKINETICS; ANTICANCER AGENTS; CANCER-PATIENTS; CREMOPHOR-FREE; PHASE-I; DELIVERY; NANOPARTICLE AB Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation. C1 [Stern, Stephan T.; Stevens, David M.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Res Technol Program, Nanotechnol Characterizat Lab, Frederick, MD USA. [Martinez, Marilyn N.] US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl,HFV-100, Rockville, MD 20855 USA. RP Martinez, MN (reprint author), US FDA, Ctr Vet Med, Off New Anim Drug Evaluat, 7500 Standish Pl,HFV-100, Rockville, MD 20855 USA. EM marilyn.martinez@fda.hhs.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Institutes of Health National Cancer Institute [HHSN261200800e001E] FX This work was supported in whole or in part with federal funds from the National Institutes of Health National Cancer Institute [Grant HHSN261200800e001E]. NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 2016 VL 44 IS 12 BP 1934 EP 1939 DI 10.1124/dmd.116.073148 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI8AN UT WOS:000392726600010 PM 27670412 ER PT J AU Nickbakhsh, S Hall, MD Dorigatti, I Lycett, SJ Mulatti, P Monne, I Fusaro, A Woolhouse, MEJ Rambaut, A Kao, RR AF Nickbakhsh, Sema Hall, Matthew D. Dorigatti, Ilaria Lycett, Samantha J. Mulatti, Paolo Monne, Isabella Fusaro, Alice Woolhouse, Mark E. J. Rambaut, Andrew Kao, Rowland R. TI Modelling the impact of co-circulating low pathogenic avian influenza viruses on epidemics of highly pathogenic avian influenza in poultry SO Epidemics LA English DT Article DE Epidemiology; Interference; Cross-protection; Poultry; Mathematical modelsa ID HONG-KONG; A VIRUS; H5N1; HEMAGGLUTININ; INTERFERENCE; TRANSMISSION; EMERGENCE; INFECTION; VIRULENCE; CHICKENS AB It is well known that highly pathogenic avian influenza (HPAI) viruses emerge through mutation of precursor low pathogenic avian influenza (LPAI) viruses in domestic poultry populations. The potential for immunological cross-protection between these pathogenic variants is recognised but the epidemiological impact during co-circulation is not well understood. Here we use mathematical models to investigate whether altered flock infection parameters consequent to primary LPAI infections can impact on the spread of HPAI at the population level. First we used mechanistic models reflecting the co-circulatory dynamics of LPAI and HPAI within a single commercial poultry flock. We found that primary infections with LPAI led to HPAI prevalence being maximised under a scenario of high but partial cross-protection. We then tested the population impact in spatially-explicit simulations motivated by a major avian influenza A(H7N1) epidemic that afflicted the Italian poultry industry in 1999-2001. We found that partial cross-protection can lead to a prolongation of HPAI epidemic duration. Our findings have implications for the control of HPAI in poultry particularly for settings in which LPAI and HPAI frequently co-circulate. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Nickbakhsh, Sema; Kao, Rowland R.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Biodivers Anim Hlth & Comparat Med, Glasgow, Lanark, Scotland. [Hall, Matthew D.; Lycett, Samantha J.; Woolhouse, Mark E. J.; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH8 9YL, Midlothian, Scotland. [Hall, Matthew D.; Lycett, Samantha J.; Woolhouse, Mark E. J.; Rambaut, Andrew] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh EH9 3FL, Midlothian, Scotland. [Dorigatti, Ilaria] Imperial Coll London, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London W2 1PG, England. [Mulatti, Paolo; Monne, Isabella; Fusaro, Alice] Ist Zooprofilatt Sperimentale Venezie, Legnaro, PD, Italy. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nickbakhsh, Sema] Univ Glasgow, MRC, Ctr Virus Res Inst Infect Immun & Inflammat, Glasgow G61 1QH, Lanark, Scotland. [Hall, Matthew D.] Imperial Coll London, Dept Infect Dis Epidemiol, London W2 1PG, England. [Lycett, Samantha J.] Univ Edinburgh, Infect & Immun Div, Roslin Inst & R D SVS, Edinburgh EH25 9RG, Midlothian, Scotland. RP Kao, RR (reprint author), Univ Glasgow, 464 Bearsden Rd, Glasgow G61 1QH, Lanark, Scotland. EM rowland.kao@glasgow.ac.uk OI Mulatti, Paolo/0000-0001-8188-997X; Lycett, Samantha/0000-0003-3159-596X; Kao, Rowland/0000-0003-0919-6401; Fusaro, Alice/0000-0002-8213-5472 FU Scottish Government's EPIC Centre of Expertise on Animal Disease Outbreaks [65206]; Wellcome Trust [WT/093724]; European Union Seventh Framework Programme [FP7] [278433-PREDEMIC]; Bill and Melinda Gates Foundation [P20064, P46908]; University of Edinburgh FX We thank Giovanni Cattoli, Stefano Marangon, and Marco de Nardi for assistance with providing genetic sequences, epidemiological data and input. We also thank Melissa Ward, Joseph Hughes, and Pablo Murcia for helpful discussions. We also thank an anonymous referee for helpful comments. This study was supported by The Scottish Government's EPIC Centre of Expertise on Animal Disease Outbreaks (65206), VIZIONS a strategic award from the Wellcome Trust (WT/093724), the European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement no 278433-PREDEMIC, and the Bill and Melinda Gates Foundation (grants P20064 and P46908). SJL is supported by a Chancellors Fellowship from the University of Edinburgh. NR 34 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD DEC PY 2016 VL 17 BP 27 EP 34 DI 10.1016/j.epidem.2016.10.005 PG 8 WC Infectious Diseases SC Infectious Diseases GA EJ1CQ UT WOS:000392948300004 PM 27788412 ER PT J AU Werkman, M Tildesley, MJ Brooks-Pollock, E Keeling, MJ AF Werkman, Marleen Tildesley, Michael J. Brooks-Pollock, Ellen Keeling, Matt J. TI Preserving privacy whilst maintaining robust epidemiological predictions SO EPIDEMICS LA English DT Article DE Metapopulation; Simulations; Stochastic model; Spatial aggregation ID MOUTH-DISEASE; GREAT-BRITAIN; METAPOPULATION MODEL; FOOT; SPREAD; DYNAMICS; STRATEGIES; MOVEMENTS; IMPACT; UK AB Mathematical models are invaluable tools for quantifying potential epidemics and devising optimal control strategies in case of an outbreak. State-of-the-art models increasingly require detailed individual farm-based and sensitive data, which may not be available due to either lack of capacity for data collection or privacy concerns. However, in many situations, aggregated data are available for use. In this study, we systematically investigate the accuracy of predictions made by mathematical models initialised with varying data aggregations, using the UK 2001 Foot-and-Mouth Disease Epidemic as a case study. We consider the scenario when the only data available are aggregated into spatial grid cells, and develop a metapopulation model where individual farms in a single subpopulation are assumed to behave uniformly and transmit randomly. We also adapt this standard metapopulation model to capture heterogeneity in farm size and composition, using farm census data. Our results show that homogeneous models based on aggregated data overestimate final epidemic size but can perform well for predicting spatial spread. Recognising heterogeneity in farm sizes improves predictions of the final epidemic size, identifying risk areas, determining the likelihood of epidemic take-off and identifying the optimal control strategy. In conclusion, in cases where individual farm-based data are not available, models can still generate meaningful predictions, although care must be taken in their interpretation and use. (C) 2016 Published by Elsevier B.V. C1 [Werkman, Marleen; Tildesley, Michael J.; Keeling, Matt J.] Univ Warwick, Math Inst, WIDER Ctr, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England. [Werkman, Marleen; Tildesley, Michael J.; Keeling, Matt J.] Univ Warwick, Sch Life Sci, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England. [Werkman, Marleen] Imperial Coll London, Fac Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, St Marys Campus, London, England. [Tildesley, Michael J.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Brooks-Pollock, Ellen] Univ Bristol, Sch Social & Community Med, Oakfield Grove BS8 2BN, Clifton, England. RP Werkman, M (reprint author), Imperial Coll London, Fac Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, St Marys Campus, London, England. EM m.werkman@imperial.ac.uk FU Research and Policy for Infectious Disease Dynamics (RAPIDD) Program, Science and Technology Directorate, US Department of Homeland Security; Fogarty International Center, National Institutes of Health; Foreign Animal Disease Modeling Program, Science and Technology Directorate, US Department of Homeland Security [ST108-000017]; BBSRC [BB/K010972/3]; ERA-NET anihwa scheme; Department for Environment, Food & Rural Affairs (Defra) FX This work was made possible by funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) Program, Science and Technology Directorate, US Department of Homeland Security and Fogarty International Center, National Institutes of Health and the Foreign Animal Disease Modeling Program, Science and Technology Directorate, US Department of Homeland Security (Grant ST108-000017) and BBSRC (grant no. BB/K010972/3). MJK was funded through the ERA-NET anihwa scheme with funding provided by the Department for Environment, Food & Rural Affairs (Defra). Data was kindly provided by Defra. We are thankful to Colleen Webb and Uno Wennergren for useful discussion on this manuscript. NR 26 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 DEC PY 2016 VL 17 BP 35 EP 41 DI 10.1016/j.epidem.2016.10.004 PG 7 WC Infectious Diseases SC Infectious Diseases GA EJ1CQ UT WOS:000392948300005 PM 27792892 ER PT J AU Xin, W Edwards, N Bonci, A AF Xin, Wendy Edwards, Nicholas Bonci, Antonello TI VTA dopamine neuron plasticity - the unusual suspects SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Review DE astrocyte; dopamine; GABA; inhibition; plasticity; VTA ID VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; ASTROCYTIC GLUTAMATE UPTAKE; IN-VIVO; SYNAPTIC PLASTICITY; D-SERINE; NMDA-RECEPTORS; SUBSTANTIA-NIGRA; GABA(B) RECEPTORS; PREFRONTAL CORTEX AB Dopamine neurons in the ventral tegmental area (VTA) are involved in a variety of physiological and pathological conditions, ranging from motivated behaviours to substance use disorders. While many studies have shown that these neurons can express plasticity at excitatory and inhibitory synapses, little is known about how inhibitory inputs and glial activity shape the output of DA neurons and therefore, merit greater discussion. In this review, we will attempt to fill in a bit more of the puzzle, with a focus on inhibitory transmission and astrocyte function. We summarize the findings within the VTA as well as observations made in other brain regions that have important implications for plasticity in general and should be considered in the context of DA neuron plasticity. C1 [Xin, Wendy; Edwards, Nicholas; Bonci, Antonello] NIDA, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Xin, Wendy; Bonci, Antonello] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. RP Bonci, A (reprint author), NIDA, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. EM Antonello.bonci@nih.gov OI Xin, Wendy/0000-0002-1425-834X NR 140 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2016 VL 44 IS 12 BP 2975 EP 2983 DI 10.1111/ejn.13425 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EJ1CS UT WOS:000392948500001 PM 27711998 ER PT J AU Rupp, B Wlodawer, A Minor, W Helliwell, JR Jaskolski, M AF Rupp, Bernhard Wlodawer, Alexander Minor, Wladek Helliwell, John R. Jaskolski, Mariusz TI Correcting the record of structural publications requires joint effort of the community and journal editors SO FEBS Journal LA English DT Article DE biomolecular crystallography; database integrity; error correction; structural databases; X-ray crystal structure models ID CRYSTAL-STRUCTURE PAPERS; UNUSUAL-FEATURES; PLASTICITY; BACTERIAL; MODEL AB Seriously flawed and even fictional models of biomolecular crystal structures, although rare, still persist in the record of structural repositories and databases. The ensuing problems of database contamination and persistence of publications based on incorrect structure models must be effectively addressed. The burden cannot be simply left to the critical voices who take the effort to contribute dissenting comments that are mostly ignored. The entire structural biology community, and particularly the journal editors who exercise significant power in this respect, must engage in a constructive dialog lest structural biology lose its credibility as an evidence-based empirical science. C1 [Rupp, Bernhard] Kk Hofkristallamt, 991 Audrey Pl, Vista, CA 92084 USA. [Rupp, Bernhard] Med Univ Innsbruck, Dept Genet Epidemiol, A-6020 Innsbruck, Austria. [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21701 USA. [Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA USA. [Helliwell, John R.] Univ Manchester, Sch Chem, Manchester M13 9PL, Lancs, England. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Polish Acad Sci, Ctr Biocrystallog Res, Inst Bioorgan Chem,Dept Crystallog,Fac Chem, Poznan, Poland. RP Rupp, B (reprint author), Kk Hofkristallamt, 991 Audrey Pl, Vista, CA 92084 USA. EM br@hofkristallamt.org OI Minor, Wladek/0000-0001-7075-7090 FU Austrian Science Foundation (FWF) [P28395-B26]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; [U01-HG008424] FX BR enjoys partial support from the Austrian Science Foundation (FWF) under project P28395-B26. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by U01-HG008424 grant to WM. NR 33 TC 2 Z9 2 U1 1 U2 1 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 DEC PY 2016 VL 283 IS 24 BP 4452 EP 4457 DI 10.1111/febs.13765 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI8GT UT WOS:000392744800004 PM 27229767 ER PT J AU Gildersleeve, J AF Gildersleeve, Jeffrey TI Understanding and Exploiting Anti-Glycan Immunity to Improve Cancer Care SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Gildersleeve, Jeffrey] NCI, Biol Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 26 BP 1385 EP 1385 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600030 ER PT J AU Nita-Lazar, A Nuccio, AG Daniels, CM AF Nita-Lazar, Aleksandra Nuccio, Arthur G. Daniels, Casey M. TI ADP-ribosylation in the innate immune response SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Nita-Lazar, Aleksandra; Nuccio, Arthur G.; Daniels, Casey M.] NIAID, Cellular Networks Prote Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural research Program of NIAID, NIH FX This research was supported by the Intramural research Program of NIAID, NIH. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 71 BP 1402 EP 1402 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600074 ER PT J AU Olivier-Van Stichelen, S Wang, P Ohde, J Comly, M Love, DC Hanover, JA AF Olivier-Van Stichelen, Stephanie Wang, Peng Ohde, Joshua Comly, Marcy Love, Dona C. Hanover, John A. TI Nutrient-driven O-GlcNAc cycling impacts Neurodevelopmental Timing and Metabolism SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Olivier-Van Stichelen, Stephanie; Wang, Peng; Ohde, Joshua; Comly, Marcy; Hanover, John A.] NIDDK, NIH, Bethesda, MD USA. [Love, Dona C.] NCI, NIH, Bethesda, MD USA. NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 110 BP 1418 EP 1419 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600113 ER PT J AU Bond, MR St Amand, MM Kolodrubetz, MC Shiloach, J Hanover, J AF Bond, Michelle R. St Amand, Melissa M. Kolodrubetz, Marcella C. Shiloach, Joseph Hanover, Johna. TI O-GlcNAcase knockout disrupts mammalian cell autophagy SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Bond, Michelle R.; Kolodrubetz, Marcella C.; Hanover, Johna.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [St Amand, Melissa M.] Schafer Corp, Arlington, VA 22203 USA. [Shiloach, Joseph] NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 159 BP 1439 EP 1439 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600162 ER PT J AU Zhao, P Zhou, TQ Ou, L Yu, WH Kwong, P Alter, G Tiemeyer, M Wells, L AF Zhao, Peng Zhou, Tongqi Ou, Li Yu, Wenhan Kwong, Peter Alter, Galit Tiemeyer, Michael Wells, Lance TI Characterizing glycoproteins using EndoH/PNGaseF in combination with high-resolution accurate-mass (HRAM) mass spectrometry SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Glycobiology CY NOV 19-22, 2016 CL New Orleans, LA SP Soc Glycobiol C1 [Zhao, Peng; Tiemeyer, Michael; Wells, Lance] Univ Georgia, Complex Carbohydrate Res Ctr, 220 Riverbend Rd, Athens, GA 30602 USA. [Yu, Wenhan; Alter, Galit] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Zhou, Tongqi; Ou, Li; Kwong, Peter] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD DEC PY 2016 VL 26 IS 12 MA 214 BP 1462 EP 1462 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EJ0XX UT WOS:000392935600217 ER PT J AU Voorhoeve, A Edejer, TTT Kapiriri, L Norheim, OF Snowden, J Basenya, O Bayarsaikhan, D Chentaf, I Eyal, N Folsom, A Halina, R Hussein, T Morales, C Ostmann, F Ottersen, T Prakongsai, P Saenz, C Saleh, K Sommanustweechai, A Wikler, D Zakariah, A AF Voorhoeve, Alex Edejer, Tessa T. T. Kapiriri, Lydia Norheim, Ole F. Snowden, James Basenya, Olivier Bayarsaikhan, Dorjsuren Chentaf, Ikram Eyal, Nir Folsom, Amanda Halina, Rozita Hussein, Tun Morales, Cristian Ostmann, Florian Ottersen, Trygve Prakongsai, Phusit Saenz, Carla Saleh, Karima Sommanustweechai, Angkana Wikler, Daniel Zakariah, Afisah TI Three Case Studies in Making Fair Choices on the Path to Universal Health Coverage SO Health and Human Rights LA English DT Article ID CARE; EXPERIENCE; COUNTRIES AB The goal of achieving Universal Health Coverage (UHC) can generally be realized only in stages. Moreover, resource, capacity, and political constraints mean governments often face difficult trade-offs on the path to UHC. In a 2014 report, Making fair choices on the path to UHC, the WHO Consultative Group on Equity and Universal Health Coverage articulated principles for making such trade-offs in an equitable manner. We present three case studies which illustrate how these principles can guide practical decision-making. These case studies show how progressive realization of the right to health can be effectively guided by priority-setting principles, including generating the greatest total health gain, priority for those who are worse off in a number of dimensions (including health, access to health services, and social and economic status), and financial risk protection. They also demonstrate the value of a fair and accountable process of priority setting. C1 [Voorhoeve, Alex] London Sch Econ, Dept Philosophy Log & Sci Method, Houghton St, London WC2A 2AE, England. [Edejer, Tessa T. T.] World Hlth Org, Costs Effectiveness Expenditure & Prior Setting H, Geneva, Switzerland. [Kapiriri, Lydia] McMaster Univ, Dept Hlth Aging & Soc, Hamilton, ON, Canada. [Norheim, Ole F.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Global Hlth Prior, Bergen, Norway. [Snowden, James] Ctr Effect Altruism, Giving What We Can, Oxford, England. [Basenya, Olivier] Minist Hlth, Bujumbura, Burundi. [Bayarsaikhan, Dorjsuren] World Hlth Org, Dept Hlth Syst Governance & Financing, Geneva, Switzerland. [Chentaf, Ikram] Minist Hlth, Cooperat Div, Rabat, Morocco. [Eyal, Nir] Harvard Univ, TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Folsom, Amanda] Results Dev Inst, Washington, DC USA. [Halina, Rozita] Minist Hlth, Planning & Dev Div, Unit Natl Hlth Financing, Putrajaya, Malaysia. [Morales, Cristian] PAHO WHO Cuba, Havana, Cuba. [Ostmann, Florian] UCL, Sch Publ Policy, London, England. [Ottersen, Trygve] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Ottersen, Trygve] Univ Oslo, Ctr Global Hlth, Oslo Grp Global Hlth Policy, Bergen, Norway. [Prakongsai, Phusit] Minist Publ Hlth, Bur Int Hlth, Nonthaburi, Thailand. [Saenz, Carla] Pan Amer Hlth Org, Washington, DC USA. [Saleh, Karima] World Bank, Hlth, 1818 H St NW, Washington, DC 20433 USA. [Sommanustweechai, Angkana] Minist Publ Hlth, Nonthaburi, Thailand. [Wikler, Daniel] Harvard Univ, TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Eth & Populat Hlth, Boston, MA 02115 USA. [Zakariah, Afisah] Minist Hlth, Policy Planning Monitoring & Evaluat, Accra, Ghana. RP Voorhoeve, A (reprint author), London Sch Econ, Dept Philosophy Log & Sci Method, Houghton St, London WC2A 2AE, England.; Voorhoeve, A (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM a.e.voorhoeve@lse.ac.uk FU Ministry of Foreign Affairs of Norway; Norwegian Agency for Development Cooperation (NORAD); Norwegian Research Council; Pan-American Health Organization; British Arts and Humanities Research Council [AH/J006033/1]; Uehiro Centre for Practical Ethics FX Work on these case studies was supported by the Ministry of Foreign Affairs of Norway, the Norwegian Agency for Development Cooperation (NORAD), the Norwegian Research Council, the Pan-American Health Organization, grant AH/J006033/1 of the British Arts and Humanities Research Council, and the Uehiro Centre for Practical Ethics. We thank Daniel Cotlear, Agnes Couffinhal, Amanda Glassman, Gina Lagomarsino, Ewan Rodgers, Hasbullah Thabrany, two anonymous referees and the editors of this journal for their comments. The opinions expressed are the views of the authors, who alone are responsible for the views expressed in this publication. They do not represent any position, decision, or policy of Giving What We Can, the Ministries of Health of Burundi, Ghana, Malaysia, or Morocco, the US National Institutes of Health, the US Public Health Service, the US Department of Health and Human Services, the Pan-American Health Organization, the World Bank, or the World Health Organization. NR 38 TC 0 Z9 0 U1 3 U2 3 PU HARVARD UNIV PRESS PI CAMBRIDGE PA 79 GARDEN ST, CAMBRIDGE, MA 02138 USA SN 1079-0969 EI 2150-4113 J9 HEALTH HUM RIGHTS JI Health Hum. Rights PD DEC PY 2016 VL 18 IS 2 SI SI BP 11 EP 22 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI8IJ UT WOS:000392749200003 ER PT J AU Engel, KW Khan, I Arany, PR AF Engel, Karl W. Khan, Imran Arany, Praveen R. TI Cell lineage responses to photobiomodulation therapy SO Journal of Biophotonics LA English DT Article DE photobiomodulation; low level laser; light therapy; wound healing; oral cell lines; catalase; melatonin; NIR laser phototoxicity ID LEVEL LASER THERAPY; ANTIOXIDANT ENZYMES; ANIMAL-MODEL; STEM-CELLS; KERATINOCYTES; CATALASE; PROLIFERATION; MECHANISMS; MUCOSITIS; RADICALS AB Photobiomodulation (PBM) therapy has been noted to promote cell proliferation and growth in many different cell types shown both in vitro and in vivo. Currently, treatment regimens are used in the clinic for a variety of ailments, including wound healing. However, most protocols treat an anatomical site without considering individual cell types constituting the target tissues. This study investigates the maximal dose threshold for oral keratinocyte and fibroblast cell types treated with near-infrared laser therapy. We observed keratinocytes have increased sensitivity to laser irradiances (>0.047 W/cm(2), 300 sec, 14.2 J/cm(2)) compared to the fibroblast cells (>0.057 W/cm(2), 300 sec, 15.1 J/cm(2)) (p < 0.0001). Laser treatments were noted to generate increased reactive oxygen species (ROS) levels in keratinocytes compared to fibroblasts that appeared to inversely correlate with higher basal catalase expression. To validate these observations, melatonin was used to treat keratinocytes to induce catalase activity (p < 0.0001). Increased melatonin-induced catalase levels were noted to significantly improve keratinocyte survival to phototoxic laser doses. These observations suggest that clinical laser dosing should account for differential effects of lasers on individual cell types to improve safety and clinical efficacy of PBM therapy. [GRAPHICS] . C1 [Engel, Karl W.; Khan, Imran; Arany, Praveen R.] Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, 30 Convent Dr, Bethesda, MD 20814 USA. [Arany, Praveen R.] SUNY Buffalo, Dept Oral Biol, Sch Dent Med, 3435 Main St, Buffalo, NY 14214 USA. RP Arany, PR (reprint author), Natl Inst Dent & Craniofacial Res, Cell Regulat & Control Unit, NIH, 30 Convent Dr, Bethesda, MD 20814 USA.; Arany, PR (reprint author), SUNY Buffalo, Dept Oral Biol, Sch Dent Med, 3435 Main St, Buffalo, NY 14214 USA. EM prarany@buffalo.edu FU National Institute of Dental and Craniofacial Research, National Institutes of Health FX We would like to thank Elieza Tang for help with experiments in the project. This work was supported by the Intramural Research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 39 TC 1 Z9 1 U1 1 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD DEC PY 2016 VL 9 IS 11-12 SI SI BP 1148 EP 1156 DI 10.1002/jbio.201600025 PG 9 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EJ0QS UT WOS:000392915800004 PM 27392170 ER PT J AU Kim, C Rajan, A DeBrito, PA Giaccone, G AF Kim, Chul Rajan, Arun DeBrito, Pedro A. Giaccone, Giuseppe TI Metastatic lymphoepithelioma-like carcinoma of the lung treated with nivolumab: a case report and focused review of literature SO TRANSLATIONAL LUNG CANCER RESEARCH LA English DT Review DE Lymphoepithelioma-like carcinoma of the lung (LELC of the lung); immunotherapy; nivolumab ID EPSTEIN-BARR-VIRUS; CELL CARCINOMA; PD-1 BLOCKADE; MULTIMODALITY TREATMENT; CANCER-IMMUNOTHERAPY; PEMBROLIZUMAB; RECEPTOR; OUTCOMES; THERAPY; EXPRESSION AB In recent years, significant advances have been made in cancer immunotherapy. Here, we present the first report of a patient with lymphoepithelioma-like carcinoma (LELC) of the lung, an Epstein-Barr virus (EBV)-associated lung cancer, who was treated with nivolumab, a fully human IgG4 anti-PD-1 monoclonal antibody. We also carry out a focused review to identify and examine studies of LELC of the lung in the literature. This case report highlights the need to further assess the role of immune checkpoint inhibitors in LELC of the lung. C1 [Kim, Chul; Rajan, Arun] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [DeBrito, Pedro A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Pathol, 3970 Reservoir Rd, Washington, DC 20007 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, 3970 Reservoir Rd, Washington, DC 20007 USA. EM gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 40 TC 0 Z9 0 U1 2 U2 2 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-6751 EI 2226-4477 J9 TRANSL LUNG CANCER R JI Transl. Lung Cancer Res. PD DEC PY 2016 VL 5 IS 6 BP 720 EP 726 DI 10.21037/tlcr.2016.11.06 PG 7 WC Oncology SC Oncology GA EI5QW UT WOS:000392550400021 PM 28149767 ER PT J AU Del Rivero, J Enewold, L Thomas, A AF Del Rivero, Jaydira Enewold, Lindsey Thomas, Anish TI Metastatic lung cancer in the age of targeted therapy: improving long-term survival SO TRANSLATIONAL LUNG CANCER RESEARCH LA English DT Article DE Lung cancer; epidermal growth factor receptor (EGFR); genetics; erlotinib; survival ID GROWTH-FACTOR RECEPTOR; 1ST-LINE TREATMENT; EGFR MUTATIONS; OPEN-LABEL; PHASE-III; CHEMOTHERAPY; ERLOTINIB; ADENOCARCINOMA; GEFITINIB; AFATINIB AB Epidermal growth factor receptor (EGFR) mutations are the most frequent targetable genetic abnormality observed in non-small cell lung cancer (NSCLC). More than a decade after EGFR mutations were shown to predict sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKI), retrospective cohort studies are now identifying and characterizing 5-year survivors. While these studies indicate subsets of patients achieving long-term survival, there is paucity of data pertaining to the long-term survival benefits of these targeted therapies at a population level. Improving access to molecular testing and treatment are key to maximizing the survival benefits at a population level. C1 [Del Rivero, Jaydira] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Enewold, Lindsey] NCI, Healthcare Assessment Res Branch, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Thomas, Anish] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM lindsey.enewold@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 22 TC 0 Z9 0 U1 1 U2 1 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-6751 EI 2226-4477 J9 TRANSL LUNG CANCER R JI Transl. Lung Cancer Res. PD DEC PY 2016 VL 5 IS 6 BP 727 EP 730 DI 10.21037/tlcr.2016.11.08 PG 4 WC Oncology SC Oncology GA EI5QW UT WOS:000392550400022 PM 28149768 ER PT J AU Bae, WK Ik-Joo, C Kang, K Hennighausen, L AF Bae, W. K. Ik-Joo, C. Kang, K. Hennighausen, L. TI Oncogenic deregulation of the methyltransferase EZH2 in hepatocellular carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Bae, W. K.; Ik-Joo, C.] Chonnam Natl Univ, Hwasun Hosp, Hematol Oncol, Hwasun, Jeonnam, South Korea. [Kang, K.] Dankook Univ, Dept Microbiol, Cheonan, South Korea. [Hennighausen, L.] NIDDKD, NIH, Bethesda, MD USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 262 BP S88 EP S88 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500252 ER PT J AU Berdeja, JG Lin, Y Raje, N Siegel, D Munshi, N Turka, A Lam, LP Quigley, MT Kochenderfer, JN AF Berdeja, J. G. Lin, Y. Raje, N. Siegel, D. Munshi, N. Turka, A. Lam, L. P. Quigley, M. T. Kochenderfer, J. N. TI Clinical remissions and limited toxicity in a first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Berdeja, J. G.] Sarah Cannon Res Inst, Nashville, TN USA. [Berdeja, J. G.] Tennessee Oncol, Nashville, TN USA. [Lin, Y.] Mayo Clin, Rochester, MN USA. [Raje, N.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Siegel, D.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Munshi, N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Turka, A.; Lam, L. P.; Quigley, M. T.] Bluebird Bio Inc, Cambridge, MA USA. [Kochenderfer, J. N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 14LBA BP S5 EP S5 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500009 ER PT J AU Bernal, F Whiting, AL Aguilar, F Marshall, E AF Bernal, F. Whiting, A. L. Aguilar, F. Marshall, E. TI Disruption of the linear ubiquitin chain assembly complex (LUBAC) with hydrocarbon stapled alpha helices SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Bernal, F.; Whiting, A. L.; Aguilar, F.; Marshall, E.] NCI, NIH, CCR, LPDS, Frederick, MD 21701 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 425 BP S139 EP S139 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500408 ER PT J AU Chen, A Conley, B Hamilton, S Williams, M O'Dwyer, P Arteaga, C Gray, R McShane, L Li, S Rubinstein, L Patton, D Sazali, K Zwiebel, J Mitchell, E Smith, ML Dragaud, D Little, R Comis, R Abrams, J Flaherty, K AF Chen, A. Conley, B. Hamilton, S. Williams, M. O'Dwyer, P. Arteaga, C. Gray, R. McShane, L. Li, S. Rubinstein, L. Patton, D. Sazali, K. Zwiebel, J. Mitchell, E. Smith, M. L. Dragaud, D. Little, R. Comis, R. Abrams, J. Flaherty, K. TI NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial: A novel public-private partnership SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Chen, A.] NCI, Early Clin Trials Dev Program, Bethesda, MD 20892 USA. [Conley, B.] NCI, CDP, Bethesda, MD 20892 USA. [Hamilton, S.] MD Anderson, Pathol, Houston, TX USA. [Williams, M.] NCI, Mol Characterizat Lab, Frederick, MD 21701 USA. [O'Dwyer, P.] Univ Penn, Med, Philadelphia, PA 19104 USA. [Arteaga, C.] NCI, Med Hem Onc, Nashville, TN USA. [Gray, R.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [McShane, L.; Rubinstein, L.; Zwiebel, J.; Little, R.; Abrams, J.] NCI, CTEP, Rockville, MD USA. [Li, S.] Dana Farber, Hematol Oncol, Boston, MA USA. [Patton, D.] NCI, CBIIT, Rockville, MD USA. [Sazali, K.; Dragaud, D.; Comis, R.] ECOG ACRIN, Canc Res Grp, Philadelphia, PA USA. [Mitchell, E.] Thomas Jefferson Univ, Med Oncol, Philadelphia, PA USA. [Smith, M. L.] ECOG ACRIN, Cacner Advocacy Comm, Philadelphia, PA USA. [Flaherty, K.] Mass Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 418 BP S137 EP S137 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500401 ER PT J AU Coyne, GO Chen, AP Kummar, S Meehan, RS Collins, J Zlott, J Kelly, K Lenz, HJ Newman, EM Morgan, R Juwara, L Eiseman, J Beumer, JH Tomaszewski, J Doroshow, J AF Coyne, G. O'Sullivan Chen, A. P. Kummar, S. Meehan, R. S. Collins, J. Zlott, J. Kelly, K. Lenz, H. J. Newman, E. M. Morgan, R. Juwara, L. Eiseman, J. Beumer, J. H. Tomaszewski, J. Doroshow, J. TI Phase I trial of oral 5-fluoro-2 '-deoxycytidine with oral tetrahydrouridine in patients with advanced solid tumors SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Coyne, G. O'Sullivan; Chen, A. P.; Kummar, S.; Meehan, R. S.; Collins, J.; Zlott, J.; Tomaszewski, J.; Doroshow, J.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kelly, K.] Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA USA. [Lenz, H. J.] USC, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Newman, E. M.; Morgan, R.] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Juwara, L.] Frederick Natl Lab, DCTD, Frederick, MD USA. [Eiseman, J.; Beumer, J. H.] Univ Pittsburgh, UPMC, Inst Canc, Pittsburgh, PA 15260 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 269 BP S90 EP S90 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500259 ER PT J AU Ferry-Galow, K Makhlouf, H Kinders, R Chen, A Doroshow, JH Parchment, R AF Ferry-Galow, K. Makhlouf, H. Kinders, R. Chen, A. Doroshow, J. H. Parchment, R. TI Suitability of post-diagnostic core needle tumor biopsies for correlative studies of molecular drug action (pharmacodynamics) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Ferry-Galow, K.; Kinders, R.; Parchment, R.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Toxicol & Pharmacol, Appl Dev Directorate, Frederick, MD USA. [Makhlouf, H.] NCI, Div Canc Treatment & Diag, Canc Diag Program, Rockville, MD USA. [Chen, A.; Doroshow, J. H.] NCI, Div Canc Treatment & Diag, Early Clin Trials Dev Program, Bethesda, MD 20892 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 185 BP S65 EP S66 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500179 ER PT J AU Houghton, P Kang, M Reynolds, CP Kurmasheva, R Smith, M AF Houghton, P. Kang, M. Reynolds, C. P. Kurmasheva, R. Smith, M. TI Initial testing by the Pediatric Preclinical Testing Program (PPTP) of the ATR Inhibitor VX-970 alone or in combination with cisplatin in pediatric solid tumor xenografts SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Houghton, P.; Kurmasheva, R.] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Kang, M.; Reynolds, C. P.] Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, Lubbock, TX 79430 USA. [Smith, M.] NCI, Canc Treatment & Evaluat Program, Bethesda, MD 20892 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 132 BP S49 EP S49 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500126 ER PT J AU Meehan, RS Kummar, S Coyne, GO Zlott, J Horneffer, Y Juwara, L Streicher, H Sharon, E Harris, P Doroshow, JH Chen, A AF Meehan, R. S. Kummar, S. Coyne, G. O'Sullivan Zlott, J. Horneffer, Y. Juwara, L. Streicher, H. Sharon, E. Harris, P. Doroshow, J. H. Chen, A. TI Phase I study of ganetespib and ziv-aflibercept in patients with advanced gastrointestinal carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Meehan, R. S.; Kummar, S.; Coyne, G. O'Sullivan; Zlott, J.; Horneffer, Y.; Streicher, H.; Sharon, E.; Harris, P.; Doroshow, J. H.; Chen, A.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Juwara, L.] Frederick Natl Lab Canc Res, DCTD, Frederick, MD USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 466 BP S152 EP S153 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500448 ER PT J AU Strauss, J Heery, C Schlom, J Madan, RA Lamping, E Marte, J Cordes, L Lan, Y Mahnke, L Helwig, C Lo, KM Gulley, J AF Strauss, J. Heery, C. Schlom, J. Madan, R. A. Lamping, E. Marte, J. Cordes, L. Lan, Y. Mahnke, L. Helwig, C. Lo, K. M. Gulley, J. TI A phase I, open-label, multiple-ascending-dose trial to investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity of M7824, a novel bifunctional fusion protein targeting the PD-L1 and TGF-beta pathways, in patients with metastatic or locally advanced solid tumors SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Strauss, J.] NCI, Ctr Canc Res, NIH, Med Oncol Serv, Bethesda, MD 20892 USA. [Heery, C.; Schlom, J.; Madan, R. A.] NCI, Ctr Canc Res, NIH, Genitourinary Malignancies Branch,Lab Tumor Immun, Bethesda, MD 20892 USA. [Lamping, E.] NCI, NIH, Off Clin Director, Bethesda, MD 20892 USA. [Marte, J.] NCI, NIH, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. [Cordes, L.] NCI, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Lan, Y.; Lo, K. M.] EMD Serono Inc, TIP Immunooncol, Billerca, MA USA. [Mahnke, L.] EMD Serono Inc, Clin Dev, Billerca, MA USA. [Helwig, C.] Merck KGaA, Biostat Oncol, Darmstadt, Germany. [Gulley, J.] NCI, NIH, Genitourinary Malignancies Branch, Lab Tumor Immunol & Biol,Med Oncol Serv,Ctr Canc, Bethesda, MD 20892 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 314 BP S103 EP S104 PG 2 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500301 ER PT J AU Teicher, B Kunkel, M Evans, D Delosh, R Laudeman, J Chad, O Reinhart, R Michael, S Thomas, S Kaur, G Monks, A Morris, J AF Teicher, B. Kunkel, M. Evans, D. Delosh, R. Laudeman, J. Chad, O. Reinhart, R. Michael, S. Thomas, S. Kaur, G. Monks, A. Morris, J. TI Adult and pediatric sarcoma cell line screen findings in Notch, DNA repair and cell cycle gene and miR expression and compound response SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Teicher, B.; Kunkel, M.; Kaur, G.; Morris, J.] NCI, DCTD, Bethesda, MD 20892 USA. [Evans, D.; Delosh, R.; Laudeman, J.; Chad, O.; Reinhart, R.; Michael, S.; Thomas, S.; Monks, A.; Morris, J.] Leidos, Frederick Natl Lab Canc Res, Target Validat & Screening Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 232 BP S78 EP S78 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500222 ER PT J AU Wan, X Issak, S Yeung, C McCalla, A Helman, L AF Wan, X. Issak, S. Yeung, C. McCalla, A. Helman, L. TI Histone deacetylase inhibition triggers suppression of the IGF-1R/Akt pathway in rhabdomyosarcoma and Pax3-Foxo1 in alveolar rhabdomyosarcoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Wan, X.; Issak, S.; Yeung, C.; McCalla, A.; Helman, L.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 102 BP S40 EP S40 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500095 ER PT J AU Yang, SX Nguyen, D Hollingshead, M Rubinstein, L Doroshow, JH AF Yang, S. X. Nguyen, D. Hollingshead, M. Rubinstein, L. Doroshow, J. H. TI DNMT3B expression patterns in human lymphomas and xenograft tumors SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics CY NOV 29-DEC 02, 2016 CL Munich, GERMANY SP EORTC, Natl Canc Inst, Amer Assoc Canc Res C1 [Yang, S. X.; Nguyen, D.] NCI, DCTD NCTVL, Bethesda, MD 20892 USA. [Hollingshead, M.] NCI, DCTD BTB, Bethesda, MD 20892 USA. [Rubinstein, L.] NCI, DCTD BRB, Bethesda, MD 20892 USA. [Doroshow, J. H.] NCI, DCTD, Bethesda, MD 20892 USA. NR 0 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD DEC PY 2016 VL 69 SU 1 MA 178 BP S63 EP S63 PG 1 WC Oncology SC Oncology GA EF7IO UT WOS:000390503500172 ER PT J AU Nadon, NL AF Nadon, Nancy L. TI The NIA interventions testing program announces the 2016 solicitation of proposals SO AGING CELL LA English DT Editorial Material DE aging; health span; lifespan ID LIFE-SPAN; MICE AB The NIA Interventions Testing Program encourages participation by the research community though its annual call-for-proposals. This Short Take serves as a brief introduction to the program and announcement for the next proposal receipt date. C1 [Nadon, Nancy L.] NIA, Bethesda, MD 20892 USA. RP Nadon, NL (reprint author), NIA, Div Aging Biol, 7201 Wisconsin Ave,GW 3N300, Bethesda, MD 20892 USA. EM nadonn@nia.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD DEC PY 2016 VL 15 IS 6 BP 1153 EP 1153 DI 10.1111/acel.12542 PG 1 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EI1ZR UT WOS:000392286200016 ER PT J AU Tanamas, SK Wong, E Backholer, K Abdullah, A Wolfe, R Barendregt, J Peeters, A AF Tanamas, Stephanie K. Wong, Evelyn Backholer, Kathryn Abdullah, Asnawi Wolfe, Rory Barendregt, Jan Peeters, Anna TI Age of onset of obesity and risk of type 2 diabetes SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH LA English DT Article DE obesity; body mass index; obese-years; age of onset; type 2 diabetes ID DURATION AB Objective: To compare a simple measure - age of onset of obesity - to an obese-years construct (a product of duration and magnitude of obesity) as risk factors for type 2 diabetes. Method: Participants from the Framingham Heart Study who were not obese and did not have diabetes at baseline were included (n=4,320). The Akaike Information Criterion (AIC) was computed to compare four Cox proportional hazards models with incident diabetes as the outcome and: (i) obese-years; (ii) age of onset of obesity; (iii) body mass index (BMI); and (iv) age of onset of obesity plus magnitude of BMI combined, as exposures. Results: AIC indicated that the model with obese-years provided a more effective explanation of incidence of type 2 diabetes compared to the remaining three models. Models including age of onset of obesity plus BMI were not appreciably different from the model with BMI alone, except in those aged >= 60. Conclusions: While obese-years was the optimal obesity construct to explain risk of type 2 diabetes, age of onset may be a useful, practical addition to current BMI in the elderly. Implications: Where computation of obese-years is not possible or impractical, age of onset of obesity combined with BMI may provide a useful alternative. C1 [Tanamas, Stephanie K.; Wong, Evelyn; Backholer, Kathryn; Peeters, Anna] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Abdullah, Asnawi] Univ Muhammadiyah Aceh, Dept Biostat & Populat Hlth, Fac Publ Hlth, Banda Aceh, Indonesia. [Abdullah, Asnawi] Monash Univ, Dept Epidemiol & Prevent Med, Fac Publ Hlth, Clayton, Vic, Australia. [Barendregt, Jan] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. RP Tanamas, SK (reprint author), NIDDK, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM stephanie.tanamas@nih.gov FU National Health and Medical Research Council (NHMRC) [1044366]; NHLBI FX This study was supported by the National Health and Medical Research Council (NHMRC 1044366). The FHS is conducted and supported by the NHLBI in collaboration with study investigators. The manuscript was prepared using a limited access data set obtained from the NHLBI and does not necessarily reflect the opinions or views of the FHS or the NHLBI. The authors thank the FHS investigators for permission to use their data set for the present study. NR 7 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1326-0200 EI 1753-6405 J9 AUST NZ J PUBL HEAL JI Aust. N. Z. Publ. Health PD DEC PY 2016 VL 40 IS 6 BP 579 EP 581 DI 10.1111/1753-6405.12593 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI7DB UT WOS:000392656600016 PM 27774719 ER PT J AU Smith, CL Reese, TS AF Smith, Carolyn L. Reese, Thomas S. TI Adherens Junctions Modulate Diffusion between Epithelial Cells in Trichoplax adhaerens SO BIOLOGICAL BULLETIN LA English DT Article ID EVOLUTION; ORIGIN; PLACOZOA; LOCOMOTION; CNIDARIANS; SYSTEMS; GENOME; BRAIN; VIEW AB Trichoplax adhaerens is the sole named member of Placozoa, an ancient metazoan phylum. This coin-shaped animal glides on ventral cilia to find and digest algae on the substrate. It has only six cell types, all but two of which are incorporated into the epithelium that encloses it. The upper epithelium is thin, composed of a pavement of relatively large polygonal disks, each bearing a cilium. The lower epithelium is thick and composed primarily of narrow ciliated cells that power locomotion. Interspersed among these cells are two different secretory cells: one containing large lipophilic granules that, when released, lyse algae under the animal; the other, less abundant, is replete with smaller secretory granules containing neuropeptides. All cells within both epithelia are joined by adherens junctions that are stabilized by apical actin networks. Cells are held in place during shape changes or under osmotic stress, but dissociate in low calcium. Neither tight, septate, nor gap junctions are evident, leaving only the adherens junction to control the permeability of the epithelium. Small (<4 kDa) fluorescent dextrans introduced into artificial seawater readily penetrate into the animal between the cells. Larger dextrans enter slowly, except in animals treated with reduced calcium, indicating that the adherens junctions form a circumferential belt around each cell that impedes diffusion into the animal. During feeding, the limited permeability of the adherens junctions helps to confine material released from lysed algae within the narrow space under the animal, where it is absorbed by endocytosis. C1 [Smith, Carolyn L.; Reese, Thomas S.] NINDS, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. RP Reese, TS (reprint author), NINDS, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM treese@mbl.edu NR 36 TC 0 Z9 0 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0006-3185 EI 1939-8697 J9 BIOL BULL-US JI Biol. Bull. PD DEC PY 2016 VL 231 IS 3 BP 216 EP 224 PG 9 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA EI2WA UT WOS:000392347900006 PM 28048952 ER PT J AU Yonemori, K Hirakawa, A Kawachi, A Kinoshita, F Okuma, H Nishikawa, T Tamura, K Fujiwara, Y Takebe, N AF Yonemori, Kan Hirakawa, Akihiro Kawachi, Asuka Kinoshita, Fumie Okuma, Hitomi Nishikawa, Tadaaki Tamura, Kenji Fujiwara, Yasuhiro Takebe, Naoko TI Drug induced interstitial lung disease in oncology phaseI trials SO CANCER SCIENCE LA English DT Article DE Drug induced interstitial lung disease; investigational new drug; oncology; phaseI trial pulmonary toxicity ID CANCER-STUDY-GROUP; JAPANESE PATIENTS; GEFITINIB AB Interstitial lung disease is a serious drug-related condition that can cause life threatening organ failure. The incidence and risk factors of drug-induced interstitial lung disease (DILD) are unknown in oncology phaseI trials. This study analyzed clinical information from 8906 patients with malignancies who were enrolled in 470 phaseI trials sponsored by the Cancer Therapy Evaluation Program, National Cancer Institute, from 1988 to 2014. Logistic and Cox statistical analyses were utilized to determine clinical differences between patients who developed DILD and patients who did not. In this study, the overall incidence rate of patients with pulmonary toxicity was 2.7%. The overall incidence rate for DILD was 0.77%, whereas for grade3 or 4 DILD it was 0.31%. Median time to occurrence of DILD was 1.4months. The Cox hazard analysis indicated smaller body surface area and a combination of thoracic radiation with investigational drug regimens were significant risk factors for time to occurrence of interstitial lung disease. Investigators should carefully monitor for DILD in oncology patients enrolled in phaseI trials with identified risk factors. A 6-month observation period would be sufficient to detect the onset of most DILD in such patients. C1 [Yonemori, Kan; Kawachi, Asuka; Okuma, Hitomi; Nishikawa, Tadaaki; Tamura, Kenji; Fujiwara, Yasuhiro] Natl Canc Ctr, Dept Breast & Med Oncol, Natl Canc Ctr, Tokyo, Japan. [Yonemori, Kan; Fujiwara, Yasuhiro] Natl Canc Ctr, Off Adv Med Care Evaluat, Tokyo, Japan. [Yonemori, Kan; Takebe, Naoko] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Hirakawa, Akihiro; Kinoshita, Fumie] Nagoya Univ, Biostat & Bioinformat Sect, Ctr Adv Med & Clin Res, Grad Sch Med, Nagoya, Aichi, Japan. RP Takebe, N (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA.; Yonemori, K (reprint author), Natl Canc Ctr, Dept Breast & Med Oncol, Natl Canc Ctr Hosp, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. EM kyonemor@ncc.go.jp; takeben@mail.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD DEC PY 2016 VL 107 IS 12 BP 1830 EP 1836 DI 10.1111/cas.13087 PG 7 WC Oncology SC Oncology GA EH7VT UT WOS:000391981400014 PM 27685762 ER PT J AU Abu-Tayeh, H Weidenfeld, K Zhilin-Roth, A Schif-Zuck, S Thaler, S Cotarelo, C Tan, TZ Thiery, JP Green, JE Klorin, G Sabo, E Sleeman, JP Tzukerman, M Barkan, D AF Abu-Tayeh, Hanan Weidenfeld, Keren Zhilin-Roth, Alisa Schif-Zuck, Sagi Thaler, Sonja Cotarelo, Cristina Tan, Tuan Z. Thiery, Jean P. Green, Jeffrey E. Klorin, Geula Sabo, Edmond Sleeman, Jonathan P. Tzukerman, Maty Barkan, Dalit TI 'Normalizing' the malignant phenotype of luminal breast cancer cells via alpha(v) beta(3)-integrin SO CELL DEATH & DISEASE LA English DT Article ID BASEMENT-MEMBRANE CULTURES; EMBRYONIC STEM-CELLS; ADULT HUMAN BREAST; MAMMARY-GLAND; EXPERIMENTAL PLATFORM; BIOLOGICAL-ACTIVITY; TUMOR-GROWTH; IN-VITRO; INTEGRIN; MORPHOGENESIS AB Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v) beta(3) integrin (Int-alpha v beta 3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int-alpha v beta 3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids' reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAM(high)CD49f(low)CD24(+) and Int-alpha v beta 3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int-alpha v beta 3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int-alpha v beta 3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int-alpha v beta 3 can potentially promote 'normalization' of their malignant phenotype and may prevent the malignant cells from progressing. C1 [Abu-Tayeh, Hanan; Weidenfeld, Keren; Zhilin-Roth, Alisa; Schif-Zuck, Sagi; Barkan, Dalit] Univ Haifa, Dept Human Biol, Haifa, Israel. [Thaler, Sonja; Sleeman, Jonathan P.] Heidelberg Univ, Med Fac Mannheim, Ctr Biomed & Med Technol Mannheim CBTM, Mannheim, Germany. [Cotarelo, Cristina] Univ Med Ctr Mainz, Dept Pathol, Langenbeckstr, Mainz, Germany. [Tan, Tuan Z.] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore. [Thiery, Jean P.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore. [Thiery, Jean P.] ASTAR, Inst Mol & Cell Biol, Singapore, Singapore. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Klorin, Geula; Sabo, Edmond] Rambam Med Ctr, Dept Pathol, Haifa, Israel. [Sleeman, Jonathan P.] Karlsruhe Inst Technol, Inst Genet & Toxikol, Campus Nord, Karlsruhe, Germany. [Tzukerman, Maty] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Tzukerman, Maty] Technion Israel Inst Technol, Res Inst, Haifa, Israel. RP Barkan, D (reprint author), Univ Haifa, Dept Human Biol, Fac Nat Sci, IL-31905 Haifa, Israel. EM dalitbrk@gmail.com FU University of Haifa; Daniel M. Soref Charitable Trust; Skirball Foundation; Richard D. Satell Foundation; Sohnis family; Forman family; Israel Science Foundation [62/10 MT] FX We thank Dr. Amiram Ariel for the use of FACSCanto II (BD) equipment. We Thank Professor Israel Voldavsky and Dr. Neta Ilan for providing the immunohistochemistry platform. This research was supported by the British and Swiss friends of University of Haifa (DB) and by grants from the Daniel M. Soref Charitable Trust, Skirball Foundation, Richard D. Satell Foundation, Sohnis and Forman families and the Israel Science Foundation (Grant No. 62/10 MT). NR 55 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 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD DEC PY 2016 VL 7 AR e2491 DI 10.1038/cddis.2016.387 PG 15 WC Cell Biology SC Cell Biology GA EH5LY UT WOS:000391815800012 PM 27906177 ER PT J AU Chen, X Cao, XW Sun, XH Lei, R Chen, PF Zhao, YX Jiang, YH Yin, J Chen, R Ye, DJ Wang, Q Liu, ZJ Liu, SH Cheng, CY Mao, J Hou, YY Wang, ML Siebenlist, U Chin, YE Wang, Y Cao, L Hu, GH Zhang, XR AF Chen, Xi Cao, Xinwei Sun, Xiaohua Lei, Rong Chen, Pengfei Zhao, Yongxu Jiang, Yuhang Yin, Jie Chen, Ran Ye, Deji Wang, Qi Liu, Zhanjie Liu, Sanhong Cheng, Chunyan Mao, Jie Hou, Yingyong Wang, Mingliang Siebenlist, Ulrich Chin, Y. Eugene Wang, Ying Cao, Liu Hu, Guohong Zhang, Xiaoren TI Bcl-3 regulates TGF beta signaling by stabilizing Smad3 during breast cancer pulmonary metastasis SO CELL DEATH & DISEASE LA English DT Article ID GROWTH-FACTOR-BETA; CANDIDATE PROTOONCOGENE BCL-3; FAMILY-MEMBER BCL-3; ONCOPROTEIN BCL-3; P50 HOMODIMERS; ROLES; CELLS; DEGRADATION; ACTIVATION; TRANSITION AB Transforming growth factor beta (TGF beta) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the I kappa B family, serves as a critical regulator in TGF beta signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGF beta signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGF beta treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis. C1 [Chen, Xi; Cao, Xinwei; Sun, Xiaohua; Lei, Rong; Chen, Pengfei; Zhao, Yongxu; Jiang, Yuhang; Yin, Jie; Chen, Ran; Ye, Deji; Wang, Qi; Liu, Zhanjie; Liu, Sanhong; Cheng, Chunyan; Mao, Jie; Chin, Y. Eugene; Wang, Ying; Hu, Guohong; Zhang, Xiaoren] Shanghai Jiao Tong Univ, Sch Med SJTUSM, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200025, Peoples R China. [Chen, Xi; Cao, Xinwei; Sun, Xiaohua; Lei, Rong; Chen, Pengfei; Zhao, Yongxu; Jiang, Yuhang; Yin, Jie; Chen, Ran; Ye, Deji; Wang, Qi; Liu, Zhanjie; Liu, Sanhong; Cheng, Chunyan; Mao, Jie; Chin, Y. Eugene; Wang, Ying; Hu, Guohong; Zhang, Xiaoren] Chinese Acad Sci, SIBS, Shanghai 200025, Peoples R China. [Hou, Yingyong] Fudan Univ, Zhongshan Hosp, Dept Pathol, Sch Med, Shanghai 200032, Peoples R China. [Wang, Mingliang] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Gen Surg, Sch Med, Shanghai 200025, Peoples R China. [Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chin, Y. Eugene] Shanghai Jiao Tong Univ, Collaborat Innovat Ctr Syst Biomed, Sch Med, Shanghai 200240, Peoples R China. [Cao, Liu] Liaoning Prov Collaborat Innovat Ctr Aging Relate, Shenyang 110001, Peoples R China. [Cao, Liu] China Med Univ, Key Iaboratory Med Cell Biol, Shenyang 110001, Peoples R China. RP Hu, GH; Zhang, XR (reprint author), Shanghai Jiao Tong Univ, Inst Hlth Sci, Sch Med, Key Lab Stem Cell Biol,Shanghai Inst Biol Sci, Room 1126,Biol Res Bldg A,320 Yueyang Rd, Shanghai 200025, Peoples R China. EM ghhu@sibs.ac.cn; xrzhang@sibs.ac.cn FU National Basic Research Program [2014CB541904, 2014CB943600]; National Natural Science Foundation of China [31570902, 31370881] FX This study was supported by grants from the National Basic Research Program (2014CB541904, 2014CB943600), the National Natural Science Foundation of China (31570902, 31370881). We thank Drs. F Liu for her gifts of antibodies, A Chariot and Y Zhang for their constructs, H Wei and Y Liu for their suggestions, and Q Jing for his support. NR 47 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 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD DEC PY 2016 VL 7 AR e2508 DI 10.1038/cddis.2016.405 PG 12 WC Cell Biology SC Cell Biology GA EH5LY UT WOS:000391815800026 PM 27906182 ER PT J AU Griner, LAM Zhang, XH Guha, R McKnight, C Goldlust, IS Lal-Nag, M Wilson, K Michael, S Titus, S Shinn, P Thomas, CJ Ferrer, M AF Griner, Lesley A. Mathews Zhang, Xiaohu Guha, Rajarshi McKnight, Crystal Goldlust, Ian S. Lal-Nag, Madhu Wilson, Kelli Michael, Sam Titus, Steve Shinn, Paul Thomas, Craig J. Ferrer, Marc TI Large-scale pharmacological profiling of 3D tumor models of cancer cells SO CELL DEATH & DISEASE LA English DT Article ID BREAST-CANCER; DNA-REPAIR; STEM-CELLS; PHARMACOKINETICS; METABOLISM; PHARMACODYNAMICS; CARFILZOMIB; VALIDATION; SPHEROIDS; SCREEN AB The discovery of chemotherapeutic agents for the treatment of cancer commonly uses cell proliferation assays in which cells grow as two-dimensional (2D) monolayers. Compounds identified using 2D monolayer assays often fail to advance during clinical development, most likely because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three-dimensional (3D) cellular systems have been explored as enabling more predictive in vitro tumor models for drug discovery. To date, small-scale screens have demonstrated that pharmacological responses tend to differ between 2D and 3D cancer cell growth models. However, the limited scope of screens using 3D models has not provided a clear delineation of the cellular pathways and processes that differentially regulate cell survival and death in the different in vitro tumor models. Here we sought to further understand the differences in pharmacological responses between cancer tumor cells grown in different conditions by profiling a large collection of 1912 chemotherapeutic agents. We compared pharmacological responses obtained from cells cultured in traditional 2D monolayer conditions with those responses obtained from cells forming spheres versus cells already in 3D spheres. The target annotation of the compound library screened enabled the identification of those key cellular pathways and processes that when modulated by drugs induced cell death in all growth conditions or selectively in the different cell growth models. In addition, we also show that many of the compounds targeting these key cellular functions can be combined to produce synergistic cytotoxic effects, which in many cases differ in the magnitude of their synergism depending on the cellular model and cell type. The results from this work provide a high-throughput screening framework to profile the responses of drugs both as single agents and in pairwise combinations in 3D sphere models of cancer cells. C1 [Griner, Lesley A. Mathews; Zhang, Xiaohu; Guha, Rajarshi; McKnight, Crystal; Goldlust, Ian S.; Lal-Nag, Madhu; Wilson, Kelli; Michael, Sam; Titus, Steve; Shinn, Paul; Thomas, Craig J.; Ferrer, Marc] NIH, Natl Ctr Advancing Translat Sci, Div Preclin Innovat, Bldg 10, Bethesda, MD 20892 USA. RP Griner, LAM; Ferrer, M (reprint author), NCATS, 9800 Med Ctr Dr Bldg B,Room 3005 Stop Code 3370, Rockville, MD 20850 USA. EM mathews.lesley1@gmail.com; ferrerm@mail.nih.gov FU NIH Intramural Research Program at NCATS FX We would like to thank Kyle Brimacombe for the formatting of the figures for the manuscript, Christopher Dextras for help with quantitation of the apoptosis dot blots, and Dr Serena Silver for critical reading of the manuscript. This work was funded by the NIH Intramural Research Program at NCATS. NR 42 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 DEC PY 2016 VL 7 AR e2492 DI 10.1038/cddis.2016.360 PG 11 WC Cell Biology SC Cell Biology GA EH5LY UT WOS:000391815800004 ER PT J AU Lipton, SA Rezaie, T Nutter, A Lopez, KM Parker, J Kosaka, K Satoh, T McKercher, SR Masliah, E Nakanishi, N AF Lipton, Stuart A. Rezaie, Tayebeh Nutter, Anthony Lopez, Kevin M. Parker, James Kosaka, Kunio Satoh, Takumi McKercher, Scott R. Masliah, Eliezer Nakanishi, Nobuki TI Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models SO CELL DEATH & DISEASE LA English DT Article ID CARNOSIC ACID; MOUSE MODEL; TRANSGENIC MOUSE; PROTEIN; ANTIOXIDANT; MECHANISMS; EXPRESSION; DEPLETION; DEFICITS; INJURY AB Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-beta (A beta)-peptide. Carnosic acid (CA), a chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric A beta. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric A beta. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, A beta plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the 'generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited. C1 [Lipton, Stuart A.; Lopez, Kevin M.; Parker, James; McKercher, Scott R.; Nakanishi, Nobuki] Scintillon Inst, Neurodegenerat Dis Ctr, 6868 Nancy Ridge Dr, San Diego, CA 92121 USA. [Lipton, Stuart A.; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Lipton, Stuart A.; Rezaie, Tayebeh; Nutter, Anthony; Lopez, Kevin M.; Parker, James; Satoh, Takumi; McKercher, Scott R.; Nakanishi, Nobuki] Sanford Burnham Prebys Med Discovery Inst, Neurosci & Aging Res Ctr, La Jolla, CA 92037 USA. [Kosaka, Kunio] Nagase CO LTD, Ctr Res & Dev, Kobe, Hyogo 6512241, Japan. [Rezaie, Tayebeh] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Satoh, Takumi] Tokyo Univ Technol, Sch Biosci & Biotechnol, Dept Antiaging Food Res, Tokyo 1920982, Japan. RP Lipton, SA; Nakanishi, N (reprint author), Scintillon Inst, Neurodegenerat Dis Ctr, 6868 Nancy Ridge Dr, San Diego, CA 92121 USA.; Lipton, SA; Nakanishi, N (reprint author), Univ Calif San Diego, 6868 Nancy Ridge Dr, San Diego, CA 92121 USA. EM slipton@ucsd.edu; nnakanishi@scintillon.org FU NIH [R21 NS080799, P01 HD029587, P30 NS076411]; Brain & Behavior Research Foundation FX This work was supported in part by NIH grants R21 NS080799, P01 HD029587, and the La Jolla Interdisciplinary Neuroscience Center Core Grant P30 NS076411 and by a Distinguished Investigator Award from the Brain & Behavior Research Foundation (to SAL). WE appreciate the contributions of Sara Sanz-Blasco, Zaneta Cha, Brian Lee and Marcos Valencia. NR 28 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD DEC PY 2016 VL 7 AR e2499 DI 10.1038/cddis.2016.389 PG 8 WC Cell Biology SC Cell Biology GA EH5LY UT WOS:000391815800013 PM 27906174 ER PT J AU Kadri, SS Miller, AC Hohmann, S Bonne, S Nielsen, C Wells, C Gruver, C Quraishi, SA Sun, JF Cai, RM Morris, PE Freeman, BD Holmes, JH Cairns, BA Suffredini, AF AF Kadri, Sameer S. Miller, Andrew C. Hohmann, Samuel Bonne, Stephanie Nielsen, Carrie Wells, Carmen Gruver, Courtney Quraishi, Sadeq A. Sun, Junfeng Cai, Rongman Morris, Peter E. Freeman, Bradley D. Holmes, James H. Cairns, Bruce A. Suffredini, Anthony F. CA US Critical Illness Injury Trials Smoke Inhalation Associated Acute TI Risk Factors for In-Hospital Mortality in Smoke Inhalation- Associated Acute Lung Injury Data From 68 United States Hospitals SO CHEST LA English DT Article DE adult respiratory distress syndrome; burns; epidemiology; risk factors; smoke inhalation ID BURN PATIENTS; MECHANICAL VENTILATION; RESUSCITATION; PROGNOSIS; OUTCOMES; SCORE AB BACKGROUND: Mortality after smoke inhalation-associated acute lung injury (SI-ALI) remains substantial. Age and burn surface area are risk factors of mortality, whereas the impact of patient-and center-level variables and treatments on survival are unknown. METHODS: We performed a retrospective cohort study of burn and non-burn centers at 68 US academic medical centers between 2011 and 2014. Adult inpatients with SI-ALI were identified using an algorithm based on a billing code for respiratory conditions from smoke inhalation who were mechanically ventilated by hospital day 4, with either a length-of-stay >= 5 days or death within 4 days of hospitalization. Predictors of in-hospital mortality were identified using logistic regression. The primary outcome was the odds ratio for in-hospital mortality. RESULTS: A total of 769 patients (52.9 +/- 18.1 years) with SI-ALI were analyzed. In-hospital mortality was 26% in the SI-ALI cohort and 50% in patients with >= 20% surface burns. In addition to age > 60 years (OR 5.1, 95% CI 2.53-10.26) and >= 20% burns (OR 8.7, 95% CI 4.55-16.75), additional risk factors of in-hospital mortality included initial vasopressor use (OR 5.0, 95% CI 3.16-7.91), higher diagnostic-related group-based risk-of-mortality assignment and lower hospital bed capacity (OR 2.3, 95% CI 1.23-4.15). Initial empiric antibiotics (OR 0.93, 95% CI 0.58-1.49) did not impact survival. These new risk factors improved mortality prediction by 9.9% (P < .001). CONCLUSIONS: In addition to older age and major surface burns, mortality in SI-ALI is predicted by initial vasopressor use, higher diagnostic-related group-based risk-of-mortality assignment, and care at centers with < 500 beds, but not by initial antibiotic therapy. C1 [Kadri, Sameer S.; Miller, Andrew C.; Sun, Junfeng; Cai, Rongman; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. [Kadri, Sameer S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Miller, Andrew C.] West Virginia Univ, Dept Emergency Med, Morgantown, WV 26506 USA. [Hohmann, Samuel] Univ Hlth Syst Consortium, Chicago, IL USA. [Hohmann, Samuel] Rush Univ, Dept Hlth Syst Management, Chicago, IL 60612 USA. [Bonne, Stephanie; Freeman, Bradley D.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Nielsen, Carrie; Cairns, Bruce A.] Univ North Carolina Hosp, North Carolina Jaycee Burn Ctr, Chapel Hill, NC USA. [Wells, Carmen; Gruver, Courtney; Holmes, James H.] Wake Forest Sch Med, Wake Forest Med Ctr, Dept Gen Surg, Winston Salem, NC USA. [Quraishi, Sadeq A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anethesia Crit Care & Pain Med, Boston, MA 02114 USA. [Quraishi, Sadeq A.] Harvard Med Sch, Dept Anesthesia, Boston, MA USA. [Morris, Peter E.] Wake Forest Sch Med, Wake Forest Med Ctr, Div Pulm & Crit Care Med, Winston Salem, NC USA. RP Kadri, SS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM sameer.kadri@nih.gov FU Intramural Research Program, National Institutes of Health FX This study was funded by the Intramural Research Program, National Institutes of Health. NR 30 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2016 VL 150 IS 6 BP 1260 EP 1268 DI 10.1016/j.chest.2016.06.008 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EI1VQ UT WOS:000392274600026 PM 27316558 ER PT J AU Drabek, J Smolikova, M Kalendar, R Pinto, FAL Pavlousek, P Kleparnik, K Frebort, I AF Drabek, Jiri Smolikova, Michaela Kalendar, Ruslan Pinto, Fernando A. Lopes Pavlousek, Pavel KleparnIk, Karel Frebort, Ivo TI Design and validation of an STR hexaplex assay for DNA profiling of grapevine cultivars SO ELECTROPHORESIS LA English DT Article DE Grapevine DNA analysis; Multiplex PCR; STRs; Vitis vinifera L ID VITIS-VINIFERA L.; POLYMERASE-CHAIN-REACTION; MICROSATELLITE MARKERS; MOLECULAR TOOLS; GENETIC-MARKERS; MULTIPLEX PCR; IDENTIFICATION; WINES; SET; DIFFERENTIATION AB Although the analysis of length polymorphism at STR loci has become a method of choice for grape cultivar identification, the standardization of methods for this purpose lags behind that of methods for DNA profiling in human and animal forensic genetics. The aim of this study was thus to design and validate a grapevine STR protocol with a practically useful level of multiplexing. Using free bioinformatics tools, published primer sequences, and nucleotide databases, we constructed and optimized a primer set for the simultaneous analysis of six STR loci (VVIi51, scu08vv, scu05vv, VVMD17, VrZAG47, and VrZAG83) by multiplex PCR and CE with laser-induced fluorescence, and tested it on 90 grape cultivars. The new protocol requires subnanogram quantities of the DNA template and enables automated, high-throughput genetic analysis with reasonable discriminatory power. As such, it represents a step toward further standardization of grape DNA profiling. C1 [Drabek, Jiri] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Hnevotinska 5, Olomouc 77900, Czech Republic. [Smolikova, Michaela] Palacky Univ, Dept Biochem, Olomouc, Czech Republic. [Kalendar, Ruslan] Univ Helsinki, LUKE BI Plant Genome Dynam, Inst Biotechnol, Helsinki, Finland. [Kalendar, Ruslan] Minist Educ & Sci Republ Kazakhstan, Sci Comm, RSE Natl Ctr Biotechnol, Astana, Kazakhstan. [Pinto, Fernando A. Lopes] Uppsala Univ, Dept Photochem & Mol Sci, Uppsala, Sweden. [Pavlousek, Pavel] Mendel Univ Brno, Dept Viticulture & Enol, Brno, Czech Republic. [KleparnIk, Karel] ASCR, Inst Analyt Chem, Brno, Czech Republic. [Frebort, Ivo] Palacky Univ, Fac Sci, Ctr Reg Hana Biotechnol & Agr Res, Olomouc, Czech Republic. RP Drabek, J (reprint author), Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Hnevotinska 5, Olomouc 77900, Czech Republic. EM jiri.drabek@upol.cz RI Kalendar, Ruslan/D-9751-2012 OI Kalendar, Ruslan/0000-0003-3986-2460 FU [LO1304]; [LM2010004]; [TE02000058] FX This work was supported by grants LO1304, LM2010004, and TE02000058. We thank Drs. S. Lalet, N. Goto-Yamamoto, M. Galimberti, Nikos, J. Benes, O. Jandurova, P. Kocar, P. Madera, M. Michlovsky, P. Pavlousek, J. Stavek, and M. Prazak for grapevine samples. Wealso thank Profs. L. Bocak, M. Navratil, and Dr. M. Valarik (Olomouc, the Czech Republic) for generously providing access to instruments, and Veronika Toupalikova, MSc. for technical help in addressing reviewers' comments. NR 69 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 EI 1522-2683 J9 ELECTROPHORESIS JI Electrophoresis PD DEC PY 2016 VL 37 IS 23-24 BP 3059 EP 3067 DI 10.1002/elps.201600068 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA EI3VW UT WOS:000392421400003 PM 27696463 ER PT J AU Chawla, N Blanch-Hartigan, D Virgo, KS Ekwueme, DU Han, XS Forsythe, L Rodriguez, J McNeel, TS Yabroff, KR AF Chawla, Neetu Blanch-Hartigan, Danielle Virgo, Katherine S. Ekwueme, Donatus U. Han, Xuesong Forsythe, Laura Rodriguez, Juan McNeel, Timothy S. Yabroff, K. Robin TI Quality of Patient-Provider Communication Among Cancer Survivors: Findings From a Nationally Representative Sample SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID PROSTATE-CANCER; UNITED-STATES; CARE PLANS; PHYSICAL-ACTIVITY; OF-CARE; EXPERIENCES; OUTCOMES; BREAST; SURVEILLANCE; TIME AB Purpose Although patient-provider communication is an essential component of health care delivery, little is known about the quality of these discussions among patients with cancer. Methods Data are from the 2011 Medical Expenditure Panel Survey Experiences with Cancer survey among 1,202 adult cancer survivors. We evaluated discussions with any provider after a cancer diagnosis about: (1) follow-up care; (2) late or long-term treatment effects; (3) lifestyle recommendations, such as diet, exercise, and quitting smoking; and (4) emotional or social needs. Using a response scale ranging from "did not discuss" to "discussed in detail," a summary score was constructed to define communication quality as high, medium, or low. Patient factors associated with the quality of provider discussions were examined using multivariable polytomous logistic regression analyses. Results At the time of the survey, approximately one half of the patients (46%) were either within 1 year (24.1%) or between 1 and 5 years (22.0%) of treatment. More than one third of cancer survivors reported that they did not receive detailed communication about follow-up care, and more than one half reported that they did not receive detailed communication regarding late or long-term effects, lifestyle recommendations, or emotional and social needs. Only 24% reported high-quality communication for all four elements, indicating that the vast majority experienced suboptimal communication. In multivariable analysis, survivors reporting a high communication quality with providers included those who were within 1 year of treatment, between the ages of 18 and 64 years, non-Hispanic black or other ethnicity, and married. Conclusion Study findings demonstrate gaps in the communication quality experienced by cancer survivors in the United States and help identify survivors for targeted interventions. C1 Kaiser Permanente Northern Calif, Oakland, CA USA. NCI, Bethesda, MD 20892 USA. Informat Management Serv Inc, Rockville, MD USA. Bentley Univ, Waltham, MA USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Amer Canc Soc, Atlanta, GA 30329 USA. Patient Ctr Outcomes Res Inst, Washington, DC USA. RP Chawla, N (reprint author), Kaiser Permanente Northern CA, Div Res, 2000 Broadway Ave, Oakland, CA 94612 USA. EM neetu.chawla@kp.org NR 53 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD DEC PY 2016 VL 12 IS 12 BP E964 EP E971 DI 10.1200/JOP.2015.006999 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI3II UT WOS:000392383200013 PM 27221992 ER PT J AU Knani, I Earley, BJ Udi, S Nemirovski, A Hadar, R Gammal, A Cinar, R Hirsch, HJ Pollak, Y Gross, I Eldar-Geva, T Reyes-Capo, DP Han, JC Haqq, AM Gross-Tsur, V Wevrick, R Tam, J AF Knani, Ibrahim Earley, Brian J. Udi, Shiran Nemirovski, Alina Hadar, Rivka Gammal, Asaad Cinar, Resat Hirsch, Harry J. Pollak, Yehuda Gross, Itai Eldar-Geva, Talia Reyes-Capo, Daniela P. Han, Joan C. Haqq, Andrea M. Gross-Tsur, Varda Wevrick, Rachel Tam, Joseph TI Targeting the endocannabinoid/CB1 receptor system for treating obesity in Pradere-Willi syndrome SO MOLECULAR METABOLISM LA English DT Article DE Endocannabinoids; PWS; Magel2; Peripheral CB1 blockade; Metabolic syndrome ID CANNABINOID CB1 RECEPTORS; CARDIOMETABOLIC RISK-FACTORS; ENERGY-BALANCE; ANTAGONIST SR141716; OVERWEIGHT PATIENTS; LEPTIN RESISTANCE; ADIPOSE-TISSUE; FOOD-INTAKE; EXPRESSION; NEURONS AB Objective: Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods: We studied eCB 'tone' in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS. (C) 2016 The Author(s). Published by Elsevier GmbH. C1 [Knani, Ibrahim; Udi, Shiran; Nemirovski, Alina; Hadar, Rivka; Gammal, Asaad; Tam, Joseph] Hebrew Univ Jerusalem, Sch Pharm, Fac Med, Obes & Metab Lab,Inst Drug Res, Jerusalem, Israel. [Earley, Brian J.; Cinar, Resat] NIAAA, Lab Physiol Studies, Bethesda, MD USA. [Hirsch, Harry J.; Pollak, Yehuda; Gross, Itai; Gross-Tsur, Varda] Shaare Zedek Med Ctr, Dept Pediat, Neuropediat Unit, Jerusalem, Israel. [Eldar-Geva, Talia] Shaare Zedek Med Ctr, Dept Obstet & Gynecol, Reprod Endocrinol & Genet Unit, Jerusalem, Israel. [Reyes-Capo, Daniela P.; Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Metab & Neuroendocrinol, Bethesda, MD USA. [Han, Joan C.] Univ Tennessee, Ctr Hlth Sci, Le Bonheur Childrens Hosp, Dept Pediat,Childrens Fdn Res Inst, Memphis, TN 38163 USA. [Han, Joan C.] Univ Tennessee, Ctr Hlth Sci, Dept Physiol, Memphis, TN 38163 USA. [Haqq, Andrea M.] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. [Wevrick, Rachel] Univ Alberta, Dept Med Genet, Edmonton, AB, Canada. RP Tam, J (reprint author), Inst Drug Res, Obes & Metab Lab, Sch Pharm, Fac Med, POB 12065, IL-91120 Jerusalem, Israel. EM yossit@ekmd.huji.ac.il FU Foundation for Prader Willi Research (FPWR) grants; Israel Science Foundation (ISF) (ISF Grant) [617/14]; Canadian Institutes of Health Research [MOP 130367]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Pradere-Willi Syndrome Association (USA) grant FX This work was supported by Foundation for Prader Willi Research (FPWR) grants to JT and AMH, the Israel Science Foundation (ISF) (ISF Grant #617/14 to JT), the Canadian Institutes of Health Research (MOP 130367 to RW), the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (JCH), and a Pradere-Willi Syndrome Association (USA) grant to JCH. We are grateful to Dr. Dinorah Barasch for her technical assistance with the LC-MS/MS analysis, and to Ms. Nava Badichi for administrative assistance in coordinating human blood sampling and data analysis. NR 63 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD DEC PY 2016 VL 5 IS 12 BP 1187 EP 1199 DI 10.1016/j.molmet.2016.10.004 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EI3DN UT WOS:000392370000005 PM 27900261 ER PT J AU Klaus, A Plenz, D AF Klaus, Andreas Plenz, Dietmar TI A Low-Correlation Resting State of the Striatum during Cortical Avalanches and Its Role in Movement Suppression SO PLOS BIOLOGY LA English DT Article ID FAST-SPIKING INTERNEURONS; RANGE TEMPORAL CORRELATIONS; SPINY PROJECTION NEURONS; BASAL GANGLIA; CHOLINERGIC INTERNEURONS; SYNAPTIC-TRANSMISSION; CELL ASSEMBLIES; FUNCTIONAL-ORGANIZATION; GABAERGIC INTERNEURONS; DOPAMINERGIC-NEURONS AB During quiet resting behavior, involuntary movements are suppressed. Such movement control is attributed to cortico-basal ganglia loops, yet population dynamics within these loops during resting and their relation to involuntary movements are not well characterized. Here, we show by recording cortical and striatal ongoing population activity in awake rats during quiet resting that intrastriatal inhibition maintains a low-correlation striatal resting state in the presence of cortical neuronal avalanches. Involuntary movements arise from disturbed striatal resting activity through two different population dynamics. Nonselectively reducing intrastriatal.-aminobutyric acid (GABA) receptor-A inhibition synchronizes striatal dynamics, leading to involuntary movements at low rate. In contrast, reducing striatal interneuron (IN)-mediated inhibition maintains decorrelation and induces intermittent involuntary movements at high rate. This latter scenario was highly effective in modulating cortical dynamics at a subsecond timescale. To distinguish intrastriatal processing from loop dynamics, cortex-striatum-midbrain cultures, which lack feedback to cortex, were used. Cortical avalanches in vitro were accompanied by low-correlated resting activity in the striatum and nonselective reduction in striatal inhibition synchronized striatal neurons similar to in vivo. Importantly, reduction of inhibition from striatal INs maintained low correlations in the striatum while reorganizing functional connectivities among striatal neurons. Our results demonstrate the importance of two major striatal microcircuits in distinctly regulating striatal and cortical resting state dynamics. These findings suggest that specific functional connectivities of the striatum that are maintained by local inhibition are important in movement control. C1 [Klaus, Andreas; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [Klaus, Andreas] Champalimaud Ctr Unknown, Champalimaud Neurosci Program, Ave Brasilia, Lisbon, Portugal. RP Klaus, A (reprint author), NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA.; Klaus, A (reprint author), Champalimaud Ctr Unknown, Champalimaud Neurosci Program, Ave Brasilia, Lisbon, Portugal. EM andreas.klaus@neuro.fchampalimaud.org OI Klaus, Andreas/0000-0002-4133-351X FU NIMH Division of Intramural Research Programs; NIH-Karolinska Institute FX This work was supported by the NIMH Division of Intramural Research Programs. AK was in addition supported by the NIH-Karolinska Institute joint PhD program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD DEC PY 2016 VL 14 IS 12 AR e1002582 DI 10.1371/journal.pbio.1002582 PG 30 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EH9VQ UT WOS:000392120100011 PM 27923040 ER PT J AU Barik, D Ball, DA Peccoud, J Tyson, JJ AF Barik, Debashis Ball, David A. Peccoud, Jean Tyson, John J. TI A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MULTISITE PROTEIN-PHOSPHORYLATION; APC-DEPENDENT PROTEOLYSIS; BUDDING-YEAST; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; MITOTIC EXIT; POSITIVE FEEDBACK; G1 CYCLINS; PHOSPHATASE CDC14; DNA-REPLICATION AB The cell division cycle of eukaryotes is governed by a complex network of cyclin-dependent protein kinases (CDKs) and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild-type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization) of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of similar to 30 mutant yeast strains that have not yet been characterized experimentally. C1 [Barik, Debashis] Univ Hyderabad, Sch Chem, Hyderabad, Telangana, India. [Ball, David A.; Peccoud, Jean; Tyson, John J.] Virginia Polytech Inst & State Univ, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Tyson, John J.] Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA. [Ball, David A.] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Peccoud, Jean] Colorado State Univ, Dept Chem & Biol Engn, Ft Collins, CO 80523 USA. RP Barik, D (reprint author), Univ Hyderabad, Sch Chem, Hyderabad, Telangana, India.; Tyson, JJ (reprint author), Virginia Polytech Inst & State Univ, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA.; Tyson, JJ (reprint author), Virginia Polytech Inst & State Univ, Dept Biol Sci, Blacksburg, VA 24061 USA. EM dbariksc@uohyd.ac.in; tyson@vt.edu OI Barik, Debashis/0000-0003-1681-1273; Tyson, John/0000-0001-7560-6013 FU University Grants Commission (India) [F30-24/2014(BSR)]; National Institutes of Health (USA) [1R01-GM078989-09] FX This work was supported by funding from the University Grants Commission (India) Start-Up Research Grant F30-24/2014(BSR) to DB and from the National Institutes of Health (USA) 1R01-GM078989-09 to JJT and JP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2016 VL 12 IS 12 AR e1005230 DI 10.1371/journal.pcbi.1005230 PG 36 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EH9XT UT WOS:000392126000020 PM 27935947 ER PT J AU Neuwald, AF Altschul, SF AF Neuwald, Andrew F. Altschul, Stephen F. TI Inference of Functionally-Relevant N-acetyltransferase Residues Based on Statistical Correlations SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENTS; PROTEIN DOMAIN HIERARCHIES; GIBBS SAMPLING STRATEGIES; JOINT BAYESIAN-ESTIMATION; DIRECT-COUPLING ANALYSIS; METHIONINE SULFOXIMINE; STRUCTURE PREDICTION; EVOLUTIONARY TRACE; ACCURATE ALIGNMENT; CLUSTAL OMEGA AB Over evolutionary time, members of a superfamily of homologous proteins sharing a common structural core diverge into subgroups filling various functional niches. At the sequence level, such divergence appears as correlations that arise from residue patterns distinct to each subgroup. Such a superfamily may be viewed as a population of sequences corresponding to a complex, high-dimensional probability distribution. Here we model this distribution as hierarchical interrelated hidden Markov models (hiHMMs), which describe these sequence correlations implicitly. By characterizing such correlations one may hope to obtain information regarding functionally-relevant properties that have thus far evaded detection. To do so, we infer a hiHMM distribution from sequence data using Bayes' theorem and Markov chain Monte Carlo (MCMC) sampling, which is widely recognized as the most effective approach for characterizing a complex, high dimensional distribution. Other routines then map correlated residue patterns to available structures with a view to hypothesis generation. When applied to N-acetyltransferases, this reveals sequence and structural features indicative of functionally important, yet generally unknown biochemical properties. Even for sets of proteins for which nothing is known beyond unannotated sequences and structures, this can lead to helpful insights. We describe, for example, a putative coenzyme-A-induced-fit substrate binding mechanism mediated by arginine residue switching between salt bridge and pi-pi stacking interactions. A suite of programs implementing this approach is available (psed.igs.umaryland.edu). C1 [Neuwald, Andrew F.] Univ Maryland, Sch Med, Inst Genome Sci, BioPark II,Room 617, Baltimore, MD 21201 USA. [Neuwald, Andrew F.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, BioPark II,Room 617, Baltimore, MD 21201 USA. [Altschul, Stephen F.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Neuwald, AF (reprint author), Univ Maryland, Sch Med, Inst Genome Sci, BioPark II,Room 617, Baltimore, MD 21201 USA.; Neuwald, AF (reprint author), Univ Maryland, Sch Med, Dept Biochem & Mol Biol, BioPark II,Room 617, Baltimore, MD 21201 USA. EM aneuwald@som.umaryland.edu FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX SFA was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. AFN received no specific funding for this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2016 VL 12 IS 12 AR e1005294 DI 10.1371/journal.pcbi.1005294 PG 30 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EH9XT UT WOS:000392126000052 PM 28002465 ER PT J AU Shi, JX Park, JH Duan, JB Berndt, ST Moy, W Yu, K Song, L Wheeler, W Hua, X Silverman, D Garcia-Closas, M Hsiung, CA Figueroa, JD Cortessis, VK Malats, N Karagas, MR Vineis, P Chang, IS Lin, DX Zhou, BS Seow, A Matsuo, K Hong, YC Caporaso, NE Wolpin, B Jacobs, E Petersen, GM Klein, AP Li, DH Risch, H Sanders, AR Hsu, L Schoen, RE Brenner, H Stolzenberg-Solomon, R Gejman, P Lan, Q Rothman, N Amundadottir, LT Landi, MT Levinson, DF Chanock, SJ Chatterjee, N AF Shi, Jianxin Park, Ju-Hyun Duan, Jubao Berndt, Sonja T. Moy, Winton Yu, Kai Song, Lei Wheeler, William Hua, Xing Silverman, Debra Garcia-Closas, Montserrat Hsiung, Chao Agnes Figueroa, Jonine D. Cortessis, Victoria K. Malats, Nuria Karagas, Margaret R. Vineis, Paolo Chang, I-Shou Lin, Dongxin Zhou, Baosen Seow, Adeline Matsuo, Keitaro Hong, Yun-Chul Caporaso, Neil E. Wolpin, Brian Jacobs, Eric Petersen, Gloria M. Klein, Alison P. Li, Donghui Risch, Harvey Sanders, Alan R. Hsu, Li Schoen, Robert E. Brenner, Hermann Stolzenberg-Solomon, Rachael Gejman, Pablo Lan, Qing Rothman, Nathaniel Amundadottir, Laufey T. Landi, Maria Teresa Levinson, Douglas F. Chanock, Stephen J. Chatterjee, Nilanjan CA MGS Mol Genetics Schizophrenia GWA GAME-ON TRICL Transdisciplinary Re PRACTICAL PRostate Canc Assoc Grp PanScan Consortium GAME-ON ELLIPSE Consortium TI Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data SO PLOS GENETICS LA English DT Article ID BODY-MASS INDEX; SUSCEPTIBILITY LOCI; HUMAN HEIGHT; PARTITIONING HERITABILITY; PSYCHIATRIC-DISORDERS; INCREASES ACCURACY; GENETIC-VARIATION; COMMON VARIANTS; CANCER RISK; PREDICTION AB Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R-2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R-2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R-2 to 3.53% (P = 2x10(-5)). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure. C1 [Shi, Jianxin; Berndt, Sonja T.; Yu, Kai; Song, Lei; Hua, Xing; Silverman, Debra; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Caporaso, Neil E.; Stolzenberg-Solomon, Rachael; Lan, Qing; Rothman, Nathaniel; Amundadottir, Laufey T.; Chanock, Stephen J.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Park, Ju-Hyun] Dongguk Univ, Dept Stat, Seoul, South Korea. [Duan, Jubao; Gejman, Pablo] Univ Chicago, North Shore Univ Hlth Syst, Pritzker Sch Med, Ctr Psychiat Genet,Dept Psychiat & Behav Sci,Res, Evanston, IL USA. [Moy, Winton] Northern Illinois Univ, Dept Stat, De Kalb, IL USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Hsiung, Chao Agnes] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Figueroa, Jonine D.] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Karagas, Margaret R.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Vineis, Paolo] Imperial Coll London, MRC, PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England. [Chang, I-Shou] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan, Taiwan. [Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing, Peoples R China. [Lin, Dongxin] Peking Union Med Coll, Beijing, Peoples R China. [Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing, Peoples R China. [Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang, Peoples R China. [Seow, Adeline] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Chikusa Ku, Nagoya, Aichi, Japan. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Wolpin, Brian] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Wolpin, Brian] Harvard Med Sch, Boston, MA USA. [Jacobs, Eric] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Klein, Alison P.; Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Hsu, Li] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Hsu, Li] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Shi, JX; Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM Jianxin.Shi@nih.gov; nilanjan@jhu.edu RI Brenner, Hermann/B-4627-2017 OI Brenner, Hermann/0000-0002-6129-1572 FU NIH Intramural Research program; NIH [U19 CA148127]; National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045]; Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Institutes of Health [R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003, UM1 CM 86107, R01 CM 37178, P01 CA87969, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, U01 CA074783, R01 CA076366, K05 CA154337]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The research was supported by the NIH Intramural Research program. The TRICL Consortium was supported by NIH grant U19 CA148127. Funding for GECCO consortium: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery). HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993 and P50 CA127003), NHS by the National Institutes of Health (UM1 CM 86107, R01 CM 37178, P01 CA87969, R01 CA151993 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PMH: National Institutes of Health (R01 CA076366 to P.A. Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 1 Z9 1 U1 5 U2 5 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 DEC PY 2016 VL 12 IS 12 AR e1006493 DI 10.1371/journal.pgen.1006493 PG 24 WC Genetics & Heredity SC Genetics & Heredity GA EI0CD UT WOS:000392138700036 PM 28036406 ER PT J AU Zhang, HH Kamiya, N Tsuji, T Takeda, H Scott, G Rajderkar, S Ray, MK Mochida, Y Allen, B Lefebvre, V Hung, IH Ornitz, DM Kunieda, T Mishina, Y AF Zhang, Honghao Kamiya, Nobuhiro Tsuji, Takehito Takeda, Haruko Scott, Greg Rajderkar, Sudha Ray, Manas K. Mochida, Yoshiyuki Allen, Benjamin Lefebvre, Veronique Hung, Irene H. Ornitz, David M. Kunieda, Tetsuo Mishina, Yuji TI Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice SO PLOS GENETICS LA English DT Article ID VAN-CREVELD-SYNDROME; INDIAN HEDGEHOG; PRIMARY CILIUM; CHONDROCYTE PROLIFERATION; THANATOPHORIC DYSPLASIA; SKELETAL DEVELOPMENT; BONE-DEVELOPMENT; RECEPTOR-3 GENE; DIFFERENTIATION; ACTIVATION AB Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome. C1 [Zhang, Honghao; Kamiya, Nobuhiro; Rajderkar, Sudha; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Kamiya, Nobuhiro; Takeda, Haruko; Mishina, Yuji] NIEHS, RDBL, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Tsuji, Takehito; Kunieda, Tetsuo] Okayama Univ, Grad Sch Environm & Life Sci, Okayama, Japan. [Scott, Greg; Ray, Manas K.; Mishina, Yuji] NIEHS, Knock Out Core, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Mochida, Yoshiyuki] Boston Univ, Dept Mol & Cell Biol, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. [Allen, Benjamin] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Lefebvre, Veronique] Cleveland Clin, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44106 USA. [Hung, Irene H.] Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT USA. [Hung, Irene H.; Ornitz, David M.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA. [Kamiya, Nobuhiro] Tenri Univ, Fac Budo & Sport Studies, Nara, Japan. [Takeda, Haruko] Univ Liege, Unit Anim Genom, GIGA R, Liege, Belgium. [Takeda, Haruko] Univ Liege, Fac Vet Med, Liege, Belgium. RP Mishina, Y (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA.; Mishina, Y (reprint author), NIEHS, RDBL, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.; Mishina, Y (reprint author), NIEHS, Knock Out Core, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mishina@umich.edu OI Rajderkar, Sudha/0000-0003-2001-3450 FU NIH [R01DE020843, YMi R01HD049808, R01DE019527]; Washington University Musculoskeletal Research Center [P30 AR057235]; DDRCC [P30 DK052574]; University of Michigan FX This work was supported by NIH grants (R01DE020843 to YMi R01HD049808 to DMO, and R01DE019527 to YMo), Washington University Musculoskeletal Research Center (P30 AR057235) and DDRCC (P30 DK052574), and University of Michigan funds (M-Cubed fund, Hedgehog pathway cancer therapy and taste and smell defects, Team A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2016 VL 12 IS 12 AR e1006510 DI 10.1371/journal.pgen.1006510 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA EI0CD UT WOS:000392138700044 PM 28027321 ER PT J AU Shi, JX Hua, X Zhu, B Ravichandran, S Wang, MY Nguyen, C Brodie, SA Palleschi, A Alloisio, M Pariscenti, G Jones, K Zhou, WY Bouk, AJ Boland, J Hicks, B Risch, A Bennett, H Luke, BT Song, L Duan, JB Liu, PY Kohno, T Chen, QR Meerzaman, D Marconett, C Laird-Offringa, I Mills, I Caporaso, NE Gail, MH Pesatori, AC Consonni, D Bertazzi, PA Chanock, SJ Landi, MT AF Shi, Jianxin Hua, Xing Zhu, Bin Ravichandran, Sarangan Wang, Mingyi Nguyen, Cu Brodie, Seth A. Palleschi, Alessandro Alloisio, Marco Pariscenti, Gianluca Jones, Kristine Zhou, Weiyin Bouk, Aaron J. Boland, Joseph Hicks, Belynda Risch, Adam Bennett, Hunter Luke, Brian T. Song, Lei Duan, Jubao Liu, Pengyuan Kohno, Takashi Chen, Qingrong Meerzaman, Daoud Marconett, Crystal Laird-Offringa, Ite Mills, Ian Caporaso, Neil E. Gail, Mitchell H. Pesatori, Angela C. Consonni, Dario Bertazzi, Pier Alberto Chanock, Stephen J. Landi, Maria Teresa TI Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study SO PLOS MEDICINE LA English DT Article ID BREAST-CANCER CELLS; FAMILY TRANSCRIPTION FACTOR; GASTRIC-CANCER; MUTUAL EXCLUSIVITY; DNA METHYLATION; TUMOR MUTATIONS; CPG SITES; EXPRESSION; GENE; IDENTIFICATION AB Background Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression. Methods and Findings We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5x10(-50)). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5x10(-4)) were associated with increased risk of distant metastasis. Our study's limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality. Conclusions These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD's high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes. C1 [Shi, Jianxin; Hua, Xing; Zhu, Bin; Wang, Mingyi; Brodie, Seth A.; Jones, Kristine; Zhou, Weiyin; Bouk, Aaron J.; Boland, Joseph; Hicks, Belynda; Bennett, Hunter; Song, Lei; Caporaso, Neil E.; Gail, Mitchell H.; Chanock, Stephen J.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ravichandran, Sarangan; Luke, Brian T.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Wang, Mingyi; Brodie, Seth A.; Jones, Kristine; Zhou, Weiyin; Bouk, Aaron J.; Boland, Joseph; Hicks, Belynda; Song, Lei] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD USA. [Nguyen, Cu; Chen, Qingrong; Meerzaman, Daoud] NCI, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. [Palleschi, Alessandro] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Div Thorac Surg, Milan, Italy. [Alloisio, Marco] Ist Clin Humanitas, Div Thorac Surg, Milan, Italy. [Pariscenti, Gianluca] Community Hosp, Thorac Surg Unit, Brescia, Italy. [Risch, Adam] Informat Management Serv Inc, Rockville, MD USA. [Duan, Jubao] Univ Chicago, Pritzker Sch Med, North Shore Univ Hlth Syst Res Inst, Ctr Psychiat Genet,Dept Psychiat & Behav Sci, Evanston, IL USA. [Liu, Pengyuan] Med Coll Wisconsin, Dept Physiol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Liu, Pengyuan] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Kohno, Takashi] Natl Canc Ctr, Div Genome Biol, Tokyo, Japan. [Marconett, Crystal; Laird-Offringa, Ite] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Surg, Los Angeles, CA USA. [Marconett, Crystal; Laird-Offringa, Ite] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Biochem & Mol Biol, Los Angeles, CA USA. [Mills, Ian] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Prostate Canc UK Movember Ctr Excellence Prostate, Belfast, Antrim, North Ireland. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, Milan, Italy. [Pesatori, Angela C.; Bertazzi, Pier Alberto] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. RP Landi, MT (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Risch, Angela/H-2669-2013; bertazzi, pietro alberto/D-5039-2017; OI Risch, Angela/0000-0002-8026-5505; bertazzi, pietro alberto/0000-0003-3475-2449; pesatori, angela/0000-0002-0261-3252; Palleschi, Alessandro/0000-0003-4510-5167; RAVICHANDRAN, SARANGAN/0000-0001-6349-0172 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD; NIH [1 R01 HL114094]; Thomas G. Labrecque Foundation; Norris Comprehensive Cancer Center from the National Cancer Institute [P30CA014089] 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, United States Department of Health and Human Services, Bethesda, MD. CM and ILO were supported by NIH grant (1 R01 HL114094, NHLBI: http://www.nhlbi.nih.gov/). ILO was supported by the Thomas G. Labrecque Foundation (https:// tglfoundation.com/), and in part by the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the National Cancer Institute (https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-in stitute-nci). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD DEC PY 2016 VL 13 IS 12 AR e1002162 DI 10.1371/journal.pmed.1002162 PG 24 WC Medicine, General & Internal SC General & Internal Medicine GA EI0DJ UT WOS:000392142400002 PM 27923066 ER PT J AU Osamor, PE Grady, C AF Osamor, Pauline E. Grady, Christine TI Zika Virus: Promoting Male Involvement in the Health of Women and Families SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article C1 [Osamor, Pauline E.; Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Osamor, PE (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM pauline.osamor@nih.gov NR 14 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2016 VL 10 IS 12 AR e0005127 DI 10.1371/journal.pntd.0005127 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA EI0IX UT WOS:000392158100020 PM 28033340 ER PT J AU Adnan, S Reeves, RK Gillis, J Wong, FE Yu, Y Camp, JV Li, QS Connole, M Li, Y Piatak, M Lifson, JD Li, WJ Keele, BF Kozlowski, PA Desrosiers, RC Haase, AT Johnson, RP AF Adnan, Sama Reeves, R. Keith Gillis, Jacqueline Wong, Fay E. Yu, Yi Camp, Jeremy V. Li, Qingsheng Connole, Michelle Li, Yuan Piatak, Michael, Jr. Lifson, Jeffrey D. Li, Wenjun Keele, Brandon F. Kozlowski, Pamela A. Desrosiers, Ronald C. Haase, Ashley T. Johnson, R. Paul TI Persistent Low-Level Replication of SIV Delta nef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection SO PLOS PATHOGENS LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; HIGHLY PATHOGENIC SIV; RHESUS MACAQUES; ATTENUATED SIV; VACCINE PROTECTION; HIV-1 INFECTION; LIVE; CHALLENGE; TRANSMISSION; EFFICACY AB Defining the correlates of immune protection conferred by SIV Delta nef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIV Delta nef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIV Delta nef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIV Delta nef antigenic load. In conclusion, maturation of SIV Delta nef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination. C1 [Adnan, Sama; Johnson, R. Paul] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Adnan, Sama; Reeves, R. Keith; Gillis, Jacqueline; Wong, Fay E.; Yu, Yi; Connole, Michelle; Johnson, R. Paul] Harvard Med Sch, New England Primate Res Ctr, Southborough Campus,Pine Hill Dr, Southborough, MA 01772 USA. [Reeves, R. Keith] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Camp, Jeremy V.; Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA USA. [Li, Qingsheng] Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE USA. [Li, Qingsheng] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. [Li, Yuan; Piatak, Michael, Jr.; Lifson, Jeffrey D.; Keele, Brandon F.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Desrosiers, Ronald C.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. [Johnson, R. Paul] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. RP Johnson, RP (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA.; Johnson, RP (reprint author), Harvard Med Sch, New England Primate Res Ctr, Southborough Campus,Pine Hill Dr, Southborough, MA 01772 USA.; Johnson, RP (reprint author), Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. EM rpaul.johnson@emory.edu FU International AIDS Vaccine Initiative; National Institutes of Health [AI071306, AI095985]; Office of Research Infrastructure Programs [P51 OD011103, RR00168, P51 OD011132]; Emory Center for AIDS Research [P30AI050409]; Harvard Multidisciplinary Training grant [T32 AI07387-24]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the International AIDS Vaccine Initiative (www.iavi.org). It was also funded by National Institutes of Health (http://www.nih.gov) grants AI071306 (RPJ), AI095985 (RPJ), and grants P51 OD011103 (formerly RR00168) and P51 OD011132 from the Office of Research Infrastructure Programs, and the Emory Center for AIDS Research (P30AI050409). The research was also funded by the Harvard Multidisciplinary Training grant (T32 AI07387-24). In addition, this research was supported by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (BFK, JDL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006104 DI 10.1371/journal.ppat.1006104 PG 29 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100065 PM 27959961 ER PT J AU Ericsen, AJ Lauck, M Mohns, MS DiNapoli, SR Mutschler, JP Greene, JM Weinfurter, JT Lehrer-Brey, G Prall, TM Gieger, SM Buechler, CR Crosno, KA Peterson, EJ Reynolds, MR Wiseman, RW Burwitz, BJ Estes, JD Sacha, JB Friedrich, TC Brenchley, JM O'Connor, DH AF Ericsen, Adam J. Lauck, Michael Mohns, Mariel S. DiNapoli, Sarah R. Mutschler, James P. Greene, Justin M. Weinfurter, Jason T. Lehrer-Brey, Gabrielle Prall, Trent M. Gieger, Samantha M. Buechler, Connor R. Crosno, Kristin A. Peterson, Eric J. Reynolds, Matthew R. Wiseman, Roger W. Burwitz, Benjamin J. Estes, Jacob D. Sacha, Jonah B. Friedrich, Thomas C. Brenchley, Jason M. O'Connor, David H. TI Microbial Translocation and Inflammation Occur in Hyperacute Immunodeficiency Virus Infection and Compromise Host Control of Virus Replication SO PLOS PATHOGENS LA English DT Article ID CD4(+) T-CELLS; POLYMERASE-CHAIN-REACTION; IMMUNE ACTIVATION; HIV-INFECTION; VIRAL REPLICATION; SIV INFECTION; PLASMA-LEVELS; SOLUBLE CD14; ENDOTOXEMIA; EXPRESSION AB Within the first three weeks of human immunodeficiency virus (HIV) infection, virus replication peaks in peripheral blood. Despite the critical, causal role of virus replication in determining transmissibility and kinetics of progression to acquired immune deficiency syndrome (AIDS), there is limited understanding of the conditions required to transform the small localized transmitted founder virus population into a large and heterogeneous systemic infection. Here we show that during the hyperacute "pre-peak" phase of simian immunodeficiency virus (SIV) infection in macaques, high levels of microbial DNA transiently translocate into peripheral blood. This, heretofore unappreciated, hyperacute-phase microbial translocation was accompanied by sustained reduction of lipopolysaccharide (LPS)-specific antibody titer, intestinal permeability, increased abundance of CD4+CCR5+ T cell targets of virus replication, and T cell activation. To test whether increasing gastrointestinal permeability to cause microbial translocation would amplify viremia, we treated two SIV-infected macaque 'elite controllers' with a short-course of dextran sulfate sodium (DSS)-stimulating a transient increase in microbial translocation and a prolonged recrudescent viremia. Altogether, our data implicates translocating microbes as amplifiers of immunodeficiency virus replication that effectively undermine the host's capacity to contain infection. C1 [Ericsen, Adam J.; Lauck, Michael; Mohns, Mariel S.; Greene, Justin M.; Weinfurter, Jason T.; Gieger, Samantha M.; Buechler, Connor R.; Reynolds, Matthew R.; Wiseman, Roger W.; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Ericsen, Adam J.] Univ Wisconsin, Virol Training Program, Madison, WI USA. [DiNapoli, Sarah R.; Brenchley, Jason M.] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD USA. [Mutschler, James P.; Lehrer-Brey, Gabrielle; Prall, Trent M.; Crosno, Kristin A.; Peterson, Eric J.; Friedrich, Thomas C.; O'Connor, David H.] Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Burwitz, Benjamin J.; Sacha, Jonah B.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Oregon Natl Primate Res Ctr, Portland, OR 97201 USA. [Burwitz, Benjamin J.; Sacha, Jonah B.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Estes, Jacob D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Friedrich, Thomas C.] Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA.; O'Connor, DH (reprint author), Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM doconnor@primate.wisc.edu OI Mohns, Mariel/0000-0002-3609-8447; Lauck, Michael/0000-0003-2813-3705; Ericsen, Adam/0000-0003-4176-8270; Friedrich, Thomas/0000-0001-9831-6895 FU National Institutes of Health [R01 AI077376, R01 AI084787, T32 AI078985]; National Center for Research Resources [P51 RR000167, P51 OD011092]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; Division of Intramural Research at the National Institutes of Allergies and Infectious Diseases; National Cancer Institute (NIH) [HHSN261200800001E] FX This research was supported by National Institutes of Health (http://www.nih.gov) grants R01 AI077376, awarded to DHO, R01 AI084787, awarded to DHO and TCF, and T32 AI078985 supporting AJE. This work was conducted at facilities supported (P51 RR000167 and P51 OD011092) by National Center for Research Resources (htttp://www.ncrr.nih.gov), and in a facility constructed with support (RR15459-01 and RR020141-01) from the Research Facilities Improvement Program. Funding for this study was provided in part by the Division of Intramural Research at the National Institutes of Allergies and Infectious Diseases (htttp://www.niaid.nih.gov). This work was supported in part with federal funds from the National Cancer Institute (htttp://www.cancer.nih.gov) (NIH Contract HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of DHHS, or does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006048 DI 10.1371/journal.ppat.1006048 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100029 PM 27926931 ER PT J AU Furuyama, W Marzi, A Carmody, AB Maruyama, J Kuroda, M Miyamoto, H Nanbo, A Manzoor, R Yoshida, R Igarashi, M Feldmann, H Takada, A AF Furuyama, Wakako Marzi, Andrea Carmody, Aaron B. Maruyama, Junki Kuroda, Makoto Miyamoto, Hiroko Nanbo, Asuka Manzoor, Rashid Yoshida, Reiko Igarashi, Manabu Feldmann, Heinz Takada, Ayato TI Fc gamma-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection SO PLOS PATHOGENS LA English DT Article ID PROTEIN-TYROSINE KINASE; NIEMANN-PICK C1; CYTOPLASMIC DOMAIN; IN-VITRO; DC-SIGN; CELLS; ENTRY; DENGUE; GLYCOPROTEIN; MACROPHAGES AB Antibody-dependent enhancement (ADE) of Ebola virus (EBOV) infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fc gamma-receptor IIa (Fc gamma RIIa)-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs) is required for ADE of EBOV infection. We found that deletion of the Fc gamma RIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface Fc gamma RIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection. C1 [Furuyama, Wakako; Maruyama, Junki; Kuroda, Makoto; Miyamoto, Hiroko; Manzoor, Rashid; Yoshida, Reiko; Igarashi, Manabu; Takada, Ayato] Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Carmody, Aaron B.] NIAID, Res Technol Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Nanbo, Asuka] Hokkaido Univ, Grad Sch Med, Dept Cell Physiol, Sapporo, Hokkaido, Japan. [Igarashi, Manabu; Takada, Ayato] Hokkaido Univ, Global Stn Zoonosis Control, Global Inst Collaborat Res & Educ, Sapporo, Hokkaido, Japan. [Takada, Ayato] Univ Zambia, Sch Vet Med, Lusaka, Zambia. [Kuroda, Makoto] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. RP Takada, A (reprint author), Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan.; Takada, A (reprint author), Hokkaido Univ, Global Stn Zoonosis Control, Global Inst Collaborat Res & Educ, Sapporo, Hokkaido, Japan.; Takada, A (reprint author), Univ Zambia, Sch Vet Med, Lusaka, Zambia. EM atakada@czc.hokudai.ac.jp RI Nanbo, Asuka/C-6630-2012 OI Nanbo, Asuka/0000-0001-8764-1350 FU KAKENHI [14J06186, 15H01249]; Ministry of Education, Culture, Sports, Science and Technology (MEXT); Japan Society for the Promotion of Science (JSPS), Japan; Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from Ministry of Education, Culture, Sport, Science & Technology in Japan; Japan Agency for Medical Research and Development (AMED); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by KAKENHI (14J06186 and 15H01249), Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Japan Society for the Promotion of Science (JSPS), Japan, and partly by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from Ministry of Education, Culture, Sport, Science & Technology in Japan, and Japan Agency for Medical Research and Development (AMED), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006139 DI 10.1371/journal.ppat.1006139 PG 22 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100074 PM 28036370 ER PT J AU Lubaki, NM Younan, P Santos, RI Meyer, M Iampietro, M Koup, RA Bukreyev, A AF Lubaki, Ndongala Michel Younan, Patrick Santos, Rodrigo I. Meyer, Michelle Iampietro, Mathieu Koup, Richard A. Bukreyev, Alexander TI The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses SO PLOS PATHOGENS LA English DT Article ID INFLUENZA-VIRUS INFECTION; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; CD8(+) T-CELLS; PBL-SCID MICE; DENDRITIC CELLS; NK CELLS; ZAIRE-EBOLAVIRUS; VIRAL-INFECTION; IFN-ALPHA AB Ebola virus (EBOV) infections are characterized by deficient T-lymphocyte responses, T-lymphocyte apoptosis and lymphopenia. We previously showed that disabling of interferon-inhibiting domains (IIDs) in the VP24 and VP35 proteins effectively unblocks maturation of dendritic cells (DCs) and increases the secretion of cytokines and chemokines. Here, we investigated the role of IIDs in adaptive and innate cell-mediated responses using recombinant viruses carrying point mutations, which disabled IIDs in VP24 (EBOV/VP24m), VP35 (EBOV/VP35m) or both (EBOV/VP35m/VP24m). Peripheral blood mononuclear cells (PBMCs) from cytomegalovirus (CMV)-seropositive donors were inoculated with the panel of viruses and stimulated with CMV pp65 peptides. Disabling of the VP35 IID resulted in increased proliferation and higher percentages of CD4(+) T cells secreting IFN. and/or TNFa. To address the role of aberrant DC maturation in the IID-mediated suppression of T cell responses, CMV-stimulated DCs were infected with the panel of viruses and co-cultured with autologous T-lymphocytes. Infection with EBOV/VP35m infection resulted in a significant increase, as compared to wt EBOV, in proliferating CD4(+) cells secreting IFN gamma, TNF alpha and IL-2. Experiments with expanded CMV-specific T cells demonstrated their increased activation following co-cultivation with CMV-pulsed DCs pre-infected with EBOV/VP24m, EBOV/VP35m and EBOV/VP35m/VP24m, as compared to wt EBOV. Both IIDs were found to block phosphorylation of TCR complex-associated adaptors and downstream signaling molecules. Next, we examined the effects of IIDs on the function of B cells in infected PBMC. Infection with EBOV/VP35m and EBOV/VP35m/VP24m resulted in significant increases in the percentages of phenotypically distinct B-cell subsets and plasma cells, as compared to wt EBOV, suggesting inhibition of B cell function and differentiation by VP35 IID. Finally, infection with EBOV/VP35m increased activation of NK cells, as compared to wt EBOV. These results demonstrate a global suppression of cell-mediated responses by EBOV IIDs and identify the role of DCs in suppression of T-cell responses. C1 [Lubaki, Ndongala Michel; Younan, Patrick; Santos, Rodrigo I.; Meyer, Michelle; Iampietro, Mathieu; Bukreyev, Alexander] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Lubaki, Ndongala Michel; Younan, Patrick; Santos, Rodrigo I.; Meyer, Michelle; Iampietro, Mathieu; Bukreyev, Alexander] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bukreyev, Alexander] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA.; Bukreyev, A (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA.; Bukreyev, A (reprint author), Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. EM alexander.bukreyev@utmb.edu FU National Institutes of Health / National Institute of Allergy and Infectious Diseases [U19AI109945]; John Sealy Memorial Endowment; McLaughlin Fellowship FX This study was funded by the National Institutes of Health / National Institute of Allergy and Infectious Diseases, grant U19AI109945 (AB), John Sealy Memorial Endowment http://research.utmb-edu/sealy/Awardees.aspx Pilot Grant "Mechanisms of 'Immune Paralysis' in Ebola Infections (AB), and McLaughlin Fellowship http://www.utmb.edu/mclaughlin/posdoctoral.shtml .shtml (NML). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 94 TC 0 Z9 0 U1 8 U2 8 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 DEC PY 2016 VL 12 IS 12 AR e1006031 DI 10.1371/journal.ppat.1006031 PG 34 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100018 PM 27930745 ER PT J AU Mehedi, M McCarty, T Martin, SE Le Nouen, C Buehler, E Chen, YC Smelkinson, M Ganesan, S Fischer, ER Brock, LG Liang, B Munir, S Collins, PL Buchholz, UJ AF Mehedi, Masfique McCarty, Thomas Martin, Scott E. Le Nouen, Cyril Buehler, Eugen Chen, Yu-Chi Smelkinson, Margery Ganesan, Sundar Fischer, Elizabeth R. Brock, Linda G. Liang, Bo Munir, Shirin Collins, Peter L. Buchholz, Ursula J. TI Actin-Related Protein 2 (ARP2) and Virus-Induced Filopodia Facilitate Human Respiratory Syncytial Virus Spread SO PLOS PATHOGENS LA English DT Article ID HUMAN DENDRITIC CELLS; GROWTH CONE MOTILITY; IN-VITRO MODEL; PARAINFLUENZA VIRUS; HUMAN METAPNEUMOVIRUS; CELLULAR ACTIN; F-ACTIN; INFECTION; COMPLEX; MORPHOGENESIS AB Human respiratory syncytial virus (RSV) is an enveloped RNA virus that is the most important viral cause of acute pediatric lower respiratory tract illness worldwide, and lacks a vaccine or effective antiviral drug. The involvement of host factors in the RSV replicative cycle remains poorly characterized. A genome-wide siRNA screen in human lung epithelial A549 cells identified actin-related protein 2 (ARP2) as a host factor involved in RSV infection. ARP2 knockdown did not reduce RSV entry, and did not markedly reduce gene expression during the first 24 hr of infection, but decreased viral gene expression thereafter, an effect that appeared to be due to inhibition of viral spread to neighboring cells. Consistent with reduced spread, there was a 10-fold reduction in the release of infectious progeny virions in ARP2-depleted cells at 72 hr post-infection. In addition, we found that RSV infection induced filopodia formation and increased cell motility in A549 cells and that this phenotype was ARP2 dependent. Filopodia appeared to shuttle RSV to nearby uninfected cells, facilitating virus spread. Expression of the RSV F protein alone from a plasmid or heterologous viral vector in A549 cells induced filopodia, indicating a new role for the RSV F protein, driving filopodia induction and virus spread. Thus, this study identified roles for ARP2 and filopodia in RSV-induced cell motility, RSV production, and RSV cell-to-cell spread. C1 [Mehedi, Masfique; McCarty, Thomas; Le Nouen, Cyril; Brock, Linda G.; Liang, Bo; Munir, Shirin; Collins, Peter L.; Buchholz, Ursula J.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Martin, Scott E.; Buehler, Eugen; Chen, Yu-Chi] Natl Ctr Adv Translat Sci, Div Preclin Innovat, Rockville, MD USA. [Smelkinson, Margery; Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIAID, Microscopy Unit, Rocky Mt Labs, Res Technol Branch,NIH, Hamilton, MT USA. [Martin, Scott E.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA. RP Mehedi, M (reprint author), NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM masfique.mehedi@nih.gov OI Mehedi, Masfique/0000-0003-1728-3126 FU Intramural Research Program of NIAID, NIH FX This study was supported by the Intramural Research Program of NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006062 DI 10.1371/journal.ppat.1006062 PG 35 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100039 PM 27926942 ER PT J AU Ratner, D Orning, MPA Proulx, MK Wang, DH Gavrilin, MA Wewers, MD Alnemri, ES Johnson, PF Lee, B Mecsas, J Kayagaki, N Goguen, JD Lien, E AF Ratner, Dmitry Orning, M. Pontus A. Proulx, Megan K. Wang, Donghai Gavrilin, Mikhail A. Wewers, Mark D. Alnemri, Emad S. Johnson, Peter F. Lee, Bettina Mecsas, Joan Kayagaki, Nobuhiko Goguen, Jon D. Lien, Egil TI The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation SO PLOS PATHOGENS LA English DT Article ID III SECRETION SYSTEM; NF-KAPPA-B; BURKHOLDERIA-CENOCEPACIA; C/EBP-BETA; VIRULENCE; CASPASE-1; GTPASES; FEVER; LIPOPOLYSACCHARIDE; RECOGNITION AB Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1 beta and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1 beta/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1 beta/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8-dependent IL-1 beta activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1 beta generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1 beta/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague. C1 [Ratner, Dmitry; Orning, M. Pontus A.; Wang, Donghai; Lien, Egil] UMass Med Sch, Div Infect Dis & Immunol, Program Innate Immun, Dept Med, Worcester, MA 01655 USA. [Orning, M. Pontus A.; Lien, Egil] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Ctr Mol Inflammat Res, Trondheim, Norway. [Proulx, Megan K.; Goguen, Jon D.] UMass Med Sch, Dept Microbiol & Physiol Syst, Worcester, MA USA. [Wang, Donghai] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Gavrilin, Mikhail A.; Wewers, Mark D.] Ohio State Univ, Dept Internal Med, Div Pulm Allergy Crit Care & Sleep Med, Davis Heart & Lung Res Inst,Wexner Med Ctr, Columbus, OH 43210 USA. [Alnemri, Emad S.] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Johnson, Peter F.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Lee, Bettina; Kayagaki, Nobuhiko] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA. [Mecsas, Joan] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Lien, E (reprint author), UMass Med Sch, Div Infect Dis & Immunol, Program Innate Immun, Dept Med, Worcester, MA 01655 USA.; Lien, E (reprint author), Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Ctr Mol Inflammat Res, Trondheim, Norway. EM Egil.Lien@umassmed.edu OI Proulx, Megan/0000-0002-9524-8302; Wewers, Mark/0000-0002-7079-5633; Johnson, Peter/0000-0002-4145-4725 FU National Institutes of Health [AI07538, U19 AI057319, AI095213, HL076278, AR055398, AI113166, AI110695]; Norwegian Cancer Society; Research Council of Norway Center of Excellence Funding Scheme Project [223255/F50]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The work was supported by National Institutes of Health Grants AI07538 and U19 AI057319 (to EL), AI095213 (to DR), HL076278 (to MAG and MDW), AR055398 (to ESA), AI113166 (to JM), AI110695 (to DW), the Norwegian Cancer Society, and Research Council of Norway Center of Excellence Funding Scheme Project 223255/F50 (to EL). The research of PFJ was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. URLs: https://www.nih.gov/, https://kreftforeningen.no/, http://www.forskningsradet.no/en/Home_page/1177315753906, http://www.cancer.gov/ NR 46 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006035 DI 10.1371/journal.ppat.1006035 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100020 PM 27911947 ER PT J AU Swanson, PA Hart, GT Russo, MV Nayak, D Yazew, T Pena, M Khan, SM Janse, CJ Pierce, SK McGavern, DB AF Swanson, Phillip A., II Hart, Geoffrey T. Russo, Matthew V. Nayak, Debasis Yazew, Takele Pena, Mirna Khan, Shahid M. Janse, Chris J. Pierce, Susan K. McGavern, Dorian B. TI CD8(+) T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature SO PLOS PATHOGENS LA English DT Article ID CHEMOKINE RECEPTOR 2; FALCIPARUM-MALARIA; ENDOTHELIAL-CELLS; MULTIPLE-SCLEROSIS; MALIAN CHILDREN; IN-VIVO; PATHOGENESIS; PARASITE; MICE; INFECTION AB Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8(+) T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8(+) T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-gamma, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8(+) T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8(+) T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8(+) T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature. C1 [Swanson, Phillip A., II; Russo, Matthew V.; McGavern, Dorian B.] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hart, Geoffrey T.; Yazew, Takele; Pena, Mirna; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Nayak, Debasis] Indian Inst Technol Indore, Ctr Biosci & Biomed Engn, Indore, Madhya Pradesh, India. [Khan, Shahid M.; Janse, Chris J.] Leiden Univ, Leiden Malaria Res Grp, Ctr Infect Dis, Dept Parasitol,Med Ctr, Leiden, Netherlands. RP McGavern, DB (reprint author), NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mcgavernd@mail.nih.gov FU National Institutes of Health FX This research was supported by the intramural program at 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 91 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 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD DEC PY 2016 VL 12 IS 12 AR e1006022 DI 10.1371/journal.ppat.1006022 PG 34 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI0YQ UT WOS:000392202100017 PM 27907215 ER PT J AU Ognibene, FP Gallin, JI Baum, BJ Wyatt, RG Gottesman, MM AF Ognibene, Frederick P. Gallin, John I. Baum, Bruce J. Wyatt, Richard G. Gottesman, Michael M. TI Outcomes From the NIH Clinical Research Training Program: A Mentored Research Experience to Enhance Career Development of Clinician-Scientists SO ACADEMIC MEDICINE LA English DT Article ID PHYSICIAN-SCIENTIST; MEDICAL-STUDENTS; INVESTIGATOR; CHALLENGES; CURRICULUM; WORKFORCE; FUTURE; HEALTH; SCHOOL; DUKE AB Purpose Clinician-scientists are considered an endangered species for many reasons, including challenges with establishing and maintaining a career pipeline. Career outcomes from yearlong medical and dental students' research enrichment programs have not been well determined. Therefore, the authors assessed career and research outcome data from a cohort of participants in the National Institutes of Health (NIH) Clinical Research Training Program (CRTP). Method The CRTP provided a yearlong mentored clinical or translational research opportunity for 340 medical and dental students. Of these, 135 completed their training, including fellowships, from 1997 to January 2014. Data for 130 of 135 were analyzed: time conducting research, types of public funding (NIH grants), and publications from selfreported surveys that were verified via the NIH Research Portfolio Online Reporting Tools Web site and PubMed. Results Nearly two-thirds (84 of 130) indicated that they were conducting research, and over half of the 84 (approximately one-third of the total cohort) spent more than 25% of time conducting research. Of those 84, over 25% received grant support from the NIH, and those further in their careers published more scholarly manuscripts. Conclusions Data suggest that the CRTP helped foster the careers of research-oriented medical and dental students as measured by time conducting research, successful competition for federal funding, and the publication of their research. Longer follow-up is warranted to assess the impact of these mentored research experiences. Investments in mentored research programs for health professional students are invaluable to support the dwindling pipeline of biomedical researchers and clinician-scientists. C1 [Ognibene, Frederick P.] NIH, Educ Affairs & Strateg Partnerships, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Ognibene, Frederick P.] NIH, Clin Res Training Program, Bldg 10, Bethesda, MD 20892 USA. [Gallin, John I.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gallin, John I.] NIH, Clin Res, Bldg 10, Bethesda, MD 20892 USA. [Gallin, John I.] NIH, Clin Res Training, Bldg 10, Bethesda, MD 20892 USA. [Baum, Bruce J.] NIH, Med Res Scholars Program, Bldg 10, Bethesda, MD 20892 USA. [Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Wyatt, Richard G.] NIH, Off Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Gottesman, Michael M.] NIH, Intramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Ognibene, FP (reprint author), NIH, Bldg 10 CRC,6-5530, Bethesda, MD 20892 USA. EM fognibene@cc.nih.gov FU NIH Common Fund FX The authors wish to thank the 130 Clinical Research Training Program alumni for participating in this long-term follow-up, and for providing their responses to annual career outcome surveys. The authors also thank Ms. Jennifer Simmons and Mr. Kenny J. Williams from the National Institutes of Health (NIH) Clinical Center's Office of Clinical Research Training and Medical Education for their assistance in collecting and providing baseline analysis of the data and Dr. Elaine K. Gallin for her thoughtful review of this manuscript. The authors thank the NIH Common Fund and the staff of the NIH Office of Strategic Coordination, Division of Program Coordination, Planning, and Strategic Initiatives for their guidance and program support. NR 22 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 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD DEC PY 2016 VL 91 IS 12 BP 1684 EP 1690 DI 10.1097/ACM.0000000000001245 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EH7NL UT WOS:000391959600049 ER PT J AU Keutgen, XM Nilubol, N Agarwal, S Welch, J Cochran, C Marx, SJ Weinstein, LS Simonds, WF Kebebew, E AF Keutgen, Xavier M. Nilubol, Naris Agarwal, Sunita Welch, James Cochran, Craig Marx, Steve J. Weinstein, Lee S. Simonds, William F. Kebebew, Electron TI Reoperative Surgery in Patients with Multiple Endocrine Neoplasia Type 1 Associated Primary Hyperparathyroidism SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TERM-FOLLOW-UP; PARATHYROIDECTOMY; OPERATION; MANAGEMENT; MEN1 AB Background. Persistent/recurrent primary hyperparathyroidism (pHPT) occurs frequently in multiple endocrine neoplasia type 1 (MEN1). We assessed the usefulness of intraoperative PTH (IOPTH) and preoperative localizing studies based on the outcome of patients with MEN1-associated pHPT undergoing reoperative surgery. Methods. A retrospective analysis identified MEN1 patients with persistent/recurrent pHPT. Patient outcome was defined as postoperative serum calcium and PTH levels (cured, persistent or recurrent) at last follow-up. Positive predictive value (PPV) was calculated for imaging studies and IOPTH. Results. Thirty patients with MEN1-associated recurrent/persistent pHPT underwent 69 reoperative parathyroidectomies. Median follow-up time was 33 months. Persistent pHPT occurred in four (13 %) patients. IOPTH had a 92 % PPV for postoperative eucalcemia. Ultrasound and Tc99msestamibi had sensitivities of 100 and 85 % for localizing an enlarged parathyroid gland. However, five (17 %) patients had additional enlarged glands, not visualized preoperatively that were removed after IOPTH did not drop appropriately. Bone mineral density scores did not improve after reoperation (p = 0.60), but the rate of postoperative nephrocalcinosis did (p = 0.046). Patients with pancreatic neuroendocrine tumors had significantly higher rates of persistent/recurrent pHPT compared with those without (40 vs. 0 %, p = 0.021). Intraoperative and delayed parathyroid autotransplantation was performed in nine (30 %) and four (14 %) patients, respectively. Conclusions. Although preoperative localizing studies are helpful for guiding reoperative strategy in MEN1 with persistent/recurrent pHPT, additional enlarged glands may be missed by conventional imaging. IOPTH should therefore be employed routinely in this setting. Routine cryopreservation should be considered in all patients. Pancreatic manifestation may be associated with earlier recurrence or persistent disease. C1 [Keutgen, Xavier M.; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Agarwal, Sunita; Welch, James; Cochran, Craig; Marx, Steve J.; Weinstein, Lee S.; Simonds, William F.] Natl Inst Diabet & Digest & Kidney Dis, Metab Dis Branch, NIH, Bethesda, MD USA. RP Keutgen, XM (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM xavier.keutgen@nih.gov OI Weinstein, Lee/0000-0002-1899-5152 NR 24 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2016 VL 23 SU 5 BP S701 EP S707 DI 10.1245/s10434-016-5467-x PG 7 WC Oncology; Surgery SC Oncology; Surgery GA EH1FK UT WOS:000391508800026 PM 27464610 ER PT J AU Satoh, K Sadowski, SM Dieckmann, W Quezado, M Nilubol, N Kebebew, E Patel, D AF Satoh, Kei Sadowski, Samira M. Dieckmann, William Quezado, Martha Nilubol, Naris Kebebew, Electron Patel, Dhaval TI F-18-FDG PET/CT Volumetric Parameters are Associated with Tumor Grade and Metastasis in Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TOTAL LESION GLYCOLYSIS; POSITRON-EMISSION-TOMOGRAPHY; BODY RADIATION-THERAPY; FINE-NEEDLE-ASPIRATION; PROGNOSTIC VALUE; ENDOCRINE TUMORS; CLINICAL UTILITY; LABELING INDEX; CANCER; NEOPLASMS AB Background. Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of prognosis. Objective. The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. Methods. Sixty-two patients with VHL-associated PNETs prospectively underwent F-18-fluorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT). MTV, TLG, and maximum standardized uptake value (SUVmax) were measured using a semi-automatic method. Surgically resected PNETs were classified according to 2010 World Health Organization tumor grade classification. MTV, TLG, and SUVmax were analyzed by metastatic disease and tumor grade using the MannWhitney test. Results. A total of 88 PNETs were identified by CT and F-18-FDG PET/CT, 10 of which were non-FDG-avid. Histologic grading was available for 20 surgical patients. Patients with metastatic PNETs had a higher TLG (median 25.9 vs. 7.7 mean SUV [SUVmean]* mL; p = 0.0092) compared with patients without metastasis, while patients with grade 2 PNETs had a higher MTV (median 6.9 vs. 2.6 mL; p = 0.034) and TLG (median 41.2 vs. 13.1 SUVmean* mL; p = 0.0035) compared with patients with grade 1 PNETs. No difference in tumor size or SUVmax was observed between the groups. Conclusions. Patients with metastatic PNETs have a higher TLG compared with patients without metastasis. Grade 2 PNETs have a higher MTV and TLG compared with grade 1 PNETs. Tumor size and SUVmax were not associated with grade. Volumetric parameters on F-18-FDG PET/CT may be useful in detecting higher grade PNETs with a higher malignant potential that may need surgical intervention. C1 [Satoh, Kei; Sadowski, Samira M.; Nilubol, Naris; Kebebew, Electron; Patel, Dhaval] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Satoh, Kei] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dieckmann, William] NIH, PET Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Patel, D (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM pateldt@nih.gov FU NIH Medical Research Scholars Program by NIH FX This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Newport 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, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 45 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2016 VL 23 SU 5 BP S714 EP S721 DI 10.1245/s10434-016-5541-4 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA EH1FK UT WOS:000391508800028 PM 27638678 ER PT J AU Jha, S Bhattacharyya, T AF Jha, Smita Bhattacharyya, Timothy TI Utilization and cost of anti-osteoporosis therapy among US Medicare beneficiaries SO ARCHIVES OF OSTEOPOROSIS LA English DT Article DE Osteoporosis; Cost; Brand name drugs; Generic drugs; Primary care providers; Utilization ID PRIMARY-CARE PHYSICIANS; LOW BONE-DENSITY; POSTMENOPAUSAL OSTEOPOROSIS; GENERIC DRUGS; FRACTURE RISK; UNITED-STATES; ALENDRONATE; WOMEN; TRIAL; BRAND AB A Summary There is a strong impetus to prevent and treat osteoporosis to prevent fractures. $990 million dollars was spent on anti-osteoporosis drugs in 2013. As we shift our focus on primary prevention of fractures, providers are encouraged to find themost cost-effective anti-osteoporosis therapy for patients. Purpose Osteoporosis is a major global problem with osteoporotic fractures posing a potentially avoidable burden on healthcare resources. We studied the utilization and cost of anti-osteoporotic therapy using the 2013 Medicare Part D data. Methods Descriptive data were produced from Microsoft Excel and SPSS regarding the anti-osteoporotic drugs of interest. Results In total, Medicare and its beneficiaries spent approximately $990 million on anti-osteoporotic therapy in 2013. Despite this cost, only one in two adults with osteoporosis aged 65 and older received a prescription for an anti-osteoporosis drug. $756 million (77 %) was attributable to brand name drugs which accounted for 2,459,931 claims (22 %). Generic dispensing rate varied from 57-86 % (mean 77 + 6) across the different states in the USA. States that mandate substitution with generic equivalents had a higher generic dispensing rate compared to the states that permit generic substitution (92 vs. 90 %; p < 0.05). After adjusting for claim counts, we found that if the states that permit substitution with generic equivalents showed the same generic dispensing rate of 92 % as the states that mandate such substitution, there is a potential for savings of $7.5 million, approximately 9 % of the total expenditure in these states on oral bisphosphonates alone. Thirty-eight percent of the total prescriptions from orthopedic surgeons were for Forteo (R) or Prolia (R) compared to 12.5 % from specialists. Conclusions These findings highlight the need for ongoing training for physicians who engage in the care of patients with osteoporosis to manage the disease in a cost-effective manner. C1 [Jha, Smita; Bhattacharyya, Timothy] NIAMSD, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4-1341, Bethesda, MD 20892 USA. RP Jha, S (reprint author), NIAMSD, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4-1341, Bethesda, MD 20892 USA. EM smita.jha@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) FX We thank Dr. Abhijit Dasgupta, PhD, for his kind review of statistical methods. This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). NR 34 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1862-3522 EI 1862-3514 J9 ARCH OSTEOPOROS JI Arch. Osteoporos. PD DEC PY 2016 VL 11 IS 1 AR 28 DI 10.1007/s11657-016-0283-2 PG 8 WC Endocrinology & Metabolism; Orthopedics SC Endocrinology & Metabolism; Orthopedics GA EH0BC UT WOS:000391426300005 PM 27576482 ER PT J AU Gabriel, EE Daniels, MJ Halloran, ME AF Gabriel, Erin E. Daniels, Michael J. Halloran, M. Elizabeth TI Comparing Biomarkers as Trial Level General Surrogates SO BIOMETRICS LA English DT Article DE Bayesian non-parametrics; Cross-Validation; Meta-analysis; Surrogate markers; Vaccines ID PENTAVALENT ROTAVIRUS VACCINE; RANDOMIZED CLINICAL-TRIALS; END-POINTS; IMMUNOGENICITY; METAANALYSIS; VALIDATION; INFANTS; MODELS AB An intermediate response measure that accurately predicts efficacy in a new setting can reduce trial cost and time to product licensure. In this article, we define a trial level general surrogate, which is an intermediate response that can be used to accurately predict efficacy in a new setting. Methods for evaluating general surrogates have been developed previously. Many methods in the literature use trial level intermediate responses for prediction. However, all existing methods focus on surrogate evaluation and prediction in new settings, rather than comparison of candidate general surrogates, and few formalize the use of cross validation to quantify the expected prediction error. Our proposed method uses Bayesian non-parametric modeling and cross-validation to estimate the absolute prediction error for use in evaluating and comparing candidate trial level general surrogates. Simulations show that our method performs well across a variety of scenarios. We use our method to evaluate and to compare candidate trial level general surrogates in several multi-national trials of a pentavalent rotavirus vaccine. We identify at least one immune measure that has potential value as a trial level general surrogate and use it to predict efficacy in a new trial where the clinical outcome was not measured. C1 [Gabriel, Erin E.] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Daniels, Michael J.] Univ Texas Austin, Dept Stat & Data Sci, Austin, TX 78712 USA. [Daniels, Michael J.] Univ Texas Austin, Dept Integrat Biol, Austin, TX 78712 USA. [Halloran, M. Elizabeth] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Halloran, M. Elizabeth] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Halloran, M. Elizabeth] Ctr Inference & Dynam Infect Dis, Seattle, WA USA. RP Gabriel, EE (reprint author), NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM erin.gabriel@nih.gov; mjdaniels@austin.utexas.edu; betz@fhcrc.org OI Gabriel, Erin/0000-0002-0504-8404 FU National Institutes of Health [R01 CA183854, R37 AI032042]; NIAID NIH [R37AI054165] FX We are grateful to Merck & Co. Inc. (Kenilworth, New Jersey) for sharing their RotaTeqTM clinical trial data with us. The authors received no funding from Merck & Co. Inc. for this analysis nor did Merck & Co. Inc. influence the analysis in any way. M.J. Daniels was partially supported by National Institutes of Health R01 CA183854. M.E. Halloran was partially supported by National Institutes of Health R37 AI032042. We would also like to acknowledge Peter Gilbert, Michael Sachs, and James Dai for their helpful ideas, programming expertise and discussions. Peter Gilbert is partially supported by NIAID NIH Award Number R37AI054165. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 24 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 DEC PY 2016 VL 72 IS 4 BP 1046 EP 1054 DI 10.1111/biom.12513 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA EH7DC UT WOS:000391932100004 PM 27038302 ER PT J AU Rueda, C Fernandez, MA Barragan, S Mardia, KV Peddada, SD AF Rueda, Cristina Fernandez, Miguel A. Barragan, Sandra Mardia, Kanti V. Peddada, Shyamal D. TI Circular Piecewise Regression with Applications to Cell-Cycle Data SO BIOMETRICS LA English DT Article DE Circular data; Circular-circular regression; Change points; Gene expression; Generalized AIC; Von Mises distribution ID MODEL SELECTION; REGULATED GENES; ORDER; IDENTIFICATION; FREEDOM; CIRCLE AB Applications of circular regression models appear in many different fields such as evolutionary psychology, motor behavior, biology, and, in particular, in the analysis of gene expressions in oscillatory systems. Specifically, for the gene expression problem, a researcher may be interested in modeling the relationship among the phases of cell-cycle genes in two species with differing periods. This challenging problem reduces to the problem of constructing a piecewise circular regression model and, with this objective in mind, we propose a flexible circular regression model which allows different parameter values depending on sectors along the circle. We give a detailed interpretation of the parameters in the model and provide maximum likelihood estimators. We also provide a model selection procedure based on the concept of generalized degrees of freedom. The model is then applied to the analysis of two different cell-cycle data sets and through these examples we highlight the power of our new methodology. C1 [Rueda, Cristina; Fernandez, Miguel A.; Barragan, Sandra] Univ Valladolid, Dept Estadist eIO, E-47011 Valladolid, Spain. [Mardia, Kanti V.] Univ Oxford, Dept Stat, Oxford, England. [Mardia, Kanti V.] Univ Leeds, Dept Stat, Leeds, W Yorkshire, England. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Rueda, C (reprint author), Univ Valladolid, Dept Estadist eIO, E-47011 Valladolid, Spain. EM crueda@eio.uva.es; miguelaf@eio.uva.es; sandraba@eio.uva.es; K.V.Mardia@leeds.ac.uk; peddada@niehs.nih.gov OI Fernandez, Miguel/0000-0002-1272-8950 FU Spanish MCI grant [MTM2012-37129]; Junta de Castilla y Leon; European Social Fund within Programa Operativo Castilla y Leon; Intramural Research Program of the NIEHS [Z01 ES101744-04] FX This work was supported by Spanish MCI grant (MTM2012-37129 to S.B., C.R., and M.A.F.), Junta de Castilla y Leon and the European Social Fund within the Programa Operativo Castilla y Leon (2007-2013 to S.B.) and the Intramural Research Program of the NIEHS (Z01 ES101744-04 to S.D.P.). The authors thank the anonymous reviewers and the associate editor for several useful comments which improved this manuscript. 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 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD DEC PY 2016 VL 72 IS 4 BP 1266 EP 1274 DI 10.1111/biom.12512 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA EH7DC UT WOS:000391932100026 PM 26991351 ER PT J AU Potgieter, CJ Wei, RB Kipnis, V Freedman, LS Carroll, RJ AF Potgieter, Cornelis J. Wei, Rubin Kipnis, Victor Freedman, Laurence S. Carroll, Raymond J. TI Moment Reconstruction and Moment-Adjusted Imputation When Exposure Is Generated by a Complex, Nonlinear Random Effects Modeling Process SO BIOMETRICS LA English DT Article DE Berkson-type error; Classical measurement error; Computer models; Healthy Eating Index-2005; Latent variable models; Moment-adjusted imputation; Moment reconstruction; Nutritional epidemiology ID MEASUREMENT ERROR MODEL; LOGISTIC-REGRESSION; INTAKE DISTRIBUTIONS; BERKSON ERRORS; CALIBRATION; VARIABLES; DESIGNS; HEALTH; RISK AB For the classical, homoscedastic measurement error model, moment reconstruction (Freedman et al., 2004, 2008) and moment-adjusted imputation (Thomas et al., 2011) are appealing, computationally simple imputation-like methods for general model fitting. Like classical regression calibration, the idea is to replace the unobserved variable subject to measurement error with a proxy that can be used in a variety of analyses. Moment reconstruction and moment-adjusted imputation differ from regression calibration in that they attempt to match multiple features of the latent variable, and also to match some of the latent variable's relationships with the response and additional covariates. In this note, we consider a problem where true exposure is generated by a complex, nonlinear random effects modeling process, and develop analogues of moment reconstruction and moment-adjusted imputation for this case. This general model includes classical measurement errors, Berkson measurement errors, mixtures of Berkson and classical errors and problems that are not measurement error problems, but also cases where the data-generating process for true exposure is a complex, nonlinear random effects modeling process. The methods are illustrated using the National Institutes of Health-AARP Diet and Health Study where the latent variable is a dietary pattern score called the Healthy Eating Index-2005. We also show how our general model includes methods used in radiation epidemiology as a special case. Simulations are used to illustrate the methods. C1 [Potgieter, Cornelis J.] Southern Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. [Wei, Rubin] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Kipnis, Victor] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20814 USA. [Freedman, Laurence S.] Gertner Inst Epidemiol & Hlth Policy Res, Tel Hashomer, Israel. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Sch Math & Phys Sci, Sydney, NSW 2007, Australia. RP Potgieter, CJ (reprint author), Southern Methodist Univ, Dept Stat Sci, Dallas, TX 75275 USA. EM cpotgieter@smu.edu; weirubin@gmail.com; kipnisv@mail.nih.gov; lsf@actcom.co.il; carroll@stat.tamu.edu FU National Cancer Institute [U01-CA057030] FX The research of Potgieter, Wei, and Carroll was supported by a grant from the National Cancer Institute (U01-CA057030). NR 29 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 72 IS 4 BP 1369 EP 1377 DI 10.1111/biom.12524 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA EH7DC UT WOS:000391932100036 PM 27061196 ER PT J AU Sharov, AA AF Sharov, Alexei A. TI Evolutionary Biosemiotics and Multilevel Construction Networks SO BIOSEMIOTICS LA English DT Article DE Evolutionary semiotics; Constructivism; Semiotic network; Evolvability; Metasystem transition; Constraints on learning ID LIFE; ORIGIN; PROTEINS; PATTERNS; SURFACE; CANCER; WORLD; MODEL AB In contrast to the traditional relational semiotics, biosemiotics decisively deviates towards dynamical aspects of signs at the evolutionary and developmental time scales. The analysis of sign dynamics requires constructivism (in a broad sense) to explain how new components such as subagents, sensors, effectors, and interpretation networks are produced by developing and evolving organisms. Semiotic networks that include signs, tools, and subagents are multilevel, and this feature supports the plasticity, robustness, and evolvability of organisms. The origin of life is described here as the emergence of simple self-constructing semiotic networks that progressively increased the diversity of their components and relations. Primitive organisms have no capacity to classify and track objects; thus, we need to admit the existence of proto-signs that directly regulate activities of agents without being associated with objects. However, object recognition and handling became possible in eukaryotic species with the development of extensive rewritable epigenetic memory as well as sensorial and effector capacities. Semiotic networks are based on sequential and recursive construction, where each step produces components (i.e., agents, scaffolds, signs, and resources) that are needed for the following steps of construction. Construction is not limited to repair and reproduction of what already exists or is unambiguously encoded, it also includes production of new components and behaviors via learning and evolution. A special case is the emergence of new levels of organization known as metasystem transition. Multilevel semiotic networks reshape the phenotype of organisms by combining a mosaic of features developed via learning and evolution of cooperating and/or conflicting subagents. C1 [Sharov, Alexei A.] NIA, Genet Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), NIA, Genet Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sharoval@mail.nih.gov FU Intramural Research Program of the National Institute on Aging (NIA/NIH) [Z01 AG000656-13] FX This paper was supported entirely by the Intramural Research Program of the National Institute on Aging (NIA/NIH), project Z01 AG000656-13. The content of the paper is not endorsed by the funding organization. NR 73 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 EI 1875-1350 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD DEC PY 2016 VL 9 IS 3 BP 399 EP 416 DI 10.1007/s12304-016-9269-0 PG 18 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA EH0KC UT WOS:000391451800007 PM 28163801 ER PT J AU Yanik, EL AF Yanik, E. L. TI Skin cancer in the end-stage renal disease population: unique risk factors for patients on dialysis SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Editorial Material ID PHOTOTHERAPY; ULTRAVIOLET C1 [Yanik, E. L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Yanik, EL (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM eliza-beth.yanik@nih.gov OI Yanik, Elizabeth/0000-0002-5835-0201 NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD DEC PY 2016 VL 175 IS 6 BP 1136 EP 1137 DI 10.1111/bjd.15032 PG 2 WC Dermatology SC Dermatology GA EH5NZ UT WOS:000391821300041 PM 27996124 ER PT J AU Nemeth, K Gorog, A Mezey, E Pinter, D Kuroli, E Harsing, J Kovacs, L Fischer, M Rady, P Sillo, P Tyring, S Karpati, S AF Nemeth, K. Gorog, A. Mezey, E. Pinter, D. Kuroli, E. Harsing, J. Kovacs, L. Fischer, M. Rady, P. Sillo, P. Tyring, S. Karpati, S. TI Cover Image: Detection of hair follicle-associated Merkel cell polyomavirus in an immunocompromised host with follicular spicules and alopecia SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Letter C1 [Nemeth, K.; Gorog, A.; Pinter, D.; Kuroli, E.; Harsing, J.; Sillo, P.; Karpati, S.] Semmelweis Univ, Dept Dermatol, Budapest, Hungary. [Kovacs, L.] Semmelweis Univ, Dept Pediat 1, Budapest, Hungary. [Nemeth, K.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA. [Mezey, E.] NIDCR, Adult Stem Cell Sect, CSDB, NIH, Bethesda, MD USA. [Fischer, M.] Univ Maryland, Sch Med, Dept Dermatol, Baltimore, MD 21201 USA. [Rady, P.; Tyring, S.] Univ Texas Houston, Sch Med, Dept Dermatol, Houston, TX USA. RP Nemeth, K; Karpati, S (reprint author), Semmelweis Univ, Dept Dermatol, Budapest, Hungary.; Nemeth, K (reprint author), Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA. EM knemeth@mcw.edu; skarpati@t-online.hu 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 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD DEC PY 2016 VL 175 IS 6 BP 1409 EP 1409 DI 10.1111/bjd.15039 PG 1 WC Dermatology SC Dermatology GA EH5NZ UT WOS:000391821300101 PM 27996135 ER PT J AU Sadlier, M Storan, E Fitzgerald, S Neville, S Watson, R Irvine, A Leahy, R Milner, J O'Regan, G AF Sadlier, M. Storan, E. Fitzgerald, S. Neville, S. Watson, R. Irvine, A. Leahy, R. Milner, J. O'Regan, G. TI Novel gain of function mutation in STAT5b presenting with urticaria, atopic dermatitis, alopecia areata, granulomatous dermatitis and complex autoimmunity SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the British-Society-for-Paediatric-Dermatology CY NOV 18-19, 2016 CL Sheffield, ENGLAND SP British Soc Paediat Dermatol C1 [Sadlier, M.; Storan, E.; Fitzgerald, S.; Neville, S.; Watson, R.; Irvine, A.; O'Regan, G.] Our Ladys Childrens Hosp Crumlin, Dept Dermatol, Dublin, Ireland. [Leahy, R.] Our Ladys Childrens Hosp Crumlin, Dept Immunol, Dublin, Ireland. [Milner, J.] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD DEC PY 2016 VL 175 IS 6 MA P4 BP E156 EP E156 PG 1 WC Dermatology SC Dermatology GA EH5NZ UT WOS:000391821300019 ER PT J AU Cooper, LL Palmisano, JN Benjamin, EJ Larson, MG Vasan, RS Mitchell, GF Hamburg, NM AF Cooper, Leroy L. Palmisano, Joseph N. Benjamin, Emelia J. Larson, Martin G. Vasan, Ramachandran S. Mitchell, Gary F. Hamburg, Naomi M. TI Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events The Framingham Heart Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE arteries; cardiovascular diseases; endothelium; pulse wave analysis; vascular stiffness ID FLOW-MEDIATED DILATION; PULSE-WAVE VELOCITY; END-ORGAN DAMAGE; ARTERIAL STIFFNESS; PREDICTIVE-VALUE; BRACHIAL-ARTERY; VASA VASORUM; PRESSURE; RISK; DISEASE AB Background Arterial dysfunction contributes to cardiovascular disease (CVD) progression and clinical events. Interrelations of aortic stiffness and vasodilator function with incident CVD remain incompletely studied. Methods and Results We used proportional hazards models to relate individual measures of vascular function to incident CVD in 4547 participants (mean age, 51 +/- 11 years; 54% women) in 2 generations of Framingham I Ieart Study participants. During follow-up (0,02-13,83 years), 232 participants (5%) experienced new-onset CVD events, In multivariable models adjusted for cardiovascular risk factors, both higher carotid-femoral pulse wave velocity (hazard ratio [HR], 1,32; 95% confidence interval ICU 1.07-1.63; P=0,01) and lower hyperemic mean flow velocity (HR, 0,84; 95% CI, 0.71-0,99; P=0,04) were associated significantly with incident CVD, whereas primary pressure wave amplitude (HR, 1,12; 95% CI, 0.99-1,27; P=0,06), baseline brachial diameter (HR, 1.09; 95% CI, 0,90-1,31; P=0,39), and flow-mediated vasodilation (11R, 0,85; 95% CI, 0,69-1,04; P=0.12) were not. In mediation analyses, 8% to 13% of the relation between aortic stiffness and CVD events was mediated by hyperemic mean flow velocity. Conclusions Our results suggest that associations between aortic stiffness and CVD events are mediated by pathways that include microvascular damage and remodeling, C1 [Cooper, Leroy L.; Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Cooper, Leroy L.] Brown Univ, Cardiovasc Res Ctr, Lifespan Cardiovasc Inst, W Alpert Med Sch, Providence, RI 02912 USA. [Palmisano, Joseph N.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02218 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02218 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02218 USA. [Benjamin, Emelia J.; Larson, Martin G.; Vasan, Ramachandran S.] Boston Univ, Boston, MA 02218 USA. [Benjamin, Emelia J.; Larson, Martin G.; Vasan, Ramachandran S.] NHLBI, Framingham Study, Bldg 10, Bethesda, MD 20892 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02218 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02218 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.; Hamburg, Naomi M.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02218 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, 88 E Newton St,Suite C-818, Boston, MA 02218 USA. RP Hamburg, NM (reprint author), Boston Univ, Sch Med, Whitaker Cardiovasc Inst, 88 E Newton St,Suite C-818, Boston, MA 02218 USA. EM nhamburg@bu.edu FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, HL126136, HL128914, 2-K24-HL04334]; UNCF/Merck Science Initiative FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract Nos. N01-HC-25195 and HHSN268201500001I) and by HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, HL126136, HL128914, and 2-K24-HL04334. Dr Cooper was supported by the UNCF/Merck Science Initiative. NR 41 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 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD DEC PY 2016 VL 9 IS 12 AR e004979 DI 10.1161/CIRCIMAGING.116.004979 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EH5OO UT WOS:000391822800004 ER PT J AU Mehta, NN AF Mehta, Nehal N. TI Positron Emission Tomography Assessment of Left Main Coronary Arterial Inflammation With Coronary Computed Tomographic Angiography Validation Before and After Statin Therapy More Promise for Fluorodeoxyglucose Vascular Uptake? SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE Editorials; atherosclerosis; carotid artery; coronary artery disease; inflammation; positron emission tomography ID FDG PET/CT; ATHEROSCLEROSIS; REDUCTION; CALCIUM; EVENTS; RISK C1 [Mehta, Nehal N.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometabol Dis, Clin Res Ctr, 10 Ctr Dr,Room 5-5140, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD DEC PY 2016 VL 9 IS 12 AR e005745 DI 10.1161/CIRCIMAGING.116.005745 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EH5OO UT WOS:000391822800012 ER PT J AU Rogers, T Lederman, RJ AF Rogers, Toby Lederman, Robert J. TI Exercise Magnetic Resonance Imaging Is a Gas SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE Editorials; cardiac output; cardiopulmonary exercise test; congenital heart defects; magnetic resonance imaging; pediatrics; pulmonary hypertension ID MRI; CATHETERIZATION C1 [Rogers, Toby; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. RP Rogers, T (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM toby.rogers@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD DEC PY 2016 VL 9 IS 12 AR e005795 DI 10.1161/CIRCIMAGING.116.005795 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EH5OO UT WOS:000391822800013 ER PT J AU Yeboah, J Bertoni, A Qureshi, W Aggarwal, S Lima, JAC Kawel-Boehm, N Bluemke, DA Shah, SJ AF Yeboah, Joseph Bertoni, Alain Qureshi, Waqas Aggarwal, Shivani Lima, Joao A. C. Kawel-Boehm, Nadine Bluemke, David A. Shah, Sanjiv J. TI Pedal Edema as an Indicator of Early Heart Failure in the Community Prevalence and Associations With Cardiac Structure/Function and Natriuretic Peptides (MESA [Multiethnic Study of Atherosclerosis]) SO CIRCULATION-HEART FAILURE LA English DT Article DE cardiac structure and function; heart failure; natriuretic peptides; orthopnea; paroxysmal nocturnal dyspnea; pedal edema ID PRESERVED EJECTION FRACTION; RIGHT VENTRICLE; PRACTICE GUIDELINES; CLINICAL-TRIALS; TASK-FORCE; MANAGEMENT; DYSFUNCTION; PROGNOSIS; DIAGNOSIS; VALUES AB Background-The prevalence of pedal edema (PE) and its associations with abnormal cardiac structure/function, natriuretic peptides, and incident heart failure (HF) is unknown, especially in community-dwelling adults without a history of cardiovascular disease. Methods and Results-Out of 5004 MESA (Multiethnic Study of Atherosclerosis) participants who had cardiac magnetic resonance imaging, 4196 had complete data and were included in this analysis (3501 for the right ventricle analysis). Logistic regression and Cox proportional hazard analyses were used to assess the associations among self-reported PE, 2-pillow orthopnea, paroxysmal nocturnal dyspnea, left and right ventricular structure and function, natriuretic peptide levels, and incident HF. PE was present in 28% of the participants. PE was not associated with overt left or right ventricular systolic dysfunction (ejection fraction <50%). PE was associated with 2-pillow orthopnea (odds ratio 1.66; 95% confidence interval [CI], 1.30-2.12), paroxysmal nocturnal dyspnea (odds ratio 1.95; 95% CI, 1.55-2.44), and abnormal N-terminal pro-B-type natriuretic peptide levels (defined as >400 pg/mL; odds ratio 1.80; 95% CI, 1.21-2.68) in adjusted models. After a mean of 10.2 years of follow-up, 184/4196 (4.4%) participants had an adjudicated incident HF hospitalization. PE was associated with incident HF hospitalization in models adjusted for age, sex, and race (hazard ratio 1.44; 95% CI, 1.05-1.97). This association persisted after adding additional covariates, including comorbidities, baseline left ventricular ejection fraction, and antecedent myocardial infarction (hazard ratio 1.43; 95% CI, 1.02-1.99). The association of PE with incident HF was attenuated by further adjustment for N-terminal pro-B-type natriuretic peptide. Conclusions-PE is prevalent in community-dwelling adults without clinically recognized cardiovascular disease and associated with future hospitalized HF. C1 [Yeboah, Joseph; Qureshi, Waqas; Aggarwal, Shivani] Wake Forest Univ, Sch Med, Heart & Vasc Ctr Excellence, Winston Salem, NC 27109 USA. [Bertoni, Alain] Wake Forest Univ, Sch Med, Dept Epidemiol, Winston Salem, NC 27109 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol & Radiol, Baltimore, MD USA. [Kawel-Boehm, Nadine] Kantonsspital Graubuenden Clin Radiol, Loestr 170, CH-7000 Chur, Switzerland. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Shah, Sanjiv J.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. RP Yeboah, J (reprint author), Wake Forest Sch Med, Heart & Vasc Ctr Excellence, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jyeboah@wakehealth.edu FU National Heart, Lung, and Blood Institute [HHSN268201500003I, 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]; NCRR [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts HHSN268201500003I, 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 NCRR. NR 28 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD DEC PY 2016 VL 9 IS 12 AR e003415 DI 10.1161/CIRCHEARTFAILURE.116.003415 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EH5PD UT WOS:000391824300005 ER PT J AU Vo, LC Snyder, C McCracken, C McDougle, CJ McCracken, JT Aman, MG Tierney, E Arnold, LE Levi, D Kelleman, M Carroll, D Morrissey, J Vitiello, B Scahill, L AF Vo, Lan Chi Snyder, Christopher McCracken, Courtney McDougle, Christopher J. McCracken, James T. Aman, Michael G. Tierney, Elaine Arnold, L. Eugene Levi, Daniel Kelleman, Michael Carroll, Deirdre Morrissey, John Vitiello, Benedetto Scahill, Lawrence TI No Apparent Cardiac Conduction Effects of Acute Treatment with Risperidone in Children with Autism Spectrum Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article DE risperidone; electrocardiogram; QTc; autism spectrum disorder; cardiac conduction ID PERVASIVE DEVELOPMENTAL DISORDERS; ABERRANT BEHAVIOR CHECKLIST; QT INTERVAL; ANTIPSYCHOTIC TREATMENT; ADOLESCENTS; RISK; DRUG; SCHIZOPHRENIA; ARIPIPRAZOLE; MEDICATIONS AB Objectives: Risperidone is approved for the treatment of serious behavioral problems in children with autism spectrum disorder (ASD). This study examined the effects of risperidone on cardiac conduction in children with ASD. Methods: Data were collected from an 8-week, five-site trial conducted by the Research Units on Pediatric Psychopharmacology Autism Network. Children (age 5-17 years) were randomly assigned to risperidone (n = 49) or placebo (n = 52) under double-blind conditions. Risperidone was superior to placebo in reducing serious behavioral problems. A standard 12-lead, electrocardiogram (ECG) was obtained in most subjects at screening and week 8. A pediatric electrophysiologist blind to treatment assignment reviewed all available ECGs for readability, abnormalities, and cardiac conduction parameters, including QTc. The electrophysiologist measurements were compared to machine readings. A second blinded electrophysiologist examined all available ECGs for abnormalities and a 20% random sample for QTc. Results: Of the 101 randomized subjects in the trial, complete pretreatment and week 8 data were available on 65 subjects (placebo n = 30; risperidone n = 35). The electrophysiologist did not identify any cardiac conduction adverse effects of risperidone and there was no difference in mean change on the QTc compared to placebo. The Bland-Altman plot showed a systematic bias in QTc measurements by the electrophysiologist and machine. Machine readings produced higher values than the electrophysiologist for shorter QTc intervals and machine scoring was lower than electrophysiologist readings for longer QTc values (p = 0.001). Two electrophysiologists had overall percent agreements of 82.9% (95% CI: 76.3 to 89.6) on qualitative assessment and 88.6% (95% CI: 79.3 to 98.0) on QTc interval. Conclusion: Using conventional doses during acute treatment in children with ASD and serious behavioral problems, there was no difference in the mean change in QTc between risperidone and placebo. Compared to the electrophysiologist, the machine readings may miss elevated QTc measurements. C1 [Vo, Lan Chi] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Snyder, Christopher] Rainbow Babies & Childrens Hosp, Div Pediat Cardiol, Univ Hosp, 2101 Adelbert Rd, Cleveland, OH 44106 USA. [McCracken, Courtney; Kelleman, Michael] Childrens Hosp Atlanta, Atlanta, GA USA. [McCracken, Courtney; Kelleman, Michael] Emory Univ, Sch Med, Atlanta, GA USA. [McDougle, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Boston, MA USA. [McCracken, James T.] Univ Calif Los Angeles, Div Child Psychiat, Los Angeles, CA USA. [Aman, Michael G.; Arnold, L. Eugene] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Tierney, Elaine] Kennedy Krieger Inst, Baltimore, MD USA. [Levi, Daniel; Morrissey, John] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Carroll, Deirdre] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Scahill, Lawrence] Emory Univ, Sch Med, Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. RP Scahill, L (reprint author), Emory Univ, Sch Med, Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. EM lawrence.scahill@emory.edu FU National Institute of Mental Health [N01MH70009, N01MH70010, N01MH70001, N01MH80011, R25MH101079]; National Institutes of Health [M01 RR00750, M01 RR00052, M01 RR00034, M01 RR06022]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000454]; Marcus Foundation; Children's Hospital Trust Fund FX Supported by contracts from the National Institute of Mental Health (N01MH70009, to Dr. Scahill; N01MH70010, to Dr. J. McCracken; N01MH70001, to Dr. McDougle; and N01MH80011, to Dr. Aman). General Clinical Research Center grants from the National Institutes of Health (M01 RR00750, to Indiana University; M01 RR00052, to Johns Hopkins University; M01 RR00034, to Ohio State University; and M01 RR06022, to Yale University). The project was the National Center for Advancing Translational Sciences of the National Institutes of Health UL1 TR000454 (Emory University) as well as the Marcus Foundation and the Children's Hospital Trust Fund. Dr. Vo has received training support from the National Institute of Mental Health (R25MH101079) to Emory University. NR 41 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD DEC PY 2016 VL 26 IS 10 BP 900 EP 908 DI 10.1089/cap.2016.0090 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA EH5TT UT WOS:000391836500006 PM 27726426 ER PT J AU Southey, MC Goldgar, DE Winqvist, R Pylkas, K Couch, F Tischkowitz, M Foulkes, WD Dennis, J Michailidou, K van Rensburg, EJ Heikkinen, T Nevanlinna, H Hopper, JL Dork, T Claes, KBM Reis, J Teo, ZL Radice, P Catucci, I Peterlongo, P Tsimiklis, H Odefrey, FA Dowty, JG Schmidt, MK Broeks, A Hogervorst, FB Verhoef, S Carpenter, J Clarke, C Scott, RJ Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Peto, J dos-Santos-Silva, I Fletcher, O Johnson, N Bolla, MK Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Marme, F Burwinkel, B Yang, RX Guenel, P Truong, T Menegaux, F Sanchez, M Bojesen, S Nielsen, SF Flyger, H Benitez, J Zamora, MP Perez, JIA Menendez, P Anton-Culver, H Neuhausen, S Ziogas, A Clarke, CA Brenner, H Arndt, V Stegmaier, C Brauch, H Bruning, T Ko, YD Muranen, TA Aittomaki, K Blomqvist, C Bogdanova, NV Antonenkova, NN Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Spurdle, AB Wauters, E Smeets, D Beuselinck, B Floris, G Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Olson, JE Vachon, C Pankratz, VS McLean, C Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Kristensen, V Alnaes, GG Zheng, W Hunter, DJ Lindstrom, S Hankinson, SE Kraft, P Andrulis, I Knight, JA Glendon, G Mulligan, AM Jukkola-Vuorinen, A Grip, M Kauppila, S Devilee, P Tollenaar, RAEM Seynaeve, C Hollestelle, A Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Czene, K Darabi, H Eriksson, M Eccles, DM Rafiq, S Tapper, WJ Gerty, SM Hooning, MJ Martens, JWM Collee, JM Tilanus-Linthorst, M Hall, P Li, JM Brand, JS Humphreys, K Cox, A Reed, MWR Luccarini, C Baynes, C Dunning, AM Hamann, U Torres, D Ulmer, HU Rudiger, T Jakubowska, A Lubinski, J Jaworska, K Durda, K Slager, S Toland, AE Ambrosone, CB Yannoukakos, D Swerdlow, A Ashworth, A Orr, N Jones, M Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, N Herrero, D Tessier, DC Vincent, D Bacot, F Simard, J Dumont, M Soucy, P Eeles, R Muir, K Wiklund, F Gronberg, H Schleutker, J Nordestgaard, BG Weischer, M Travis, RC Neal, D Donovan, JL Hamdy, FC Khaw, KT Stanford, JL Blot, WJ Thibodeau, S Schaid, DJ Kelley, JL Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Butterbach, K Park, J Kaneva, R Batra, J Teixeira, MR Kote-Jarai, Z Al Olama, AA Benlloch, S Renner, SP Hartmann, A Hein, A Ruebner, M Lambrechts, D Van Nieuwenhuysen, E Vergote, I Lambretchs, S Doherty, JA Rossing, MA Nickels, S Eilber, U Wang-Gohrke, S Odunsi, K Sucheston-Campbell, LE Friel, G Lurie, G Killeen, JL Wilkens, LR Goodman, MT Runnebaum, I Hillemanns, PA Pelttari, LM Butzow, R Modugno, F Edwards, RP Ness, RB Moysich, KB du Bois, A Heitz, F Harter, P Kommoss, S Karlan, BY Walsh, C Lester, J Jensen, A Kjaer, SK Hogdall, E Peissel, B Bonanni, B Bernard, L Goode, EL Fridley, BL Vierkant, RA Cunningham, JM Larson, MC Fogarty, ZC Kalli, KR Liang, D Lu, KH Hildebrandt, MAT Wu, XF Levine, DA Dao, F Bisogna, M Berchuck, A Iversen, ES Marks, JR Akushevich, L Cramer, DW Schildkraut, J Terry, KL Poole, EM Stampfer, M Tworoger, SS Bandera, EV Orlow, I Olson, SH Bjorge, L Salvesen, HB van Altena, AM Aben, KKH Kiemeney, LA Massuger, LFAG Pejovic, T Bean, Y Brooks-Wilson, A Kelemen, LE Cook, LS Le, ND Grski, B Gronwald, J Menkiszak, J Hogdall, CK Lundvall, L Nedergaard, L Engelholm, SA Dicks, E Tyrer, J Campbell, I McNeish, I Paul, J Siddiqui, N Glasspool, R Whittemore, AS Rothstein, JH McGuire, V Sieh, W Cai, H Shu, XO Teten, RT Sutphen, R McLaughlin, JR Narod, SA Phelan, CM Monteiro, AN Fenstermacher, D Lin, HY Permuth, JB Sellers, TA Chen, YA Tsai, YY Chen, ZH Gentry-Maharaj, A Gayther, SA Ramus, SJ Menon, U Wu, AH Pearce, CL Van den Berg, D Pike, MC Dansonka-Mieszkowska, A Plisiecka-Halasa, J Moes-Sosnowska, J Kupryjanczyk, J Pharoah, PDP Song, HL Winship, I Chenevix-Trench, G Giles, GG Tavtigian, SV Easton, DF Milne, RL AF Southey, Melissa C. Goldgar, David E. Winqvist, Robert Pylkas, Katri Couch, Fergus Tischkowitz, Marc Foulkes, William D. Dennis, Joe Michailidou, Kyriaki van Rensburg, Elizabeth J. Heikkinen, Tuomas Nevanlinna, Heli Hopper, John L. Doerk, Thilo Claes, Kathleen B. M. Reis-Filho, Jorge Teo, Zhi Ling Radice, Paolo Catucci, Irene Peterlongo, Paolo Tsimiklis, Helen Odefrey, Fabrice A. Dowty, James G. Schmidt, Marjanka K. Broeks, Annegien Hogervorst, Frans B. Verhoef, Senno Carpenter, Jane Clarke, Christine Scott, Rodney J. Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Peto, Julian dos-Santos-Silva, Isabel Fletcher, Olivia Johnson, Nichola Bolla, Manjeet K. Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Marme, Federik Burwinkel, Barbara Yang, Rongxi Guenel, Pascal Therese Truong Menegaux, Florence Sanchez, Marie Bojesen, Stig Nielsen, Sune F. Flyger, Henrik Benitez, Javier Pilar Zamora, M. Arias Perez, Jose Ignacio Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan Ziogas, Argyrios Clarke, Christina A. Brenner, Hermann Arndt, Volker Stegmaier, Christa Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Bogdanova, Natalia V. Antonenkova, Natalia N. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Spurdle, Amanda B. Wauters, Els Smeets, Dominiek Beuselinck, Benoit Floris, Giuseppe Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Olson, Janet E. Vachon, Celine Pankratz, Vernon S. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Kristensen, Vessela Alnaes, Grethe Grenaker Zheng, Wei Hunter, David J. Lindstrom, Sara Hankinson, Susan E. Kraft, Peter Andrulis, Irene Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Jukkola-Vuorinen, Arja Grip, Mervi Kauppila, Saila Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Hollestelle, Antoinette Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Eccles, Diana M. Rafiq, Sajjad Tapper, William J. Gerty, Sue M. Hooning, Maartje J. Martens, John W. M. Collee, J. Margriet Tilanus-Linthorst, Madeleine Hall, Per Li, Jingmei Brand, Judith S. Humphreys, Keith Cox, Angela Reed, Malcolm W. R. Luccarini, Craig Baynes, Caroline Dunning, Alison M. Hamann, Ute Torres, Diana Ulmer, Hans Ulrich Ruediger, Thomas Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Slager, Susan Toland, Amanda E. Ambrosone, Christine B. Yannoukakos, Drakoulis Swerdlow, Anthony Ashworth, Alan Orr, Nick Jones, Michael Gonzalez-Neira, Anna Pita, Guillermo Rosario Alonso, M. Alvarez, Nuria Herrero, Daniel Tessier, Daniel C. Vincent, Daniel Bacot, Francois Simard, Jacques Dumont, Martine Soucy, Penny Eeles, Rosalind Muir, Kenneth Wiklund, Fredrik Gronberg, Henrik Schleutker, Johanna Nordestgaard, Borge G. Weischer, Maren Travis, Ruth C. Neal, David Donovan, Jenny L. Hamdy, Freddie C. Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Schaid, Daniel J. Kelley, Joseph L. Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Butterbach, Katja Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Renner, Stefan P. Hartmann, Arndt Hein, Alexander Ruebner, Matthias Lambrechts, Diether Van Nieuwenhuysen, Els Vergote, Ignace Lambretchs, Sandrina Doherty, Jennifer A. Rossing, Mary Anne Nickels, Stefan Eilber, Ursula Wang-Gohrke, Shan Odunsi, Kunle Sucheston-Campbell, Lara E. Friel, Grace Lurie, Galina Killeen, Jeffrey L. Wilkens, Lynne R. Goodman, Marc T. Runnebaum, Ingo Hillemanns, Peter A. Pelttari, Liisa M. Butzow, Ralf Modugno, Francesmary Edwards, Robert P. Ness, Roberta B. Moysich, Kirsten B. du Bois, Andreas Heitz, Florian Harter, Philipp Kommoss, Stefan Karlan, Beth Y. Walsh, Christine Lester, Jenny Jensen, Allan Kjaer, Susanne Kruger Hogdall, Estrid Peissel, Bernard Bonanni, Bernardo Bernard, Loris Goode, Ellen L. Fridley, Brooke L. Vierkant, Robert A. Cunningham, Julie M. Larson, Melissa C. Fogarty, Zachary C. Kalli, Kimberly R. Liang, Dong Lu, Karen H. Hildebrandt, Michelle A. T. Wu, Xifeng Levine, Douglas A. Dao, Fanny Bisogna, Maria Berchuck, Andrew Iversen, Edwin S. Marks, Jeffrey R. Akushevich, Lucy Cramer, Daniel W. Schildkraut, Joellen Terry, Kathryn L. Poole, Elizabeth M. Stampfer, Meir Tworoger, Shelley S. Bandera, Elisa V. Orlow, Irene Olson, Sara H. Bjorge, Line Salvesen, Helga B. van Altena, Anne M. Aben, Katja K. H. Kiemeney, Lambertus A. Massuger, Leon F. A. G. Pejovic, Tanja Bean, Yukie Brooks-Wilson, Angela Kelemen, Linda E. Cook, Linda S. Le, Nhu D. Grski, Bohdan Gronwald, Jacek Menkiszak, Janusz Hogdall, Claus K. Lundvall, Lene Nedergaard, Lotte Engelholm, Svend Aage Dicks, Ed Tyrer, Jonathan Campbell, Ian McNeish, Iain Paul, James Siddiqui, Nadeem Glasspool, Rosalind Whittemore, Alice S. Rothstein, Joseph H. McGuire, Valerie Sieh, Weiva Cai, Hui Shu, Xiao-Ou Teten, Rachel T. Sutphen, Rebecca McLaughlin, John R. Narod, Steven A. Phelan, Catherine M. Monteiro, Alvaro N. Fenstermacher, David Lin, Hui-Yi Permuth, Jennifer B. Sellers, Thomas A. Chen, Y. Ann Tsai, Ya-Yu Chen, Zhihua Gentry-Maharaj, Aleksandra Gayther, Simon A. Ramus, Susan J. Menon, Usha Wu, Anna H. Pearce, Celeste L. Van den Berg, David Pike, Malcolm C. Dansonka-Mieszkowska, Agnieszka Plisiecka-Halasa, Joanna Moes-Sosnowska, Joanna Kupryjanczyk, Jolanta Pharoah, Paul D. P. Song, Honglin Winship, Ingrid Chenevix-Trench, Georgia Giles, Graham G. Tavtigian, Sean V. Easton, Doug F. Milne, Roger L. CA kConFab Investigators Australian Ovarian Canc Study Grp TI PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID BREAST-CANCER; PROSTATE-CANCER; OVARIAN-CANCER; BRCA2-INTERACTING PROTEIN; SUSCEPTIBILITY LOCI; FAMILY REGISTRY; GENE; MUTATIONS; BRCA1; METAANALYSIS AB Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. C1 [Southey, Melissa C.; Teo, Zhi Ling; Tsimiklis, Helen; Odefrey, Fabrice A.] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. [Goldgar, David E.; Tavtigian, Sean V.] Huntsman Canc Inst, Salt Lake City, UT USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Canc & Translat Med Res Unit, Nordlab Oulu, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Couch, Fergus; Thibodeau, Stephen; Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Tischkowitz, Marc] Univ Cambridge, Dept Med Genet, Cambridge, England. 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[Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki 00029, Hus, Finland. [Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Modugno, Francesmary] Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [du Bois, Andreas; Heitz, Florian; Harter, Philipp] Evang Huyssens Stiftung Knappschaft GmbH, Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [du Bois, Andreas; Heitz, Florian; Harter, Philipp; Kommoss, Stefan] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Kommoss, Stefan] Tuebingen Univ Hosp, Dept Womens Hlth, Tubingen, Germany. [Karlan, Beth Y.; Walsh, Christine; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid] Danish Canc Soc, Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Kjaer, Susanne Kruger; Hogdall, Claus K.] Rigshosp, Dept Obstet & Gynecol, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Milan, Italy. [Bernard, Loris] IEO, Dept Expt Oncol, Milan, Italy. [Bernard, Loris] Cogentech Canc Genet Test Lab, Milan, Italy. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Levine, Douglas A.; Dao, Fanny; Bisogna, Maria] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Marks, Jeffrey R.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Akushevich, Lucy; Schildkraut, Joellen] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Stampfer, Meir; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Stampfer, Meir; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bandera, Elisa V.] State Univ New Jersey, Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Orlow, Irene; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Bjorge, Line; Salvesen, Helga B.] Haukeland Univ Horpital, Dept Gynecol & Obstet, Bergen, Norway. [Bjorge, Line; Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [van Altena, Anne M.; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Aben, Katja K. H.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [Aben, Katja K. H.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Bean, Yukie] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC USA. [Kelemen, Linda E.] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Grski, Bohdan; Gronwald, Jacek] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Gynecol Surg & Gynecol Oncol Adults & Adoles, Szczecin, Poland. [Lundvall, Lene] Univ Copenhagen, Rigshosp, Gyn Clin, Copenhagen, Denmark. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, Copenhagen, Denmark. [Engelholm, Svend Aage] Univ Copenhagen, Rigshosp, Dept Oncol, Copenhagen, Denmark. [Dicks, Ed; Tyrer, Jonathan; Pharoah, Paul D. P.; Song, Honglin] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge, England. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Australia. [McNeish, Iain] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Inst Canc Sci, Glasgow, Lanark, Scotland. [Paul, James] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, 1053 Great Western Rd, Glasgow G12 0YN, Lanark, Scotland. [Siddiqui, Nadeem; Glasspool, Rosalind] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland. [Whittemore, Alice S.; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Teten, Rachel T.; Sutphen, Rebecca] Univ S Florida, Coll Med, Epidemiol Ctr, Tampa, FL USA. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [Narod, Steven A.] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada. [Phelan, Catherine M.; Monteiro, Alvaro N.; Permuth, Jennifer B.; Sellers, Thomas A.; Tsai, Ya-Yu] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Fenstermacher, David; Lin, Hui-Yi; Chen, Y. Ann; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.; Van den Berg, David; Pike, Malcolm C.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Inst Oncol, Warsaw, Poland. [Winship, Ingrid] Univ Melbourne Hlth, Dept Med, Melbourne, Vic, Australia. [Winship, Ingrid] Royal Melbourne Hosp, Melbourne, Vic 3050, Australia. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Cancer Epidemiol Ctr, Melbourne, Vic, Australia. RP Southey, MC (reprint author), Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. EM msouthey@unimelb.edu.au RI Hein, Alexander/F-6999-2010; Gronwald, Jacek/A-4576-2017; Menkiszak, Janusz/I-4036-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Hartikainen, Jaana/E-6256-2015; salvesen, Helga/C-1187-2017; Knight, Julia/A-6843-2012; Brooks-Wilson, Angela/E-9399-2012; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; Peissel, Bernard/E-8187-2017; Dork, Thilo/J-8620-2012; OI Dunning, Alison Margaret/0000-0001-6651-7166; Winship, Ingrid/0000-0001-8535-6003; Arndt, Volker/0000-0001-9320-8684; Li, Jingmei/0000-0001-8587-7511; Hein, Alexander/0000-0003-2601-3398; Gronwald, Jacek/0000-0002-3643-2871; salvesen, Helga/0000-0002-4438-8831; Brooks-Wilson, Angela/0000-0003-1009-6408; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Peissel, Bernard/0000-0001-9233-3571; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, CRUK C8197/A10123]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1 U19 CA 148537]; 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; Susan G Komen FX 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, C5047/A8384, C5047/A15007, C5047/A10692, CRUK C8197/A10123), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537-the GAME-ON initiative), the 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, the Ovarian Cancer Research Fund and Susan G Komen (WF). NR 35 TC 4 Z9 4 U1 12 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2016 VL 53 IS 12 BP 800 EP 811 DI 10.1136/jmedgenet-2016-103839 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EH0MC UT WOS:000391457200003 PM 27595995 ER PT J AU Postmus, I Warren, HR Trompet, S Arsenault, BJ Avery, CL Bis, JC Chasman, DI de Keyser, CE Deshmukh, HA Evans, DS Feng, QP Li, XH Smit, RAJ Smith, AV Sun, FG Taylor, KD Arnold, AM Barnes, MR Barratt, BJ Betteridge, J Boekholdt, SM Boerwinkle, E Buckley, BM Chen, YDI de Craen, AJM Cummings, SR Denny, JC Dube, MP Durrington, PN Eiriksdottir, G Ford, I Guo, XQ Harris, TB Heckbert, SR Hofman, A Hovingh, GK Kastelein, JJP Launer, LJ Liu, CT Liu, YM Lumley, T McKeigue, PM Munroe, PB Neil, A Nickerson, DA Nyberg, F O'Brien, E O'Donnell, CJ Post, W Poulter, N Vasan, RS Rice, K Rich, SS Rivadeneira, F Sattar, N Sever, P Shaw-Hawkins, S Shields, DC Slagboom, PE Smith, NL Smith, JD Sotoodehnia, N Stanton, A Stott, DJ Stricker, BH Sturmer, T Uitterlinden, AG Wei, WQ Westendorp, RGJ Whitsel, EA Wiggins, KL Wilke, RA Ballantyne, CM Colhoun, HM Cupples, LA Franco, OH Gudnason, V Hitman, G Palmer, CNA Psaty, BM Ridker, PM Stafford, JM Stein, CM Tardif, JC Caulfield, MJ Jukema, JW Rotter, JI Krauss, RM AF Postmus, Iris Warren, Helen R. Trompet, Stella Arsenault, Benoit J. Avery, Christy L. Bis, Joshua C. Chasman, Daniel I. de Keyser, Catherine E. Deshmukh, Harshal A. Evans, Daniel S. Feng, QiPing Li, Xiaohui Smit, Roelof A. J. Smith, Albert V. Sun, Fangui Taylor, Kent D. Arnold, Alice M. Barnes, Michael R. Barratt, Bryan J. Betteridge, John Boekholdt, S. Matthijs Boerwinkle, Eric Buckley, Brendan M. Chen, Y-D Ida de Craen, Anton J. M. Cummings, Steven R. Denny, Joshua C. Dube, Marie Pierre Durrington, Paul N. Eiriksdottir, Gudny Ford, Ian Guo, Xiuqing Harris, Tamara B. Heckbert, Susan R. Hofman, Albert Hovingh, G. Kees Kastelein, John J. P. Launer, Leonore J. Liu, Ching-Ti Liu, Yongmei Lumley, Thomas McKeigue, Paul M. Munroe, Patricia B. Neil, Andrew Nickerson, Deborah A. Nyberg, Fredrik O'Brien, Eoin O'Donnell, Christopher J. Post, Wendy Poulter, Neil Vasan, Ramachandran S. Rice, Kenneth Rich, Stephen S. Rivadeneira, Fernando Sattar, Naveed Sever, Peter Shaw-Hawkins, Sue Shields, Denis C. Slagboom, P. Eline Smith, Nicholas L. Smith, Joshua D. Sotoodehnia, Nona Stanton, Alice Stott, David J. Stricker, Bruno H. Sturmer, Til Uitterlinden, Andre G. Wei, Wei-Qi Westendorp, Rudi G. J. Whitsel, Eric A. Wiggins, Kerri L. Wilke, Russell A. Ballantyne, Christie M. Colhoun, Helen M. Cupples, L. Adrienne Franco, Oscar H. Gudnason, Vilmundur Hitman, Graham Palmer, Colin N. A. Psaty, Bruce M. Ridker, Paul M. Stafford, Jeanette M. Stein, Charles M. Tardif, Jean-Claude Caulfield, Mark J. Jukema, J. Wouter Rotter, Jerome I. Krauss, Ronald M. TI Meta-analysis of genome-wide association studies of HDL cholesterol response to statins SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; TRANSFER PROTEIN GENE; CORONARY ATHEROSCLEROSIS; CARDIOVASCULAR EVENTS; LOWERING RESPONSE; LDL CHOLESTEROL; ATORVASTATIN; DISEASE; RISK; LIPIDS AB Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1x10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5x10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels. C1 [Postmus, Iris; Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Warren, Helen R.; Barnes, Michael R.; Munroe, Patricia B.; Shaw-Hawkins, Sue; Caulfield, Mark J.] Queen Mary Univ London, Dept Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Warren, Helen R.; Barnes, Michael R.; Munroe, Patricia B.; Shaw-Hawkins, Sue; Caulfield, Mark J.] Queen Mary Univ London, Barts NIHR Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Trompet, Stella; Smit, Roelof A. J.; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Arsenault, Benoit J.; Dube, Marie Pierre; Tardif, Jean-Claude] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Avery, Christy L.; Sturmer, Til; Whitsel, Eric A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Bis, Joshua C.; Lumley, Thomas; Sotoodehnia, Nona; Wiggins, Kerri L.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [de Keyser, Catherine E.; Hofman, Albert; Stricker, Bruno H.; Uitterlinden, Andre G.; Franco, Oscar H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Deshmukh, Harshal A.; Colhoun, Helen M.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland. [Evans, Daniel S.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Feng, QiPing] Vanderbilt Univ, Dept Clin Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [Sun, Fangui; Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Arnold, Alice M.; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Barratt, Bryan J.] AstraZeneca Res & Dev, Personalised Healthcare & Biomarkers, Alderley Pk, England. [Betteridge, John] Univ Coll London Hosp, London, England. [Boekholdt, S. Matthijs] Acad Med Ctr, Dept Cardiol, Amsterdam, North Holland, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Buckley, Brendan M.] Univ Coll Cork, Dept Pharmacol & Therapeut, Western Rd, Cork, Ireland. [Denny, Joshua C.; Wei, Wei-Qi] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Denny, Joshua C.; Stein, Charles M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Durrington, Paul N.] Univ Manchester, Sch Biosci, Cardiovasc Res Grp, Manchester, Lancs, England. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Harris, Tamara B.; Launer, Leonore J.] NIA, Lab Epidemiol, Demog, Biometry,NIH, Bethesda, MD 20892 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hofman, Albert; Uitterlinden, Andre G.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Hovingh, G. Kees; Kastelein, John J. P.] Acad Med Ctr, Dept Vasc Med, Amsterdam, North Holland, Netherlands. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland, New Zealand. [McKeigue, Paul M.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Neil, Andrew] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England. [Nickerson, Deborah A.; Smith, Joshua D.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Nyberg, Fredrik] AstraZeneca Gothenburg, Med Evidence & Observat Res, Molndal, Sweden. [Nyberg, Fredrik] Univ Gothenburg, Unit Occupat & Environm Med, Gothenburg, Sweden. [O'Brien, Eoin; Shields, Denis C.] Univ Coll Dublin, Conway Inst, Dublin 4, Ireland. [O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Cardiol Div, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Post, Wendy] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Poulter, Neil; Sever, Peter] Imperial Coll London, Int Ctr Circulatory Hlth, London, England. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Framingham, MA USA. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Rivadeneira, Fernando; Stricker, Bruno H.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sattar, Naveed] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Shields, Denis C.] Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA. [Sotoodehnia, Nona] Univ Washington, Harborview Med Ctr, Div Cardiol, 325 9Th Ave, Seattle, WA 98104 USA. [Stanton, Alice] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Stanton, Alice] Beaumont Hosp, Dublin, Ireland. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. [Westendorp, Rudi G. J.] Univ Copenhagen, Ctr Hlth Ageing, Dept Publ Hlth, Copenhagen, Denmark. [Whitsel, Eric A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Wilke, Russell A.] Sanford Healthcare, Dept Internal Med, Sioux Falls, SD USA. [Wilke, Russell A.] Univ South Dakota, Dept Med, Sioux Falls, SD USA. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Colhoun, Helen M.] Univ Dundee, Dept Publ Hlth, Dundee, Scotland. [Hitman, Graham] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Stafford, Jeanette M.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Stein, Charles M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Dept Atherosclerosis Res, Oakland, CA 94609 USA. RP Krauss, RM (reprint author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. EM rkrauss@chori.org RI Palmer, Colin/C-7053-2008; OI Palmer, Colin/0000-0002-6415-6560; Colhoun, Helen/0000-0002-8345-3288; Dube, Marie-Pierre/0000-0001-8442-4393 FU Bristol-Myers Squibb, USA; European Union [HEALTH-F2-2009-223004]; Netherlands Consortium for Healthy Ageing [NGI: 05060810]; Pfizer USA; National Institutes for Health Research (NIHR); NIHR Biomedical Research Centre at Imperial College; International Centre for Circulatory Health Charity; Medical Research Council [G952010]; Pfizer; Diabetes UK [07/0003525]; Department of Health; National Institutes of Health from the National Heart, Lung, and Blood Institute [U19 HL069757]; National Center for Advancing Translational Sciences [UL1TR000124, 2 UL1 TR000445]; NIH [N01-AG-1-2100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402, U01-HG04603]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIH Roadmap for Medical Research; National Center for Research Resources [UL1 RR024975]; National Institute of General Medical Sciences [RC2-GM092318]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, HL085251, HL073410, HL068986]; National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Heart Lung and Blood Institute of the National Institutes of Health; Boston University School of Medicine [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; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung and Blood Institute (NHLBI); Clinical Translational Science Institute [UL1RR033176]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW) [050-060-810]; AstraZeneca; Wellcome Trust [084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]; EU IMI-SUMMIT programme; [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]; [RR-024156] FX PROSPER/PHASE: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator initiated grant from Bristol-Myers Squibb, USA. The study was conducted, analysed and reported independently of the company. The GWAS project PHASE has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004. A part of the genotyping was funded by The Netherlands Consortium for Healthy Ageing (NGI: 05060810). Professor Dr J W Jukema is an established clinical investigator of The Netherlands Heart Foundation (2001 D 032). ASCOT: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial was funded by an investigator initiated grant from Pfizer USA. The study was investigator-led and was conducted, analysed and reported independently of the company. The Genome-wide Association Scan was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity and the Medical Research Council through G952010. CARDS: The authors thank the other investigators, the staff and the participants of the CARDS study. A full list of CARDS investigators can be found in original CARDS paper. 38 CARDS was funded by grants to the Universities of London and Manchester by Pfizer, Diabetes UK and the Department of Health. PARC: This research was supported by the National Institutes of Health: grant U19 HL069757 from the National Heart, Lung, and Blood Institute; and grant UL1TR000124 from the National Center for Advancing Translational Sciences. TNT: The TNT study was funded by Pfizer, who also provided support for genotyping. AGES: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BioVU: BioVU receives support through the National Center for Research Resources UL1 RR024975, which is now the National Center for Advancing Translational Sciences, 2 UL1 TR000445. Genotyping was supported via grant U01-HG04603 from the National Human Genome Research Institute and RC2-GM092318 from the National Institute of General Medical Sciences.; CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, 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 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 were supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham HS: The Framingham Heart Study work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (contract no. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278) and based upon analyses by Framingham Heart Study investigators participating 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 supported by R01HL103612 (PI Psaty, subcontract PI, Vasan). Health ABC: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HVH: This Heart and Vascular Health Study research was supported by NHLBI grants HL085251, HL073410, HL085251 and HL068986. MESA: The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Additional funding was supported in part by the Clinical Translational Science Institute grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124. The authors thank the other investigators in the Pharmarcogenetics Working Group, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.; Rotterdam Study: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission and Municipality of Rotterdam. This work was supported by the Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW; 050-060-810). JUPITER: Genetic analysis in JUPITER was supported by a research grant from AstraZeneca to DC and PM. GoDARTS: We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for Wellcome Trust UK Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support is provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (07/0003525) and the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). Genotyping of the GoDARTS samples (sample 2) was also funded as part of the EU IMI-SUMMIT programme. NR 38 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2016 VL 53 IS 12 BP 835 EP + DI 10.1136/jmedgenet-2016-103966 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EH0MC UT WOS:000391457200007 PM 27587472 ER PT J AU Kurtz, SL Bosio, CM De Pascalis, R Elkins, KL AF Kurtz, Sherry L. Bosio, Catharine M. De Pascalis, Roberto Elkins, Karen L. TI GM-CSF has disparate roles during intranasal and intradermal Francisella tularensis infection SO MICROBES AND INFECTION LA English DT Article DE GM-CSF; Alveolar macrophage; Francisella; Immunity ID COLONY-STIMULATING FACTOR; LIVE VACCINE STRAIN; FACTOR-DEFICIENT MICE; ALVEOLAR MACROPHAGES; IMMUNITY; HOST; TUBERCULOSIS; INTERFERON; TULAREMIA; LUNGS AB Our laboratory has employed in vitro and in vivo mouse models based on Francisella tularensis Live Vaccine Strain (LVS)-induced protection to elucidate immune correlates for intracellular bacteria. Among the effectors found was GM-CSF, a pleiotropic cytokine that is integral to the development and proliferation of myeloid cells, including alveolar macrophages. GM-CSF has roles in resistance to primary murine infection with several intracellular pathogens, but its role during Francisella infection is unknown. Francisella is an intracellular pathogen that infects lungs after inhalation, primarily invading alveolar macrophages. Here we show that GM-CSF has route-dependent roles during primary infection of mice with LVS. GM-CSF deficient (GM-CSF KO) mice were slightly more susceptible than wild type to intradermal infection, but had increased resistance to intranasal infection. Similarly, these mice had increased resistance to pulmonary infection with virulent F. tularensis (SchuS4). LVS-vaccinated GM-CSF KO mice had normal adaptive immune responses, as measured by T cell activities after LVS intradermal or intranasal vaccination, and survived lethal secondary LVS challenge. GM-CSF KO mice also had robust humoral responses, producing elevated levels of serum antibodies following LVS vaccination compared to wild type mice. Taken together, our data demonstrates that the absence of GM-CSF improves resistance to pulmonary, but not intradermal, infection with Francisella. Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Kurtz, Sherry L.; De Pascalis, Roberto; Elkins, Karen L.] US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59480 USA. RP Elkins, KL (reprint author), US FDA, Lab Mucosal Pathogens & Cellular Immunol, Div Bacterial & Allergen Prod, Ctr Biol Evaluat & Res, 10903 New Hampshire Ave,Bldg 52-72,Room 5330 5348, Silver Spring, MD 20993 USA. EM karen.elkins@fda.hhs.gov NR 28 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD DEC PY 2016 VL 18 IS 12 BP 758 EP 767 DI 10.1016/j.micinf.2016.07.003 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EH4ZB UT WOS:000391781300005 PM 27475899 ER PT J AU Sissung, TM Deeken, J Leibrand, CR Price, DK Ehrlich, S Steinberg, SM Liewehr, DJ Dahut, W Figg, WD AF Sissung, Tristan M. Deeken, John Leibrand, Crystal R. Price, Douglas K. Ehrlich, Sheryl Steinberg, Seth M. Liewehr, David J. Dahut, William Figg, William D. TI Identification of novel SNPs associated with risk and prognosis in patients with castration-resistant prostate cancer SO PHARMACOGENOMICS LA English DT Article DE castration-resistant prostate cancer; genotype; metabolism; outcome; survival; transport ID CYTOCHROME-P450 CYP 1A1; GENETIC POLYMORPHISMS; JAPANESE POPULATION; ANDROGEN BIOSYNTHESIS; SUSCEPTIBILITY; GENOTYPES; VARIANTS; SRD5A2; M1 AB Aim: Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). Materials & methods: A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. Results: No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). Conclusion: This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis. C1 [Sissung, Tristan M.; Leibrand, Crystal R.; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Deeken, John] Inova Comprehens Canc & Res Inst, Falls Church, VA 22042 USA. [Price, Douglas K.; Ehrlich, Sheryl; Figg, William D.] NCI, Mol Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Steinberg, Seth M.; Liewehr, David J.] NCI, Biostat & Data Management Sect, Off Clin Director, NIH, Shady Grove, MD 20850 USA. [Dahut, William] NCI, Prostate Canc Clin Res Sect, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Sissung, TM (reprint author), NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM sissungt@mail.nih.gov NR 36 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD DEC PY 2016 VL 17 IS 18 BP 1979 EP 1986 DI 10.2217/pgs-2016-0134 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH6EP UT WOS:000391865900003 PM 27883295 ER PT J AU Goold, S Rowe, Z Calhoun, K Campbell, T Danis, M Hammad, A Salman, C Szymecko, L Coombe, C AF Goold, Susan Rowe, Zachary Calhoun, Karen Campbell, Terrance Danis, Marion Hammad, Adnan Salman, Cengiz Szymecko, Lisa Coombe, Chris TI The State as Community in Community-Based Participatory Research SO PROGRESS IN COMMUNITY HEALTH PARTNERSHIPS-RESEARCH EDUCATION AND ACTION LA English DT Article DE Community health partnerships; Community health research; health disparities; process issues; Great Lakes Region; health priorities ID PARTNERSHIPS LESSONS; DEFINITION; STRATEGIES AB Background: Community-based participatory research (CBPR) typically defines communities by geography, ethnicity, shared health needs, or some combination. Objectives: We describe a CBPR project aiming to engage diverse minority and underserved communities throughout Michigan in deliberations about health research priorities. Methods: A steering committee (SC) with 15 members from minority and underserved communities and 4 members from research organizations led the project, with the help of regional advisory groups (RAGs) formed at the SC's request. Evaluation of the SC used questionnaires, focused group discussion, and review of SC meetings to describe engagement, partnership, and communication. Lessons Learned: An academic-community partnership with a diverse, dispersed, and broadly defined community found value in RAGs, dedicated academic staff, face-to-face meetings, varied communication modalities, capacity building tailored to varying levels of CBPR experience, and ongoing evaluation. Conclusions: A geographically and culturally diverse partnership presents challenges and opportunities in representativeness, relationship building, capacity building, and communication. C1 [Goold, Susan] Univ Michigan, Gen Med, Ann Arbor, MI 48109 USA. [Rowe, Zachary] Friends Parkside, Detroit, MI USA. [Calhoun, Karen] City Connect Detroit, Detroit, MI USA. [Calhoun, Karen] Michigan Inst Clin & Hlth Res, Ann Arbor, MI USA. [Campbell, Terrance] YOUR Ctr, Flint, MI USA. [Danis, Marion] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD USA. [Hammad, Adnan] Arab Community Ctr Econ & Social Serv, Dearborn, MI USA. [Salman, Cengiz; Szymecko, Lisa] Univ Michigan, Gen Med, Ann Arbor, MI 48109 USA. [Salman, Cengiz; Szymecko, Lisa] Ctr Bioeth & Social Sci Humanities, Ann Arbor, MI USA. [Coombe, Chris] Univ Michigan, Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. RP Goold, S (reprint author), Univ Michigan, Gen Med, Ann Arbor, MI 48109 USA. NR 20 TC 0 Z9 0 U1 1 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1557-0541 EI 1557-055X J9 PROG COMM HLTH PARTN JI Prog. Community Health Partnersh. PD WIN PY 2016 VL 10 IS 4 BP 515 EP 522 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH6RS UT WOS:000391902200005 ER PT J AU Pongas, G Cheson, BD AF Pongas, Georgios Cheson, Bruce D. TI PI3K signaling pathway in normal B cells and indolent B-cell malignancies SO SEMINARS IN ONCOLOGY LA English DT Review DE Chronic lymphocytic leukemia; Indolent non-Hodgkin lymphoma; PI3K; Lymphoma; Leukemia; Idelalisib ID CHRONIC LYMPHOCYTIC-LEUKEMIA; PHOSPHOINOSITIDE 3-KINASE; TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; EMBRYONIC LETHALITY; IDELALISIB; RECEPTOR; LYMPHOMA; CD19; ACTIVATION AB In chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs), B-cell receptor signaling leads to activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Idelalisib, a PI3K delta inhibitor was approved in 2014 by the US Food and Drug Administration (FDA) in combination with rituximab for the treatment of patients with CLL for whom single-agent rituximab would be considered appropriate and as a single agent for patients with relapsed small lymphocytic lymphoma (SLL) and relapsed follicular lymphoma (FL). Following its approval, several trials investigating various PI3K delta inhibitors as single agents or in combination with chemoimmunotherapy or other molecular targeted agents in CLL and indolent NHL (iNHL) have uncovered some severe autoimmune related toxicities. This review discusses and summarizes the biologic basis and the clinical experience of the PI3K delta inhibitors in indolent B-cell malignancies. Published by Elsevier Inc. C1 [Pongas, Georgios] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Pongas, Georgios] NCI, Womens Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Cheson, Bruce D.] Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Pongas, G (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 4B-55, Bethesda, MD 20892 USA. EM georgios.pongas@nih.gov FU Acerta; Roche-Genentech; Celgene; Pharmacyclics; Pfizer; Gilead FX G.P declares no competing financial interests. B.D.C received consulting fees from Acerta, Roche-Genentech, Celgene, Pharmacyclics, and Pfizer, and research funding to his institution from Acerta, Roche-Genentech, Celgene, Pharmacyclics, and Gilead. NR 77 TC 1 Z9 1 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 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2016 VL 43 IS 6 BP 647 EP 654 DI 10.1053/j.seminoncol.2016.11.011 PG 8 WC Oncology SC Oncology GA EH6QY UT WOS:000391900200004 PM 28061982 ER PT J AU Ahn, IE Mailankody, S AF Ahn, Inhye E. Mailankody, Sham TI Controversies in multiple myeloma: Evidence-based update SO SEMINARS IN ONCOLOGY LA English DT Review DE Multiple myeloma Smoldering multiple myeloma; Treatment; Risk-benefit; Evidence; Cost ID STEM-CELL TRANSPLANTATION; HIGH-DOSE THERAPY; LENALIDOMIDE PLUS DEXAMETHASONE; INTERNATIONAL STAGING SYSTEM; MARROW PLASMA-CELLS; TERM-FOLLOW-UP; RANDOMIZED-TRIAL; WORKING GROUP; HIGH-RISK; AUTOLOGOUS TRANSPLANTATION AB The US Food and Drug Administration (FDA) approved 10 new drugs for the treatment of multiple myeloma (MM) over the last two decades. The influx of new anti-myeloma agents with high efficacy and acceptable tolerability add complexity to the clinical decision-making process. First, treatment of smoldering multiple myeloma (SMM) remains investigational to date, although a randomized trial showed a survival gain in high-risk patients receiving lenalidomide. Second, in newly diagnosed MM, the majority of contemporary induction regimens have been studied in single-arm trials or compared to an older regimen, which complicates evidence-based treatment selection. Third, the role of consolidation chemotherapy followed by autologous stem cell transplant (ASCT) needs to be revisited in the context of highly effective agents, as newer regimens - such as carfilzomib, lenalidomide, and dexamethasone are able to achieve extremely deep responses equivalent to or exceeding those seen after conventional induction and ASCT. Fourth, risks and benefits of maintenance therapy should also be redefined and individualized, as long-term survival and safety data accumulate. Here we selected four clinical settings where controversies exist, reviewed evidences behind conflicting treatment strategies, and asked myeloma experts to discuss evidence-based recommendations. (C) 2016 Elsevier. All rights reserved. C1 [Ahn, Inhye E.] NCI, NIH, Bethesda, MD 20892 USA. [Mailankody, Sham] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. RP Mailankody, S (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Dept Hematol Oncol, Myeloma Serv, 1233 York Ave, New York, NY 10065 USA. EM mailanks@mskcc.org FU Memorial Sloan Kettering Core Grant [P30 CA008748] FX Grant support from Memorial Sloan Kettering Core Grant (P30 CA008748) . NR 68 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2016 VL 43 IS 6 BP 666 EP 675 DI 10.1053/j.seminoncol.2016.10.006 PG 10 WC Oncology SC Oncology GA EH6QY UT WOS:000391900200006 PM 28061984 ER PT J AU Kazandjian, D AF Kazandjian, Dickran TI Multiple myeloma epidemiology and survival: A unique malignancy SO SEMINARS IN ONCOLOGY LA English DT Review DE Multiple myeloma; Smoldering myeloma; MGUS; Epidemiology; Health disparity ID UNDETERMINED SIGNIFICANCE MGUS; LONG-TERM SURVIVAL; MONOCLONAL GAMMOPATHY; RACIAL DISPARITIES; NATIONAL-HEALTH; POPULATION; PROGNOSIS; CRITERIA; YOUNGER AB Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy. It is found in the spectrum of plasma cell dyscrasias, which begins with monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia and extramedullary myeloma. MM is associated with significant morbidity due to its end-organ destruction. It is a disease of the older population and its incidence in the African American population is twice that of the European American population. Improvements in the treatment of MM in the past couple of decades, beginning with the use of autologous stem cell transplantation followed by availability of novel treatments such as immunomodulatory drugs (ImIDs) and proteasome inhibitors (PIs) has transformed the natural history of the disease leading to longer survival times. Advancements in the diagnosis, monitoring, and treatment of MM are of the utmost importance as the general population lives longer due to other improvements in health care. The recent introduction of novel therapies has been paralleled by advancements in the monitoring of MM, namely, by the availability exquisitely sensitive techniques in detecting minimal residual disease. As drug development and technology continues to improve, it will be important to design rationale clinical trials enrolling patient populations that represent the overall population, including racial minorities and the elderly, so that trial results can be appropriately extrapolated. Herein, the changing epidemiology, improvements in survival, and the health disparity observed in important subgroups of MM are reviewed. Published by Elsevier Inc. C1 [Kazandjian, Dickran] NCI, Myeloma Program, Lymphoid Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Kazandjian, D (reprint author), NCI, 9000 Rockville Pike,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM kazandjiandg@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 0 Z9 0 U1 5 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2016 VL 43 IS 6 BP 676 EP 681 DI 10.1053/j.seminoncol.2016.11.004 PG 6 WC Oncology SC Oncology GA EH6QY UT WOS:000391900200007 PM 28061985 ER PT J AU Kazandjian, D Landgren, O AF Kazandjian, Dickran Landgren, Ola TI A look backward and forward in the regulatory and treatment history of multiple myeloma: Approval of novel-novel agents, new drug development, and longer patient survival SO SEMINARS IN ONCOLOGY LA English DT Review DE Myeloma; Smoldering; FDA; EMA; Approvals ID PHASE-3 TRIAL; BONE-MARROW; DEXAMETHASONE; LENALIDOMIDE; BORTEZOMIB; INHIBITOR; THERAPY; MULTICENTER; COMBINATION; DARATUMUMAB AB The past decade has seen significant advances in our understanding and treatment of multiple myeloma (MM) and its precursor diseases. These advances include gains in knowledge of the underlying pathobiology including molecular and cellular prognostic factors for disease progression. In parallel we have witnessed the availability of novel therapeutics. Together these advances have translated into improvements in long-term clinical benefit and survival in MM. Indeed, it has been shown that patients diagnosed in the last decade have experienced almost doubling of median survival time. We aim to review and give further insight into drug development and novel drug approvals that have revolutionized the treatment of MM. Published by Elsevier Inc. C1 [Kazandjian, Dickran] NCI, Myeloma Program, Lymphoid Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kazandjian, Dickran] US FDA, Off Hematol & Oncol Prod, Bethesda, MD USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. RP Kazandjian, D (reprint author), NCI, Bldg 10,Room 4N115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kazandjiandg@mail.nih.gov FU Memorial Sloan Kettering Core Grant [P30 CA008748] FX Memorial Sloan Kettering Core Grant, (P30 CA008748) for grant support. NR 30 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 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD DEC PY 2016 VL 43 IS 6 BP 682 EP 689 DI 10.1053/j.seminoncol.2016.10.008 PG 8 WC Oncology SC Oncology GA EH6QY UT WOS:000391900200008 PM 28061986 ER PT J AU Lu, TYL Pugach, O Somerville, R Rosenberg, SA Kochendefer, JN Better, M Feldman, SA AF Lu, Tangying Lily Pugach, Omar Somerville, Robert Rosenberg, Steven A. Kochendefer, James N. Better, Marc Feldman, Steven A. TI A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies SO HUMAN GENE THERAPY METHODS LA English DT Article DE anti-CD19 CAR; transduction; expansion; cryopreservation; GMP; closed system ID CHIMERIC-ANTIGEN-RECEPTOR; B-CELL; ADOPTIVE IMMUNOTHERAPY; LYMPHOMA; TRANSPLANTATION; MALIGNANCIES; REGRESSION; DEPLETION AB The treatment of B-cell malignancies by adoptive cell transfer (ACT) of anti-CD19 chimeric antigen receptor T cells (CD19 CAR-T) has proven to be a highly successful therapeutic modality in several clinical trials.(1-6) The anti-CD19 CAR-T cell production method used to support initial trials relied on numerous manual, open process steps, human serum, and 10 days of cell culture to achieve a clinical dose.(7) This approach limited the ability to support large multicenter clinical trials, as well as scale up for commercial cell production. Therefore, studies were completed to streamline and optimize the original National Cancer Institute production process by removing human serum from the process in order to minimize the risk of viral contamination, moving process steps from an open system to functionally closed system operations in order to minimize the risk of microbial contamination, and standardizing additional process steps in order to maximize process consistency. This study reports a procedure for generating CD19 CAR-T cells in 6 days, using a functionally closed manufacturing process and defined, serum-free medium. This method is able to produce CD19 CAR-T cells that are phenotypically and functionally indistinguishable from cells produced for clinical trials by the previously described production process. C1 [Lu, Tangying Lily; Somerville, Robert; Rosenberg, Steven A.; Feldman, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kochendefer, James N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Pugach, Omar] ImaginAb Inc, Inglewood, CA USA. [Pugach, Omar; Better, Marc] KITE Pharma, Santa Monica, CA USA. RP Feldman, SA (reprint author), NCI, Surg Branch, ACRF, 10 Ctr Dr,MSC 1201,Bldg 10,1B37A, Bethesda, MD 20892 USA. EM feldmanst@mail.nih.gov FU Kite Pharma, Inc. through collaborative research and development agreement (CRADA); Surgery Branch, NCI, National Institutes of Health FX This work was supported, in part, by Kite Pharma, Inc., through a collaborative research and development agreement (CRADA) with Surgery Branch, NCI, National Institutes of Health. Thanks also go to David Stroncek and the Department of Transfusion Medicine, National Institutes of Health, for technical input and discussion. NR 29 TC 0 Z9 0 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 EI 1946-6544 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD DEC PY 2016 VL 27 IS 6 BP 209 EP 218 DI 10.1089/hgtb.2016.120 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EG5VF UT WOS:000391112100001 PM 27897048 ER PT J AU Guzelsoy, M Kirkali, Z AF Guzelsoy, Muhammet Kirkali, Ziya TI Role of Transition Zone Index in the Prediction of Clinical Benign Prostatic Hyperplasia SO JOURNAL OF UROLOGICAL SURGERY LA English DT Article DE Clinical benign prostatic hyperplasia; transurethral prostatectomy; tissue amount; transition zone volume; transition zone index ID SYMPTOMS; VOLUME; SIZE; THERAPY; WEIGHT; GLAND; FLOW AB Objective The objective of this study was to determine the role of the transition zone (TZ) index (TZI) in the prediction of clinical benign prostatic hyperplasia (BPH) in patients who underwent transurethral prostatectomy (TUR-P) and to analyze the correlation between the amount of resected tissue and TZ volume (TZV). Materials and Methods Twenty-six male clinical BPH patients with obstructive complaints and 17 male benign prostate enlargement (BPE) patients without any complaints were included in the study. Both the groups were over the age of 50. Clinical BPH patients underwent complete TUR-P. Statistical analysis was done with SPSS. Sensitivity, specificity, positive and negative predictive values of TZI-as a method of assessing clinical BPH-were measured. Results There was a statistically significant difference in prostate volume, uroflowmetry patterns, prostate-specific antigen (PSA), International prostate symptom score (IPSS), TZV and TZI between the two groups. There was a correlation between TZV and the amount of resected tissue (r= 0.97; p<0.0001). TZI also correlated with IPSS, quality of life (QL) and maximum flow rate (MFR) (r= 0.58, p< 0001; r= 0.56, p< 0.000; r=-0.70, p< 0.0001, respectively). Conclusion TZI > 0.40 has a high level of sensitivity and specificity in the prediction of clinical BPH among patients who undergo TUR-P due to obstructive symptoms and reported as BPH. There is a strong correlation between the amount of resected tissue and TZV. TZI is a valuable tool in diagnosis, and TZV gives valuable information about the patient to the surgeon. C1 [Guzelsoy, Muhammet] Yuksek Ihtisas Training & Res Hosp, Urol Clin, Bursa, Turkey. [Kirkali, Ziya] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. RP Guzelsoy, M (reprint author), Yuksek Ihtisas Training & Res Hosp, Urol Clin, Bursa, Turkey. EM muhammetguzelsoy@yahoo.com.tr NR 25 TC 0 Z9 0 U1 0 U2 0 PU GALENOS YAYINCILIK PI FINDIKZADE PA ERKAN MOR, MOLLA GURANI CAD 21-1, FINDIKZADE, ISTANBUL 34093, TURKEY SN 2148-9580 J9 J UROL SURG JI J. Urol. Surg. PD DEC PY 2016 VL 3 IS 4 BP 114 EP 118 DI 10.4274/jus.960 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA EG6SM UT WOS:000391176400002 ER PT J AU Burgess, S Cheng, LZ Gu, F Huang, JJ Huang, ZW Lin, S Li, JS Li, W Qin, W Sun, YJ Zhou, SY Wei, WS Wu, Q Wang, HY Wang, XQ Xiong, JW Xi, JZ Yang, H Zhou, B Zhang, B AF Burgess, Shawn Cheng, Linzhao Gu, Feng Huang, Junjiu Huang, Zhiwei Lin, Shuo Li, Jinsong Li, Wei Qin, Wei Sun, Yujie Zhou Songyang Wei, Wensheng Wu, Qiang Wang, Haoyi Wang, Xiaoqun Xiong, Jing-Wei Xi, Jianzhong Yang, Hui Zhou, Bin Zhang, Bo TI Questions about NgAgo SO PROTEIN & CELL LA English DT Letter C1 [Burgess, Shawn] NHGRI, NIH, Bethesda, MD 20892 USA. [Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Gu, Feng] Wenzhou Med Univ, Hosp Eye, Ctr Vis Res, Wenzhou 325035, Peoples R China. [Huang, Junjiu; Zhou Songyang] Sun Yat Sen Univ, Sch Life Sci, Stem Cell & Funct Genom Lab, Guangzhou 510275, Guangdong, Peoples R China. [Huang, Zhiwei] Harbin Inst Technol, HIT Ctr Life Sci, Harbin 150080, Peoples R China. [Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Li, Jinsong; Zhou, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. [Li, Wei; Wang, Haoyi] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China. [Qin, Wei] Peking Univ, Shenzhen Grad Sch, Coll Chem Biol & Biotechnol, Shenzhen 518055, Peoples R China. [Sun, Yujie] PKU BIOPIC, Beijing 100871, Peoples R China. [Wei, Wensheng] Peking Univ, CLS, ICG, BIOPIC, Beijing 100871, Peoples R China. [Wei, Wensheng] Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China. [Wu, Qiang] Shanghai Jiao Tong Univ, Inst Syst Biomed, Ctr Comparat Biomed, Shanghai 200240, Peoples R China. [Wang, Xiaoqun] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. [Xiong, Jing-Wei] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Xi, Jianzhong] Peking Univ, Coll Engn, Beijing 100871, Peoples R China. [Yang, Hui] Shanghai Chinese Acad Sci, Inst Neurosci, Lab Dis Models Nonhuman Primates, Shanghai 200031, Peoples R China. [Zhang, Bo] Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. RP Cheng, LZ (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA.; Cheng, LZ (reprint author), Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA.; Lin, S (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA.; Wang, HY (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China.; Wei, WS (reprint author), Peking Univ, CLS, ICG, BIOPIC, Beijing 100871, Peoples R China.; Wei, WS (reprint author), Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China. EM LCheng2@jhmi.edu; shuolin@g.ucla.edu; wswei@pku.edu.cn; wanghaoyi@ioz.ac.cn NR 0 TC 2 Z9 2 U1 3 U2 3 PU HIGHER EDUCATION PRESS PI BEIJING PA NO 4 DEWAI DAJIE, BEIJING 100120, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD DEC PY 2016 VL 7 IS 12 BP 913 EP 915 DI 10.1007/s13238-016-0343-9 PG 3 WC Cell Biology SC Cell Biology GA EH0DB UT WOS:000391431600008 PM 27848216 ER PT J AU Lai, YT Hura, GL Dyer, KN Tang, HYH Tainer, JA Yeates, TO AF Lai, Yen-Ting Hura, Greg L. Dyer, Kevin N. Tang, Henry Y. H. Tainer, John A. Yeates, Todd O. TI Designing and defining dynamic protein cage nanoassemblies in solution SO SCIENCE ADVANCES LA English DT Article ID X-RAY-SCATTERING; BIOLOGICAL MACROMOLECULES; SAXS; ASSEMBLIES; CONFORMATIONS; SYSTEM; FLEXIBILITY; ACQUISITION; COMPUTATION; SOFTWARE AB Central challenges in the design of large and dynamic macromolecular assemblies for synthetic biology lie in developing effective methods for testing design strategies and their outcomes, including comprehensive assessments of solution behavior. We created and validated an advanced design of a 600-kDa protein homododecamer that self-assembles into a symmetric tetrahedral cage. The monomeric unit is composed of a trimerizing apex-forming domain genetically linked to an edge-forming dimerizing domain. Enhancing the crystallographic results, high-throughput small-angle x-ray scattering (SAXS) comprehensively contrasted our modifications under diverse solution conditions. To generate a phase diagram associating structure and assembly, we developed force plots that measure dissimilarity among multiple SAXS data sets. These new tools, which provided effective feedback on experimental constructs relative to design, have general applicability in analyzing the solution behavior of heterogeneous nanosystems and have been made available as a web-based application. Specifically, our results probed the influence of solution conditions and symmetry on stability and structural adaptability, identifying the dimeric interface as the weak point in the assembly. Force plots comparing SAXS data sets further reveal more complex and controllable behavior in solution than captured by our crystal structures. These methods for objectively and comprehensively comparing SAXS profiles for systems critically affected by solvent conditions and structural heterogeneity provide an enabling technology for advancing the design and bioengineering of nanoscale biological materials. C1 [Lai, Yen-Ting; Yeates, Todd O.] Univ Calif Los Angeles, UCLA DOE Inst Genom & Prote, Los Angeles, CA 90095 USA. [Hura, Greg L.; Dyer, Kevin N.; Tang, Henry Y. H.; Tainer, John A.] Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Hura, Greg L.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Tainer, John A.] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Yeates, Todd O.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Yeates, Todd O.] Univ Calif Los Angeles, California NanoSyst Inst, Los Angeles, CA 90095 USA. [Lai, Yen-Ting] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Yeates, TO (reprint author), Univ Calif Los Angeles, UCLA DOE Inst Genom & Prote, Los Angeles, CA 90095 USA.; Tainer, JA (reprint author), Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA.; Tainer, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA.; Yeates, TO (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.; Yeates, TO (reprint author), Univ Calif Los Angeles, California NanoSyst Inst, Los Angeles, CA 90095 USA. EM jatainer@lbl.gov; yeates@mbi.ucla.edu FU NSF [CHE-1332907]; BER program of the DOE Office of Science [DE-FC02-02ER63421]; Robert A. Welch Distinguished Chair in Chemistry; Cancer Prevention and Research Institute of Texas; University of Texas FX This work was supported by NSF grant CHE-1332907 (T.O.Y.) and by the BER program of the DOE Office of Science (DE-FC02-02ER63421). J.A.T. is supported by the Robert A. Welch Distinguished Chair in Chemistry. J.A.T. acknowledges startup funds from the Cancer Prevention and Research Institute of Texas, and the University of Texas STARs program. NR 48 TC 0 Z9 0 U1 6 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 2375-2548 J9 SCI ADV JI Sci. Adv. PD DEC PY 2016 VL 2 IS 12 AR e1501855 DI 10.1126/sciadv.1501855 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7XC UT WOS:000391268800001 PM 27990489 ER PT J AU Morgan, SJ Neumann, S Marcus-Samuels, B Gershengorn, MC AF Morgan, Sarah J. Neumann, Susanne Marcus-Samuels, Bernice Gershengorn, Marvin C. TI Thyrotropin and Insulin-Like Growth Factor 1 Receptor Crosstalk Upregulates Sodium-Iodide Symporter Expression in Primary Cultures of Human Thyrocytes SO THYROID LA English DT Article DE cAMP; sodium-iodide symporter; TSHR; IGF-1R ID RAT-THYROID CELLS; AIRWAY SMOOTH-MUSCLE; VASODILATOR-STIMULATED PHOSPHOPROTEIN; THYROGLOBULIN GENE-EXPRESSION; PROTEIN-COUPLED RECEPTOR; INTACT HUMAN PLATELETS; FACTOR-I RECEPTORS; SODIUM/IODIDE SYMPORTER; FRTL-5 CELLS; SIGNALING PATHWAYS AB Background: Major regulation of thyroid gland function is mediated by thyrotropin (TSH) activating the TSH receptor (TSHR) and inducing upregulation of genes involved in thyroid hormone synthesis. Evidence suggests that the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) may play a role in regulating TSHR functional effects. This study examined the potential role of TSHR/IGF-1R crosstalk in primary cultures of human thyrocytes. Results: TSH/IGF-1 co-treatment elicited additive effects on thyroglobulin (TG), thyroperoxidase (TPO), and deiodinase type 2 (DIO2) mRNA levels but synergistic effects on sodium-iodide symporter (NIS) mRNA. Similar cooperativity was seen on the level of TG protein secretion (additive) and NIS protein expression (synergistic). The IGF-1R tyrosine kinase inhibitor linsitinib inhibited TSH-stimulated upregulation of NIS but not TG, indicating that NIS regulation is in part IGF-1R dependent and occurs via receptor crosstalk. Cooperativity was not seen at the level of cAMP/protein kinase A (PKA) signaling, IGF-1R phosphorylation, or Akt activation. However, TSH and IGF-1 synergistically activated ERK1/2. Pharmacological inhibition of ERK1/2 by the MEK1/2 inhibitor U0126 and of Akt by MK-2206 virtually abolished NIS stimulation by TSH and the synergistic effect of IGF-1. Conclusion: As linsitinib inhibited upregulation of NIS stimulated by TSH alone, it is concluded that crosstalk between TSHR and IGF-1R, without agonist activation of IGF-1R, plays a role in NIS regulation in human thyrocytes via a mechanism involving ERK1/2 and/or Akt. Fully understanding the nature of this crosstalk has clinical implications for the treatment of thyroid diseases, including thyroid cancer. C1 [Morgan, Sarah J.; Neumann, Susanne; Marcus-Samuels, Bernice; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. RP Gershengorn, MC (reprint author), NIDDK, Bldg SO,Room 4134 50 South Dr, Bethesda, MD 20892 USA. EM marving@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [Z01 DK011006] FX We thank Monica Skarulis and Brent Abel from the Diabetes, Endocrinology, and Obesity Branch for providing human thyroid tissue. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Z01 DK011006). NR 46 TC 1 Z9 1 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD DEC PY 2016 VL 26 IS 12 BP 1794 EP 1803 DI 10.1089/thy.2016.0323 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG8OF UT WOS:000391315800018 PM 27638195 ER PT J AU Solari, N Gipponi, M Franco, DC Re, F Sonia, O Bertoglio, S Cafiero, F AF Solari, Nicola Gipponi, Marco Franco, Di Somma Carmine Re, Francesca Sonia, Olcese Bertoglio, Sergio Cafiero, Ferdinando TI Videoscopic Inguinal-iliac-obturator Lymph-node Dissection: New Videoscopic Technique for Regional Lymphadenectomy in Patients with Melanoma SO ANTICANCER RESEARCH LA English DT Article ID BLADDER-CANCER; PELVIC LYMPHADENECTOMY; MALIGNANT-MELANOMA; SENTINEL; IMPACT; RATIO; SURVIVAL; EXTENT; GROIN AB Aim: The feasibility of videoscopic inguinal-iliacobturator lymphadenectomy (VIIOL) was assessed in 20 patients with melanoma and compared with a retrospective sample of 24 patients undergoing standard 'open' technique (HOL). Results: No postoperative death occurred; the mean operative time was lower in the IIOL series (190 min vs. 302 min) but the quality of life was greatly improved in the VIIOL group thanks to earlier bladder catheter removal, no nasogastric suction, less pain, earlier mobilization, lower in hospital stay, and earlier resumption of daily activities (27.6 vs. 83.2 days, p<0.001). Six out of 20 patients in the IIOL series had wound complications (30%) as compared to one in the VIIOL series (4%) (p=0.035). Conclusion: Staging and therapeutic efficacy of VIIOL were similar to the standard technique; the longer operative time of VIIOL was greatly compensated by less pain, lower wound complication rate, and earlier discharge from hospital and recovery of daily activities. C1 [Solari, Nicola; Franco, Di Somma Carmine; Re, Francesca; Sonia, Olcese; Bertoglio, Sergio; Cafiero, Ferdinando] San Martino Hosp, Surg Unit 1, Genoa, Italy. [Solari, Nicola; Gipponi, Marco; Franco, Di Somma Carmine; Re, Francesca; Sonia, Olcese; Bertoglio, Sergio; Cafiero, Ferdinando] Natl Canc Inst, Genoa, Italy. [Gipponi, Marco] Univ Genoa, San Martino Hosp, Breast Unit, Sch Med, Genoa, Italy. [Bertoglio, Sergio] Univ Genoa, Dept Surg Sci DISC, Sch Med, Genoa, Italy. RP Gipponi, M (reprint author), IRCCS San Martino IST, Breast Unit, Lgo R Benzi 10, I-16132 Genoa, Italy. EM marco.gipponi@hsanmartino.it NR 21 TC 0 Z9 0 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD DEC PY 2016 VL 36 IS 12 BP 6579 EP 6583 DI 10.21873/anticanres.11262 PG 5 WC Oncology SC Oncology GA EG3LW UT WOS:000390946700048 PM 27919986 ER PT J AU Miller, BF Sanchez-Vega, F Elnitski, L AF Miller, Brendan F. Sanchez-Vega, Francisco Elnitski, Laura TI The Emergence of Pan-Cancer CIMP and Its Elusive Interpretation SO BIOMOLECULES LA English DT Review DE pan-cancer; CpG island methylator phenotype; DNA methylation ID ISLAND METHYLATOR PHENOTYPE; ACUTE LYMPHOBLASTIC-LEUKEMIA; TUMOR-SUPPRESSOR GENES; CELL LUNG-CANCER; DNA METHYLATION; CLINICOPATHOLOGICAL FEATURES; MICROSATELLITE INSTABILITY; HEPATOCELLULAR-CARCINOMA; PROMOTER METHYLATION; COLORECTAL-CANCER AB Epigenetic dysregulation is recognized as a hallmark of cancer. In the last 16 years, a CpG island methylator phenotype (CIMP) has been documented in tumors originating from different tissues. However, a looming question in the field is whether or not CIMP is a pan-cancer phenomenon or a tissue-specific event. Here, we give a synopsis of the history of CIMP and describe the pattern of DNA methylation that defines the CIMP phenotype in different cancer types. We highlight new conceptual approaches of classifying tumors based on CIMP in a cancer type-agnostic way that reveal the presence of distinct CIMP tumors in a multitude of The Cancer Genome Atlas (TCGA) datasets, suggesting that this phenotype may transcend tissue-type specificity. Lastly, we show evidence supporting the clinical relevance of CIMP-positive tumors and suggest that a common CIMP etiology may define new mechanistic targets in cancer treatment. C1 [Miller, Brendan F.; Elnitski, Laura] NHGRI, Rockville, MD 20852 USA. [Sanchez-Vega, Francisco] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Elnitski, L (reprint author), NHGRI, Rockville, MD 20852 USA. EM millerbf2@mail.nih.gov; sanchezf@cbio.mskcc.org; elnitski@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute FX We would like to thank Kristin Harper and Yun-Ching Chen for helpful discussions, edits, and useful feedback during the writing of this piece. This work was supported by the Intramural Research Program of the National Human Genome Research Institute. NR 91 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2218-273X J9 BIOMOLECULES JI Biomolecules PD DEC PY 2016 VL 6 IS 4 AR 45 DI 10.3390/biom6040045 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EG4BZ UT WOS:000390989700007 ER PT J AU Anandi, P Tian, X Chinian, F Cantilena, CR Dunavin, N Hensel, N Draper, D Koklanaris, E Maxwell, S Superata, J Muranski, P Battiwalla, M Paczesny, S Barrett, AJ Ito, S AF Anandi, P. Tian, X. Chinian, F. Cantilena, C. R. Dunavin, N. Hensel, N. Draper, D. Koklanaris, E. Maxwell, S. Superata, J. Muranski, P. Battiwalla, M. Paczesny, S. Barrett, A. J. Ito, S. TI Improved reproducibility and quality of GvHD biomarker assay: application of multiplex microfluidic channel system SO BONE MARROW TRANSPLANTATION LA English DT Letter ID VERSUS-HOST-DISEASE; CELL TRANSPLANTATION C1 [Anandi, P.; Chinian, F.; Cantilena, C. R.; Dunavin, N.; Hensel, N.; Draper, D.; Koklanaris, E.; Maxwell, S.; Superata, J.; Muranski, P.; Battiwalla, M.; Barrett, A. J.; Ito, S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tian, X.] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Paczesny, S.] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat, Indianapolis, IN 46202 USA. RP Ito, S (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM itos2@nhlbi.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD DEC PY 2016 VL 51 IS 12 BP 1615 EP 1616 DI 10.1038/bmt.2016.226 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA EG0YY UT WOS:000390759600016 PM 27595279 ER PT J AU Gatti-Mays, ME Manion, M Bowen, LN Brown, GT Danner, RL Khan, O Nath, A Battiwalla, M Barrett, AJ Ito, S AF Gatti-Mays, M. E. Manion, M. Bowen, L. N. Brown, G. T. Danner, R. L. Khan, O. Nath, A. Battiwalla, M. Barrett, A. J. Ito, S. TI Toxoplasmosis encephalitis with immune-reconstitution inflammatory syndrome in an allogeneic stem cell transplant patient: a case report SO BONE MARROW TRANSPLANTATION LA English DT Letter ID BONE-MARROW-TRANSPLANTATION; OF-THE-LITERATURE; INFECTION; INTERLEUKIN-2; THERAPY; TRIAL C1 [Gatti-Mays, M. E.; Brown, G. T.] NCI, NIH, Bethesda, MD 20892 USA. [Manion, M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bowen, L. N.; Khan, O.; Nath, A.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Danner, R. L.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Battiwalla, M.; Barrett, A. J.; Ito, S.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Gatti-Mays, ME (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM Margaret.gatti-mays@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD DEC PY 2016 VL 51 IS 12 BP 1622 EP 1624 DI 10.1038/bmt.2016.230 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA EG0YY UT WOS:000390759600019 PM 27643867 ER PT J AU Ramamurthi, KS AF Ramamurthi, Kumaran S. TI Editorial overview: Growth and development: prokaryotes SO CURRENT OPINION IN MICROBIOLOGY LA English DT Editorial Material C1 [Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NCI, Bldg 37, Bethesda, MD 20892 USA. RP Ramamurthi, KS (reprint author), NCI, Mol Biol Lab, NCI, Bldg 37, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD DEC PY 2016 VL 34 BP VII EP VIII DI 10.1016/j.mib.2016.159.001 PG 2 WC Microbiology SC Microbiology GA EG3TM UT WOS:000390967600002 PM 27720364 ER PT J AU Orr, MW Galperin, MY Lee, VT AF Orr, Mona W. Galperin, Michael Y. Lee, Vincent T. TI Sustained sensing as an emerging principle in second messenger signaling systems SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID CYCLIC-DI-GMP; PSEUDOMONAS-AERUGINOSA; ESCHERICHIA-COLI; BINDING-PROTEIN; VIBRIO-CHOLERAE; BACTERIAL 2ND-MESSENGER; DIGUANYLATE CYCLASE; PILZ DOMAIN; EXOPOLYSACCHARIDE PRODUCTION; CLOSTRIDIUM-DIFFICILE AB Bacteria utilize a diverse set of nucleotide second messengers to regulate cellular responses by binding macromolecular receptors (RNAs and proteins). Recent studies on cyclic di-GMP (c-di-GMP) have shown that this signaling molecule binds multiple receptors to regulate different steps in the same biological process. We propose this property of the same molecule regulating multiple steps in the same process is biologically meaningful and have termed this phenomenon `sustained sensing'. Here, we discuss the recent findings that support the concept of sustained sensing of c-di-GMP levels and provide additional examples that support the utilization of sustained sensing by other second messengers. Sustained sensing may be widespread in bacteria and provides an additional level of complexity in prokaryotic signal transduction networks. C1 [Orr, Mona W.; Lee, Vincent T.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Orr, Mona W.; Lee, Vincent T.] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Galperin, Michael Y.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Lee, VT (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM vtlee@umd.edu OI Lee, Vincent T./0000-0002-3593-0318 FU NIH Intramural Research Program at the National Library of Medicine; NIH [R01 AI110740] FX M.Y.G. was supported by the NIH Intramural Research Program at the National Library of Medicine. V.T.L. was supported by a grant from the NIH (R01 AI110740). We thank Dr. Richard Stewart for critical reading of the manuscript. NR 65 TC 0 Z9 0 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 EI 1879-0364 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD DEC PY 2016 VL 34 BP 119 EP 126 DI 10.1016/j.mib.2016.08.010 PG 8 WC Microbiology SC Microbiology GA EG3TM UT WOS:000390967600020 PM 27700990 ER PT J AU Mayer, ML AF Mayer, Mark L. TI Structural biology of glutamate receptor ion channel complexes SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID N-TERMINAL DOMAIN; MEMBRANE-PROTEINS; CRYO-EM; KAINATE RECEPTORS; CRYSTAL-STRUCTURE; AMPA; MECHANISM; ACTIVATION; DESENSITIZATION; LIGAND AB Chemical transmission at excitatory synapses in the brain is mediated by a diverse family of glutamate receptor ion channels (iGluRs), tetrameric membrane protein assemblies of molecular weight 400-600 kDa. Until recently, structural information for intact iGluRs was limited to biochemically tractable homomeric receptors trapped in different conformational states. These provided key insights into the mechanisms of iGluR activation and desensitization. Structures of heteromeric AMPA and NMDA receptors, the major iGluR families in the brain, together with long awaited cryo-EM structures of an AMPA receptor TARP complex, expand this picture and reveal surprising conformational diversity, raising many fundamental and controversial questions. C1 [Mayer, Mark L.] NINDS, Porter Neurosci Res Ctr, DHHS, NIH, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NINDS, Porter Neurosci Res Ctr, DHHS, NIH, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov FU Intramural Research Program of NINDS FX I thank Eric Gouaux and Hiro Furukawa and for sharing coordinates, maps and manuscripts prior to publication, and the Intramural Research Program of NINDS for proving support. NR 42 TC 2 Z9 2 U1 4 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2016 VL 41 BP 119 EP 127 DI 10.1016/j.sbi.2016.07.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EG3TJ UT WOS:000390967300016 PM 27454049 ER PT J AU Subramaniam, S Earl, LA Falconieri, V Milne, JLS Egelman, EH AF Subramaniam, Sriram Earl, Lesley A. Falconieri, Veronica Milne, Jacqueline L. S. Egelman, Edward H. TI Resolution advances in cryo-EM enable application to drug discovery SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID U4/U6.U5 TRI-SNRNP; ANGSTROM RESOLUTION; ELECTRON CRYOMICROSCOPY; CRYOELECTRON MICROSCOPY; ATOMIC-STRUCTURE; TRPV1 STRUCTURES; MECHANISM; ACTIVATION; INHIBITION; REVEALS AB The prospect that the structures of protein assemblies, small and large, can be determined using cryo-electron microscopy (cryo-EM) is beginning to transform the landscape of structural biology and cell biology. Great progress is being made in determining 3D structures of biological assemblies ranging from icosahedral viruses and helical arrays to small membrane proteins and protein complexes. Here, we review recent advances in this field, focusing especially on the emerging use of cryo-EM in mapping the binding of drugs and inhibitors to protein targets, an application that requires structure determination at the highest possible resolutions. We discuss methods used to evaluate the information contained in cryoEM density maps and consider strengths and weaknesses of approaches currently used to measure map resolution. C1 [Subramaniam, Sriram; Earl, Lesley A.; Falconieri, Veronica; Milne, Jacqueline L. S.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Egelman, Edward H.] Univ Virginia, Charlottesville, VA 22908 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH); NIH [GM035269] FX We would like to thank Ardan Patwardhan from the Electron Microscopy Data Bank for assistance with collating EMDB data. This work was supported by the intramural program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH) and by NIH GM035269 (to E.H.E.). NR 58 TC 4 Z9 4 U1 10 U2 10 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2016 VL 41 BP 194 EP 202 DI 10.1016/j.sbi.2016.07.009 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EG3TJ UT WOS:000390967300025 PM 27552081 ER PT J AU Liao, TJ Tsai, CJ Jang, H Fushman, D Nussinov, R AF Liao, Tsung-Jen Tsai, Chung-Jung Jang, Hyunbum Fushman, David Nussinov, Ruth TI RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID REGULATES C-MYC; K-RAS; SARAH DOMAINS; HIPPO PATHWAY; THERAPEUTIC TARGET; CELL-PROLIFERATION; PANCREATIC-CANCER; SIGNALING PATHWAY; STRUCTURAL BASIS; PROTEIN-KINASE AB Is RASSF5 a tumor suppressor or activator? RASSF5 links K Ras and the Hippo pathway. Hippo's signaling promotes YAP1 phosphorylation and degradation. YAP1 overexpression promotes cancer. Most reports point to RASSF5 suppressing cancer; however, some point to its promoting cancer. Our mechanistic view explains how RASSF5 can activate MST1/2 and suppress cancer in vivo; but inhibits MST1/2 in vitro. We propose that both activation and inhibition of MST1/2 can take place via SARAH heterodimerization. Our thesis in vivo, membrane-anchored Ras dimers (or nanoclusters) can promote SARAH domain heterodimerization, Raf-like MST1/2 kinase domain homodimerization and transautophosphorylation. In contrast, in vitro, K-Ras binding also releases the RASSF5 SARAH stimulating MST1/2's SARAH heterodimerization; however, without membrane, no MST1/2 kinase domain homodimerization/trans-autophosphorylation. C1 [Liao, Tsung-Jen; Tsai, Chung-Jung; Jang, Hyunbum; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Liao, Tsung-Jen; Fushman, David] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [Fushman, David] Univ Maryland, Ctr Biomol Struct & Org, Dept Chem & Biochem, College Pk, MD 20742 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. EM nussinor@helix.nih.gov FU NIH [GM065334]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX This work has been supported by NIH grant GM065334 (to DF). This project 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 HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 69 TC 1 Z9 1 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2016 VL 41 BP 217 EP 224 DI 10.1016/j.sbi.2016.09.001 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EG3TJ UT WOS:000390967300028 PM 27643882 ER PT J AU Yun, JS Lim, TS Cha, SA Ahn, YB Song, KH Choi, JA Kwon, J Jee, D Cho, YK Park, YM Ko, SH AF Yun, Jae-Seung Lim, Tae-Seok Cha, Seon-Ah Ahn, Yu-Bae Song, Ki-Ho Choi, Jin A. Kwon, Jinwoo Jee, Donghyun Cho, Yang Kyung Park, Yong-Moon Ko, Seung-Hyun TI Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea SO DIABETES & METABOLISM JOURNAL LA English DT Article DE Diabetes mellitus, type 2; Diabetic retinopathy; Risk factors ID CARDIOVASCULAR-DISEASE; GLYCEMIC VARIABILITY; SERUM-CHOLESTEROL; CONTROLLED-TRIAL; MACULAR EDEMA; PROGRESSION; ASSOCIATION; PREVALENCE; COMPLICATIONS; EYE AB Background: We investigated clinical course and risk factors for diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 759 patients with T2DM without DR were included from January 2001 to December 2004. Retinopathy evaluation was performed at least annually by ophthalmologists. The severity of the DR was classified into five categories according to the International Clinical Diabetic Retinopathy Severity Scales. Results: Of the 759 patients, 523 patients (68.9%) completed the follow-up evaluation. During the follow-up period, 235 patients (44.9%) developed DR, and 32 patients (13.6%) progressed to severe nonproliferative DR (NPDR) or proliferative DR (PDR). The mean duration of diabetes at the first diagnosis of mild NPDR, moderate NPDR, and severe NPDR or PDR were 14.8, 16.7, and 17.3 years, respectively. After adjusting multiple confounding factors, the significant risk factors for the incidence of DR risk in patients with T2DM were old age, longer duration of diabetes, higher mean glycosylated hemoglobin (HbA1c), and albuminuria. Even in the patients who had been diagnosed with diabetes for longer than 10 years at baseline, a decrease in HbA1c led to a significant reduction in the risk of developing DR (hazard ratio, 0.73 per 1% HbA1c decrement; 95% confidence interval, 0.58 to 0.91; P= 0.005). Conclusion: This prospective cohort study demonstrates that glycemic control, diabetes duration, age, and albuminuria are important risk factors for the development of DR. More aggressive retinal screening for T2DM patients diagnosed with DR should be required in order to not miss rapid progression of DR. C1 [Yun, Jae-Seung; Lim, Tae-Seok; Cha, Seon-Ah; Ahn, Yu-Bae; Ko, Seung-Hyun] Catholic Univ Korea, St Vincents Hosp, Div Endocrinol & Metab, Dept Internal Med,Coll Med, 93 Jungbu Daero, Suwon 16247, South Korea. [Song, Ki-Ho] Catholic Univ Korea, Yeouido St Marys Hosp, Div Endocrinol & Metab, Dept Internal Med,Coll Med, Seoul, South Korea. [Choi, Jin A.; Kwon, Jinwoo; Jee, Donghyun; Cho, Yang Kyung] Catholic Univ Korea, St Vincents Hosp, Dept Ophthalmol, Coll Med, Suwon, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, US Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Ko, SH (reprint author), Catholic Univ Korea, St Vincents Hosp, Div Endocrinol & Metab, Dept Internal Med,Coll Med, 93 Jungbu Daero, Suwon 16247, South Korea. EM kosh@catholic.ac.kr NR 45 TC 0 Z9 0 U1 1 U2 1 PU KOREAN DIABETES ASSOC PI SEOUL PA 1010 RENAISSANCE TOWER BLDG, 14 MANRIJAE-RO, MAPO-GUO, SEOUL, 121-706, SOUTH KOREA SN 2233-6079 EI 2233-6087 J9 DIABETES METAB J JI Diabetes Metab. J. PD DEC PY 2016 VL 40 IS 6 BP 482 EP 492 DI 10.4093/dmj.2016.40.6.482 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3GF UT WOS:000390931100008 PM 27766793 ER PT J AU Bogoslovsky, T Gill, J Jeromin, A Davis, C Diaz-Arrastia, R AF Bogoslovsky, Tanya Gill, Jessica Jeromin, Andreas Davis, Cora Diaz-Arrastia, Ramon TI Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use SO DIAGNOSTICS LA English DT Review DE traumatic brain injury (TBI); biomarkers; TBI management ID FIBRILLARY ACIDIC PROTEIN; C-TERMINAL HYDROLASE-L1; DIFFUSE AXONAL INJURY; GLASGOW COMA SCALE; NEURON-SPECIFIC ENOLASE; SURROGATE END-POINTS; ICE HOCKEY PLAYERS; MINOR HEAD-INJURY; CEREBROSPINAL-FLUID; POSTCONCUSSION SYNDROME AB Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind. C1 [Bogoslovsky, Tanya; Davis, Cora] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Rockville, MD 20856 USA. [Gill, Jessica] NINR, NIH, Bethesda, MD 20814 USA. [Jeromin, Andreas] Quanterix Inc, Lexington, MA 02421 USA. [Diaz-Arrastia, Ramon] Univ Penn, Dept Neurol, Traumat Brain Injury Clin Res Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Bogoslovsky, T (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Rockville, MD 20856 USA. EM tanya.bogoslovsky.ctr@usuhs.edu; jessica.gill@nih.gov; ajeromin@quanterix.com; cora.davis.ctr@usuhs.edu; ramondia@mail.med.upenn.edu FU Center for Neuroscience and Regenerative Medicine (CNRM) FX This work was supported by the Center for Neuroscience and Regenerative Medicine (CNRM). NR 123 TC 0 Z9 0 U1 4 U2 4 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2075-4418 J9 DIAGNOSTICS JI Diagnostics PD DEC PY 2016 VL 6 IS 4 AR 37 DI 10.3390/diagnostics6040037 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA EG3HY UT WOS:000390935700002 ER PT J AU Luk, JW Worley, MJ Winiger, E Trim, RS Hopfer, CJ Hewitt, JK Brown, SA Wall, TL AF Luk, Jeremy W. Worley, Matthew J. Winiger, Evan Trim, Ryan S. Hopfer, Christian J. Hewitt, John K. Brown, Sandra A. Wall, Tamara L. TI Risky driving and sexual behaviors as developmental outcomes of co-occurring substance use and antisocial behavior SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance use; Antisocial behavior; Risky driving; Sexual transmitted infections; Injection drug use ID DIAGNOSTIC INTERVIEW SCHEDULE; YOUNG ADULTHOOD; UNITED-STATES; EXTERNALIZING SPECTRUM; PSYCHIATRIC-DISORDERS; ALCOHOL-USE; DRUG-USE; ADOLESCENT; ASSOCIATION; PERSONALITY AB Purpose: To examine the associations between substance use and antisocial behavior trajectories and seven risky behaviors over time. Method: Data were collected from a high-risk sample of adolescents followed into young adulthood. Five trajectory classes, identified based on dual development of substance use and antisocial behavior symptoms, were used to predict three risky driving and four risky sexual behaviors. Results: In this high-risk sample (n = 530), participants reported notably high overall rates of reckless driving (55.5%) and unprotected sex under the influence (44.8%) in the past year. Risky behaviors that are typically of low base rates in population-based studies were also elevated, with 8.8% reporting past-year driving under the influence (DUI) charge, 17.6% reporting lifetime sexually transmitted infection (STI), and 10.4% reporting lifetime injection drug use. The Dual Chronic class had the highest levels of all seven risky behaviors, and were 3-4 times more likely to report risky driving, lifetime STI, and injection drug use than the Relatively Resolved class. Rates of past-year reckless driving and DUI were elevated among classes with persistent antisocial behavior, whereas rates of DUI, DUI charge, and unprotected sex under the influence were elevated among classes with persistent substance use. Conclusions: Young adults with persistent co-occurring substance use and antisocial behavior engage in multiple very costly risky behaviors. Differential associations between risky behaviors and trajectory classes highlight the need for targeted interventions. Published by Elsevier Ireland Ltd. C1 [Luk, Jeremy W.; Worley, Matthew J.; Winiger, Evan; Trim, Ryan S.; Brown, Sandra A.; Wall, Tamara L.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Worley, Matthew J.; Trim, Ryan S.; Wall, Tamara L.] VA San Diego Hlth Syst, La Jolla, CA USA. [Hopfer, Christian J.] Univ Colorado, Dept Psychiat, Denver, CO 80202 USA. [Hewitt, John K.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Luk, Jeremy W.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20817 USA. [Luk, Jeremy W.] 6710B Rockledge Dr,Room 3155A,MSC 7004, Bethesda, MD 20817 USA. RP Wall, TL (reprint author), Univ Calif San Diego, 3350 La Jolla Village Dr 116B, San Diego, CA 92161 USA. EM j2luk@ucsd.edu; twall@ucsd.edu FU National Institute of Drug Abuse [R01 DA035804, R01 DA021905, R01 DA012845, F31 DA030861, P60 DA011015, R01 DA021913, R01 DA015522]; National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R37 AA07033, T32 AA013525]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by National Institute of Drug Abuse grants R01 DA035804 (PIs: Hopfer, Stallings, & Wall), R01 DA021905 (PIs: Brown & Wall), R01 DA012845 (PI: Hewitt), F31 DA030861 (PI: Worley), P60 DA011015 (PI: Hewitt), R01 DA021913 (PI: Hopfer), R01 DA015522 (PI: Hopfer), and National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants R37 AA07033 (PI: Brown) and T32 AA013525 (PI: Riley). This work was also supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content of this manuscript is solely the responsibility of the authors. The sponsoring agencies had no role in the design, analyses, or writing of this paper, or the decision to submit this paper for publication. NR 40 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 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 1 PY 2016 VL 169 BP 19 EP 25 DI 10.1016/j.drugalcdep.2016.10.006 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EG3SO UT WOS:000390965200004 PM 27750183 ER PT J AU Feaster, DJ Parish, CL Gooden, L Matheson, T Castellon, PC Duan, R Pan, Y Haynes, LF Schackman, BR Malotte, CK Mandler, RN Colfax, GN Metsch, LR AF Feaster, Daniel J. Parish, Carrigan L. Gooden, Lauren Matheson, Tim Castellon, Pedro C. Duan, Rui Pan, Yue Haynes, Louise F. Schackman, Bruce R. Malotte, C. Kevin Mandler, Raul N. Colfax, Grant N. Metsch, Lisa R. TI Substance use and STI acquisition: Secondary analysis from the AWARE study SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Sexually transmitted infections; Substance use; Substance use treatment; Gender differences ID SEXUALLY-TRANSMITTED INFECTIONS; NEW-YORK-CITY; HETEROSEXUAL METHAMPHETAMINE USERS; NATIONAL EPIDEMIOLOGIC SURVEY; RANDOMIZED CLINICAL-TRIAL; RISK REDUCTION GROUPS; LOS-ANGELES-COUNTY; HIV-POSITIVE GAY; DRUG-USE; UNITED-STATES AB Objectives: Sexually transmitted infections (STIs) are significant public health and financial burdens in the United States. This manuscript examines the relationship between substance use and prevalent and incident ST1s in HIV-negative adult patients at STI clinics. Methods: A secondary analysis of Project AWARE was performed based on 5012 patients from 9 STI clinics. STIs were assessed by laboratory assay and substance use by self-report. Patterns of substance use were assessed using latent class analysis. The relationship of latent class to STI rates was investigated using Poisson regression by population groups at high risk for STIs defined by participant's and partner's gender. Results: Drug use patterns differed by risk group and substance use was related to STI rates with the relationships varying by risk behavior group. Substance use treatment participation was associated with increased STI rates. Conclusions: Substance use focused interventions may be useful in STI clinics to reduce morbidity associated with substance use. Conversely, gender-specific sexual health interventions may be useful in substance use treatment. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Feaster, Daniel J.; Duan, Rui; Pan, Yue] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, 1120 NW 14th St, Miami, FL 33136 USA. [Parish, Carrigan L.; Gooden, Lauren; Castellon, Pedro C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, Miami Res Ctr, 1120 NW 14th St, Miami, FL 33136 USA. [Matheson, Tim; Colfax, Grant N.] San Francisco Dept Publ Hlth, HIV Prevent Sect, 25 Van Ness Ave, San Francisco, CA 94102 USA. [Haynes, Louise F.] Med Univ South Carolina, Addict Sci Div, 67 President St, Charleston, SC 29425 USA. [Schackman, Bruce R.] Weill Cornell Med Coll, Dept Healthcare Policy & Res, 425 East 61st St, New York, NY USA. [Malotte, C. Kevin] Calif State Univ Long Beach, Dept Hlth Sci, Ctr Hlth Care Innovat, 5500 Atherton St, Long Beach, CA USA. [Mandler, Raul N.] NIDA, NIH, 6000 Execut Blvd, Rockville, MD 20852 USA. [Metsch, Lisa R.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 W 168th St,9th Floor, New York, NY 10032 USA. RP Feaster, DJ (reprint author), Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, 1120 NW 14th St, Miami, FL 33136 USA. EM dfeaster@med.miami.edu; cp2695@columbia.edu; lkg2129@columbia.edu; Tim.Matheson@sfdph.org; pc2594@columbia.edu; rduan@med.miami.edu; panyue@med.miami.edu; hayneslf@musc.edu; brs2006@med.cornell.edu; kmalotte@csulb.edu; mandlerr@nida.nih.gov; grant.colfax@sfdph.org; lm2892@columbia.edu FU Office of the Director, National Institutes of Health (OD) [RC2DA028973]; National Institute on Drug Abuse [R21DA038641, R01DA027379]; University of Miami Center for AIDS Research (CFAR) [P30 AI073961] FX This work was supported by the Office of the Director, National Institutes of Health (OD) (RC2DA028973), and the National Institute on Drug Abuse (R21DA038641 and R01DA027379). The infrastructure of the National Drug Abuse Treatment Clinical Trials Network was used as a platform in conducting the Project AWARE trial (U10DA13720). Support from the University of Miami Center for AIDS Research (CFAR) is also acknowledged (P30 AI073961). The NIH had no further role in study design, in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 80 TC 0 Z9 0 U1 3 U2 3 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 DEC 1 PY 2016 VL 169 BP 171 EP 179 DI 10.1016/j.drugalcdep.2016.10.027 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EG3SO UT WOS:000390965200025 PM 27837708 ER PT J AU Liang, TJ AF Liang, T. Jake TI Hepatitis C Virus: From Obscurity to the Lasker SO GASTROENTEROLOGY LA English DT Editorial Material ID INHIBITOR C1 [Liang, T. Jake] NIDDK, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2016 VL 151 IS 6 BP 1052 EP 1053 DI 10.1053/j.gastro.2016.10.011 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OV UT WOS:000390955500009 PM 27765691 ER PT J AU Schwimmer, JB Lavine, JE Wilson, LA Neuschwander-Tetri, BA Xanthakos, SA Kohli, R Barlow, SE Vos, MB Karpen, SJ Molleston, JP Whitington, PF Rosenthal, P Jain, AK Murray, KF Brunt, EM Kleiner, DE Van Natta, ML Clark, JM Tonascia, J Doo, E AF Schwimmer, Jeffrey B. Lavine, Joel E. Wilson, Laura A. Neuschwander-Tetri, Brent A. Xanthakos, Stavra A. Kohli, Rohit Barlow, Sarah E. Vos, Miriam B. Karpen, Saul J. Molleston, Jean P. Whitington, Peter F. Rosenthal, Philip Jain, Ajay K. Murray, Karen F. Brunt, Elizabeth M. Kleiner, David E. Van Natta, Mark L. Clark, Jeanne M. Tonascia, James Doo, Edward CA NASH CRN TI In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores SO GASTROENTEROLOGY LA English DT Article DE Pediatrics; ALT; AST; Obesity ID RANDOMIZED CONTROLLED-TRIAL; ENTERIC-COATED CYSTEAMINE; QUALITY-OF-LIFE; METABOLIC SYNDROME; OBESE CHILDREN; HEALTHY-ADULTS; RISK-FACTORS; ADOLESCENTS; PHARMACOKINETICS; ASSOCIATION AB BACKGROUND & AIMS: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. METHODS: We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing <= 65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis. RESULTS: There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 +/- 88 U/L vs 8 +/- 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 +/- 52 vs 4 +/- 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005). CONCLUSIONS: In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. C1 [Schwimmer, Jeffrey B.] Univ Calif San Diego, Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, La Jolla, CA 92093 USA. [Schwimmer, Jeffrey B.] Rady Childrens Hosp, Dept Gastroenterol, San Diego, CA USA. [Lavine, Joel E.] Columbia Univ, Dept Pediat, Div Gastroenterol Hepatol & Nutr, New York, NY 10027 USA. [Lavine, Joel E.] Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY USA. [Wilson, Laura A.; Van Natta, Mark L.; Clark, Jeanne M.; Tonascia, James] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. [Jain, Ajay K.] St Louis Univ, Dept Pediat, St Louis, MO 63103 USA. [Xanthakos, Stavra A.; Kohli, Rohit] Cincinnati Childrens Hosp Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Barlow, Sarah E.] Baylor Coll Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Barlow, Sarah E.] Texas Childrens Hosp, Houston, TX 77030 USA. [Vos, Miriam B.] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Dept Pediat,Div Gastroenterol Hepatol & Nutr, Atlanta, GA USA. [Karpen, Saul J.] Emory Univ, Sch Med, Childrens Hlthcare Atlanta, Div Pediat Gastroenterol Hepatol & Nutr,Dept Pedi, Atlanta, GA USA. [Molleston, Jean P.] Indiana Univ Sch Med, Riley Hosp Children, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Indianapolis, IN 46202 USA. [Whitington, Peter F.] Northwestern Univ, Feinberg Med Sch, Dept Pediat, Chicago, IL USA. [Whitington, Peter F.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Rosenthal, Philip] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, Div Gastroenterol Hepatol & Nutr, San Francisco, CA USA. [Murray, Karen F.] Univ Washington, Sch Med, Dept Pediat, Div Gastroenterol & Hepatol, Seattle, WA 98195 USA. [Murray, Karen F.] Seattle Childrens, Seattle, WA USA. [Brunt, Elizabeth M.] Washington Univ St Louis, Dept Pathol, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Doo, Edward] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. RP Schwimmer, JB (reprint author), Univ Calif San Diego, Div Gastroenterol Hepatol & Nutr, Dept Pediat, 3020 Childrens Way,MC 5030, San Diego, CA 92123 USA. EM jschwimmer@ucsd.edu OI kohli, Rohit/0000-0002-0198-7703; Towbin, Alexander/0000-0003-1729-5071; Cecil, Kim/0000-0001-8233-5485 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713]; National Center for Advancing Translational Sciences [UL1TR000077, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000454]; Intramural Research Program of the National Institutes of Health, National Cancer Institute; Raptor Pharmaceuticals; National Institute of Diabetes and Digestive and Kidney Diseases FX The Nonalcoholic Steatohepatitis Clinical Research Network is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U01DK061713). Additional support was received from the National Center for Advancing Translational Sciences (UL1TR000077, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, and UL1TR000454). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. This study also was funded in part by Raptor Pharmaceuticals via a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. NR 35 TC 1 Z9 1 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2016 VL 151 IS 6 BP 1141 EP + DI 10.1053/j.gastro.2016.08.027 PG 23 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OV UT WOS:000390955500029 PM 27569726 ER PT J AU Jaramillo-Lambert, A Fabritius, AS Hansen, TJ Smith, HE Golden, A AF Jaramillo-Lambert, Aimee Fabritius, Amy S. Hansen, Tyler J. Smith, Harold E. Golden, Andy TI The Identification of a Novel Mutant Allele of topoisomerase II in Caenorhabditis elegans Reveals a Unique Role in Chromosome Segregation During Spermatogenesis SO GENETICS LA English DT Article DE top-2; Caenorhabditis elegans; meiosis; spermatogenesis; topoisomerase II ID MEIOTIC PROPHASE; COHESIN REMOVAL; GERM-CELLS; MEIOSIS; CONDENSATION; RECOMBINATION; SYNAPSIS; OOCYTES; SPERMATIDS; SEPARATION AB Topoisomerase II alleviates DNA entanglements that are generated during mitotic DNA replication, transcription, and sister chromatid separation. In contrast to mitosis, meiosis has two rounds of chromosome segregation following one round of DNA replication. In meiosis II, sister chromatids segregate from each other, similar to mitosis. Meiosis I, on the other hand, segregates homologs, which requires pairing, synapsis, and recombination. The exact role that topoisomerase II plays during meiosis is unknown. In a screen reexamining Caenorhabditis elegans legacy mutants isolated 30 years ago, we identified a novel allele of the gene encoding topoisomerase II, top-2(it7). In this study, we demonstrate that top-2(it7) males produce dead embryos, even when fertilizing wild-type oocytes. Characterization of early embryonic events indicates that fertilization is successful and sperm components are transmitted to the embryo. However, sperm chromatin is not detected in these fertilized embryos. Examination of top-2(it7) spermatogenic germ lines reveals that the sperm DNA fails to segregate properly during anaphase I of meiosis, resulting in anucleate sperm. top-2(it7) chromosome-segregation defects observed during anaphase I are not due to residual entanglements incurred during meiotic DNA replication and are not dependent on SPO-11-induced double-strand DNA breaks. Finally, we show that TOP-2 associates with chromosomes in meiotic prophase and that chromosome association is disrupted in the germ lines of top-2(it7) mutants. C1 [Jaramillo-Lambert, Aimee; Fabritius, Amy S.; Hansen, Tyler J.; Smith, Harold E.; Golden, Andy] NIDDK, NIH, Bethesda, MD 20892 USA. RP Jaramillo-Lambert, A (reprint author), NIDDK, Lab Biochem & Genet, NIH, Room 323,Bldg 8,8 Ctr Dr, Bethesda, MD 20892 USA. EM jaramillolamban@mail.nih.gov FU National Institutes of Health Office of Research Infrastructure Programs [P40 OD-010440]; Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank K. Stein for genetic mapping of mel-15(it7ts); A. Chandra for helping with the mel- 15(it7ts) complementation tests; James Berger for analysis of TOP-2 protein structure; N. Devaul, R. Meseroll, and A. Walters for comments on the manuscript; and members of the Baltimore Worm Club for helpful discussions. We are grateful to Ken Kemphues for the original isolation and characterization of the mel-15(it7ts) allele, which inspired this project. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by National Institutes of Health Office of Research Infrastructure Programs (P40 OD-010440). Some deletion allele strains were generated by the C. elegans Gene Knockout Consortium at the University of British Columbia led by D. Moerman. 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 62 TC 0 Z9 0 U1 2 U2 2 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD DEC PY 2016 VL 204 IS 4 BP 1407 EP + DI 10.1534/genetics.116.195099 PG 25 WC Genetics & Heredity SC Genetics & Heredity GA EG1BD UT WOS:000390765500012 PM 27707787 ER PT J AU Dunleavy, K Little, RF Wilson, WH AF Dunleavy, Kieron Little, Richard F. Wilson, Wyndham H. TI Update on Burkitt Lymphoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Burkitt lymphoma; MYC; TCF3; CCND3; ID3; Risk-adapted; Endemic; Sporadic ID B-CELL LYMPHOMA; PROMOTES GENOMIC INSTABILITY; ACUTE LYMPHOBLASTIC-LEUKEMIA; MODIFIED CODOX-M/IVAC; NON-HODGKINS-LYMPHOMA; DOSE-ADJUSTED EPOCH; ADULT BURKITT; LINE AKATA; CHEMOTHERAPY; RITUXIMAB AB Because of its rarity and high curability, progress in advancing therapeutics in Burkitt lymphoma (BL) has been difficult. Over recent years, several new mutations that cooperate with MYC have been identified, and this has paved the way for testing novel agents in the disease. One of the challenges of most standard approaches typically used is severe treatment related toxicity that often leads to discontinuation of therapy. To that point, there has been recent success developing intermediate intensity approaches that are well tolerated in all patient groups and maintain high cure rates in a multicenter setting. C1 [Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, HIV & Stem Cell Therapeut, CTEP, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), Lymphoid Malignancies Branch, Bldg 10,Room 12N4114,10 Ctr Dr, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU NIH HHS [NIH0010513932] NR 41 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 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD DEC PY 2016 VL 30 IS 6 BP 1333 EP + DI 10.1016/j.hoc.2016.07.009 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA EG3UW UT WOS:000390971200014 PM 27888884 ER PT J AU Pu, J Guardia, CM Keren-Kaplan, T Bonifacino, JS AF Pu, Jing Guardia, Carlos M. Keren-Kaplan, Tal Bonifacino, Juan S. TI Mechanisms and functions of lysosome positioning SO JOURNAL OF CELL SCIENCE LA English DT Article DE Lysosome; Late endosome; Organelle positioning; Organelle motility; Kinesin; Dynein ID GTPASE-ACTIVATING PROTEIN; PLASMA-MEMBRANE REPAIR; KINESIN HEAVY-CHAIN; BREAST-CANCER CELLS; ARF-LIKE GTPASE; LATE ENDOSOMES; PREFERENTIAL BINDING; CYTOPLASMIC DYNEIN; SECRETORY GRANULES; NONNEURONAL CELLS AB Lysosomes have been classically considered terminal degradative organelles, but in recent years they have been found to participate in many other cellular processes, including killing of intracellular pathogens, antigen presentation, plasma membrane repair, cell adhesion and migration, tumor invasion and metastasis, apoptotic cell death, metabolic signaling and gene regulation. In addition, lysosome dysfunction has been shown to underlie not only rare lysosome storage disorders but also more common diseases, such as cancer and neurodegeneration. The involvement of lysosomes in most of these processes is now known to depend on the ability of lysosomes to move throughout the cytoplasm. Here, we review recent findings on the mechanisms that mediate the motility and positioning of lysosomes, and the importance of lysosome dynamics for cell physiology and pathology. C1 [Pu, Jing; Guardia, Carlos M.; Keren-Kaplan, Tal; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU intramural program of National Institute of Child Health and Human Development (NICHD) [ZIA HD001607] FX Work in the authors' laboratory is funded by the intramural program of National Institute of Child Health and Human Development (NICHD) (ZIA HD001607). Deposited in PMC for release after 12 months. NR 147 TC 2 Z9 2 U1 7 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD DEC 1 PY 2016 VL 129 IS 23 BP 4329 EP 4339 DI 10.1242/jcs.196287 PG 11 WC Cell Biology SC Cell Biology GA EG5RS UT WOS:000391102600003 PM 27799357 ER PT J AU Brown, RJ Araujo-Vilar, D Cheung, PT Dunger, D Garg, A Jack, M Mungai, L Oral, EA Patni, N Rother, KI von Schnurbein, J Sorkina, E Stanley, T Vigouroux, C Wabitsch, M Williams, R Yorifuji, T AF Brown, Rebecca J. Araujo-Vilar, David Cheung, Pik To Dunger, David Garg, Abhimanyu Jack, Michelle Mungai, Lucy Oral, Elif A. Patni, Nivedita Rother, Kristina I. von Schnurbein, Julia Sorkina, Ekaterina Stanley, Takara Vigouroux, Corinne Wabitsch, Martin Williams, Rachel Yorifuji, Tohru TI The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FAMILIAL PARTIAL LIPODYSTROPHY; CONGENITAL GENERALIZED LIPODYSTROPHY; LEPTIN-REPLACEMENT THERAPY; SEVERE INSULIN-RESISTANCE; FATTY LIVER-DISEASE; HUTCHINSON-GILFORD PROGERIA; BASE-LINE CHARACTERISTICS; ENCODING LAMIN A/C; OF-THE-LITERATURE; NONALCOHOLIC STEATOHEPATITIS AB Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated. C1 [Brown, Rebecca J.; Rother, Kristina I.] NIDDK, NIH, Bldg 10 CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. [Araujo-Vilar, David] Univ Santiago de Compostela, Dept Med, Santiago De Compostela 15782, Spain. [Cheung, Pik To] Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Dunger, David] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England. [Dunger, David] Univ Cambridge, Metab Res Labs Wellcome Trust, Med Res Council,Inst Metab Sci,MRC Epidemiol Unit, Natl Inst Hlth Res,Cambridge Comprehens Biomed Re, Cambridge CB2 0QQ, England. [Garg, Abhimanyu] UT Southwestern Med Ctr, Div Nutr & Metab Dis, Dept Internal Med, Dallas, TX 75390 USA. [Garg, Abhimanyu] UT Southwestern Med Ctr, Ctr Human Nutr, Dallas, TX 75390 USA. [Jack, Michelle] Univ Sydney, Northern Clin Sch, Royal North Shore Hosp, St Leonards, NSW 2126, Australia. [Mungai, Lucy] Univ Nairobi, Dept Paediat & Child Hlth, Nairobi 00100, Kenya. [Oral, Elif A.] Univ Michigan Med Sch & Hlth Syst, Brehm Ctr Diabet, Ann Arbor, MI 48109 USA. [Oral, Elif A.] Univ Michigan Med Sch & Hlth Syst, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Patni, Nivedita] UT Southwestern Med Ctr, Div Pediat Endocrinol, Dept Pediat, Dallas, TX 75390 USA. [von Schnurbein, Julia; Wabitsch, Martin] Univ Ulm, Dept Pediat & Adolescent Med, Div Pediat Endocrinol & Diabet, D-89075 Ulm, Germany. [Sorkina, Ekaterina] Moscow MV Lomonosov State Univ, Endocrinol Res Ctr, Clamp Technol Lab, Moscow 119991, Russia. [Sorkina, Ekaterina] Moscow MV Lomonosov State Univ, Med Sci Educ Ctr Lomonosov, Mol Endocrinol Lab, Moscow 119991, Russia. [Stanley, Takara] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02115 USA. [Stanley, Takara] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02115 USA. [Stanley, Takara] Harvard Med Sch, Boston, MA 02115 USA. [Vigouroux, Corinne] Univ Paris 06, Univ Pierre & Marie Curie,St Antoine Hosp, Sorbonne Univ,Inst Cardiometab & Nutr,AP HP,Mol B, Inserm Unite Mixte Rech Sante 938,St Antoine Res, F-75012 Paris, France. [Williams, Rachel] Cambridge Univ Hosp NHS Trust, Dept Paediat Endocrinol, Cambridge CB2 0QQ, England. [Yorifuji, Tohru] Osaka City Gen Hosp, Childrens Med Ctr, Div Pediat Endocrinol & Metab, Osaka 5340021, Japan. RP Brown, RJ (reprint author), NIDDK, NIH, Bldg 10 CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov OI Sorkina, Ekaterina/0000-0001-7006-0664 FU Pediatric Endocrine Society from AstraZeneca; intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [RO1-DK088114, RO1-DK105448, RO1-DK101941]; Sopha Fund for Lipodystrophy Research at the University of Michigan; Russian Science Foundation [14-35-00026] FX This practice guideline was sponsored and organized by the Pediatric Endocrine Society via au unrestricted education grant from AstraZeneca. Individual authors were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Grants RO1-DK088114, RO1-DK105448, and RO1-DK101941; the Sopha Fund for Lipodystrophy Research at the University of Michigan, and Grant 14-35-00026 of the Russian Science Foundation. NR 114 TC 1 Z9 1 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2016 VL 101 IS 12 BP 4500 EP 4511 DI 10.1210/jc.2016-2466 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3NE UT WOS:000390951000002 PM 27710244 ER PT J AU Nella, AA Mallappa, A Perritt, AF Gounden, V Kumar, P Sinaii, N Daley, LA Ling, A Liu, CY Soldin, SJ Merke, DP AF Nella, Aikaterini A. Mallappa, Ashwini Perritt, Ashley F. Gounden, Verena Kumar, Parag Sinaii, Ninet Daley, Lori-Ann Ling, Alexander Liu, Chia-Ying Soldin, Steven J. Merke, Deborah P. TI A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID QUALITY-OF-LIFE; 21-HYDROXYLASE DEFICIENCY; ADDISONS-DISEASE; CLINICAL-TRIAL; INSUFFICIENCY; PHARMACOKINETICS; REPLACEMENT; PROFILES; THERAPY; COHORT AB Context: Classic congenital adrenal hyperplasia (CAH) management remains challenging, given that supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction. Objective: This study sought to approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in patients with difficult-to-treat CAH. Design: Eight adult patients with classic CAH participated in a single-center open-label phase I-II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving conventional therapy at baseline and 6 months following CSHI included: 24-hour hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL), and fatigue questionnaires. Main Outcome Measures: The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700-hour 17-hydroxyprogesterone (17-OHP) <= 1200 ng/dL was measured. Results: CSHI approximated physiologic cortisol secretion. Compared with baseline, 6 months of CSHI resulted in decreased 0700-hour and 24-hour area under the curve 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (and SF-36 Vitality Score), and fatigue. One of three amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue. Conclusions: CSHI is a safe and well-tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on conventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study. C1 [Nella, Aikaterini A.; Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Nella, Aikaterini A.; Mallappa, Ashwini; Perritt, Ashley F.; Gounden, Verena; Kumar, Parag; Sinaii, Ninet; Daley, Lori-Ann; Ling, Alexander; Liu, Chia-Ying; Soldin, Steven J.; Merke, Deborah P.] Natl Inst Hlth Clin Ctr, Bethesda, MD 20892 USA. RP Nella, AA (reprint author), Univ Texas Med Branch, Div Pediat Endocrinol, Dept Pediat, Res Bldg 6,Suite 3-270C,301 Univ Blvd, Galveston, TX 77555 USA. EM ainella@utmb.edu FU Intramural programs of the National Institutes of Health (NIH) Clinical Center; Eunice Kennedy Shriver National Institute of Child Health & Human Development; Diurnal Limited, Ltd. through an NIH Cooperative Research and Development Agreement FX This work was supported by the Intramural programs of the National Institutes of Health (NIH) Clinical Center and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Medtronic Diabetes Company provided the insulin pumpsand supplies (reservoirs, infusion sets), and also training and technical support without charge, upon approval of the study by the Institutional Review Board Committee. D.P.M. received unrelated research funds from Diurnal Limited, Ltd. through an NIH Cooperative Research and Development Agreement. NR 30 TC 0 Z9 0 U1 4 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2016 VL 101 IS 12 BP 4690 EP 4698 DI 10.1210/jc.2016-1916 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3NE UT WOS:000390951000022 PM 27680873 ER PT J AU Hayakawa, K Formica, AM Brill-Dashoff, J Shinton, SA Ichikawa, D Zhou, Y Morse, HC Hardy, RR AF Hayakawa, Kyoko Formica, Anthony M. Brill-Dashoff, Joni Shinton, Susan A. Ichikawa, Daiju Zhou, Yan Morse, Herbert C., III Hardy, Richard R. TI Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID FAMILY-MEMBER BIM; BH3-ONLY PROTEINS BIM; POSITIVE SELECTION; TRANSGENIC MICE; AUTOANTIBODY PRODUCTION; B-1 CELLS; CYCLIN D2; V-REGION; MOUSE; RECEPTOR AB In mice, generation of autoreactive CD5(+) B cells occurs as a consequence of BCR signaling induced by (self)-ligand exposure from fetal/neonatal B-1 B cell development. A fraction of these cells self-renew and persist as a minor B1 B cell subset throughout life. Here, we show that transfer of early generated B1 B cells from E mu-TCL1 transgenic mice resulted in chronic lymphocytic leukemia (CLL) with a biased repertoire, including stereotyped BCRs. Thus, B1 B cells bearing restricted BCRs can become CLL during aging. Increased anti-thymocyte/Thy-1 autoreactive (ATA) BCR cells in the B1 B cell subset by transgenic expression yielded spontaneous ATA B-CLL/lymphoma incidence, enhanced by TCL1 transgenesis. In contrast, ATA B-CLL did not develop from other B cell subsets, even when the identical ATA BCR was expressed on a Thy-1 low/null background. Thus, both a specific BCR and B1 B cell context were important for CLL progression. Neonatal B1 B cells and their CLL progeny in aged mice continued to express moderately up-regulated c-Myc and down-regulated proapoptotic Bmf, unlike most mature B cells in the adult. Thus, there is a genetic predisposition inherent in B-1 development generating restricted BCRs and self-renewal capacity, with both features contributing to potential for progression to CLL. C1 [Hayakawa, Kyoko; Formica, Anthony M.; Brill-Dashoff, Joni; Shinton, Susan A.; Ichikawa, Daiju; Zhou, Yan; Hardy, Richard R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Ichikawa, Daiju] Keio Univ, Div Clin Physiol & Therapeut, Fac Pharm, Tokyo 105, Japan. RP Hayakawa, K (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. EM Kyoko.Hayakawa@fccc.edu FU National Institutes of Health (NIH) [R01 CA129330, R01 AI049335, R01 AI11320]; FCCC Blood Cell Development and Cancer Keystone program; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health (NIH) grants R01 CA129330 (K. Hayakawa), R01 AI049335 (K.H. Hayakawa), and R01 AI11320 (R.R. Hardy), and the FCCC Blood Cell Development and Cancer Keystone program, and in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 72 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 213 IS 13 BP 3007 EP 3023 DI 10.1084/jem.20160712 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZG UT WOS:000391122900014 PM 27899442 ER PT J AU Kugler, DG Flomerfelt, FA Costa, DL Laky, K Kamenyeva, O Mittelstadt, PR Gress, RE Rosshart, SP Rehermann, B Ashwell, JD Sher, A Jankovic, D AF Kugler, David G. Flomerfelt, Francis A. Costa, Diego L. Laky, Karen Kamenyeva, Olena Mittelstadt, Paul R. Gress, Ronald E. Rosshart, Stephan P. Rehermann, Barbara Ashwell, Jonathan D. Sher, Alan Jankovic, Dragana TI Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID THYMIC EPITHELIAL-CELLS; SCID-HU MOUSE; CYTOMEGALOVIRUS-INFECTION; THYMOCYTE APOPTOSIS; PATHOGEN CHALLENGE; INTERFERON-GAMMA; IMMUNE-RESPONSE; VIRAL-INFECTION; VIRUS-INFECTION; MEASLES-VIRUS AB Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4(+) Th1 cells but also a persistent decrease in the size of the naive CD4(+) T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ. Importantly, the resulting quantitative and qualitative deficiency in naive CD4(+) T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. These findings reveal that systemic infectious agents, such as T. gondii, can induce long-term immune alterations associated with impaired thymic function. When accumulated during the lifetime of the host, such events, even when occurring at low magnitude, could be a contributing factor in immunological senescence. C1 [Kugler, David G.; Costa, Diego L.; Sher, Alan; Jankovic, Dragana] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Laky, Karen] NIAID, Cell Dev Sect T, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kamenyeva, Olena] NIAID, Biol Imaging, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Flomerfelt, Francis A.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Mittelstadt, Paul R.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Rosshart, Stephan P.; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kugler, David G.] Juno Therapeut, Seattle, WA 98109 USA. RP Sher, A; Jankovic, D (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ASher@niaid.nih.gov; DJankovic@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Intramural Research Program of the National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Intramural AIDS Research Fellowship FX This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health and by an Intramural AIDS Research Fellowship (to D.G. Kugler). NR 78 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 213 IS 13 BP 3041 EP 3056 DI 10.1084/jem.20151636 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZG UT WOS:000391122900016 PM 27849554 ER PT J AU Leone, V Faraldo-Gomez, JD AF Leone, Vanessa Faraldo-Gomez, Jose D. TI Structure and mechanism of the ATP synthase membrane motor inferred from quantitative integrative modeling SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID PROTEIN-STRUCTURE PREDICTION; HIGH-RESOLUTION STRUCTURE; AMINO-ACID SUBSTITUTIONS; ESCHERICHIA-COLI; PROTON TRANSLOCATION; ALPHA-SUBUNIT; ROTOR RING; F0F1-ATP SYNTHASE; AQUEOUS ACCESS; CROSS-LINKING AB Two subunits within the transmembrane domain of the ATP synthase-the c-ring and subunit a-energize the production of 90% of cellular ATP by transducing an electrochemical gradient of H+ or Na+ into rotational motion. The nature of this turbine-like energy conversion mechanism has been elusive for decades, owing to the lack of definitive structural information on subunit a or its c-ring interface. In a recent breakthrough, several structures of this complex were resolved by cryo-electron microscopy (cryo-EM), but the modest resolution of the data has led to divergent interpretations. Moreover, the unexpected architecture of the complex has cast doubts on a wealth of earlier biochemical analyses conducted to probe this structure. Here, we use quantitative molecular-modeling methods to derive a structure of the a-c complex that is not only objectively consistent with the cryo-EM data, but also with correlated mutation analyses of both subunits and with prior cross-linking and cysteine accessibility measurements. This systematic, integrative approach reveals unambiguously the topology of subunit a and its relationship with the c-ring. Mapping of known Cd2+ block sites and conserved protonatable residues onto the structure delineates two noncontiguous pathways across the complex, connecting two adjacent proton-binding sites in the c-ring to the space on either side of the membrane. The location of these binding sites and of a strictly conserved arginine on subunit a, which serves to prevent protons from hopping between them, explains the directionality of the rotary mechanism and its strict coupling to the proton-motive force. Additionally, mapping of mutations conferring resistance to oligomycin unexpectedly reveals that this prototypical inhibitor may bind to two distinct sites at the a-c interface, explaining its ability to block the mechanism of the enzyme irrespective of the direction of rotation of the c-ring. In summary, this study is a stepping stone toward establishing the mechanism of the ATP synthase at the atomic level. C1 [Leone, Vanessa; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Leone, V; Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vanessa.leonealvarez@nih.gov; jose.faraldo@nih.gov FU Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health; Max Planck Society FX This study was funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health and previously by the Max Planck Society. NR 82 TC 2 Z9 2 U1 7 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD DEC PY 2016 VL 148 IS 6 BP 441 EP 457 DI 10.1085/jgp.201611679 PG 17 WC Physiology SC Physiology GA EG6BK UT WOS:000391128600001 PM 27821609 ER PT J AU Al-Naamani, N Chirinos, JA Zamani, P Ruthazer, R Paulus, JK Roberts, KE Barr, RG Lima, JA Bluemke, DA Kronmal, R Kawut, SM AF Al-Naamani, Nadine Chirinos, Julio A. Zamani, Payman Ruthazer, Robin Paulus, Jessica K. Roberts, Kari E. Barr, R. Graham Lima, Joao A. Bluemke, David A. Kronmal, Richard Kawut, Steven M. TI Association of Systemic Arterial Properties With Right Ventricular Morphology: The Multi-Ethnic Study of Atherosclerosis (MESA)-Right Ventricle Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE arterial stiffness; artery; magnetic resonance imaging; right ventricle; ventricle ID PRESERVED EJECTION FRACTION; INCIDENT CARDIOVASCULAR EVENTS; CONGESTIVE-HEART-FAILURE; MESA-RIGHT VENTRICLE; ENDOTHELIAL DYSFUNCTION; NONINVASIVE EVALUATION; VASCULAR-RESPONSE; AORTIC STIFFNESS; OXIDATIVE STRESS; DISTURBED FLOW AB Background-Systemic arterial stiffness is recognized as a major contributor to development of left ventricular dysfunction and failure; however, the relationship of systemic arterial properties and the right ventricle (RV) is unknown. Methods and Results-The associations between systemic arterial measures (total arterial compliance [TAC], systemic vascular resistance [SVR], and aortic augmentation index [AI]) and RV morphology (mass, end-systolic [RVESV] and end-diastolic volume [RVEDV], and ejection fraction [RVEF]) were examined using data from the Multi-Ethnic Study of Atherosclerosis. All analyses were adjusted for anthropometric, demographic, and clinical variables and the corresponding left ventricular parameter. A total of 3842 subjects without clinical cardiovascular disease were included with a mean age of 61 years, 48% male, 39% non-Hispanic white, 25% Chinese-American, 23% Hispanic, and 13% black. RV measures were within normal range for age and sex. A 1-mL/mm Hg decrease in TAC was associated with 3.9-mL smaller RVESV, 7.6-mL smaller RVEDV, and 2.4-g lower RV mass. A 5-Wood-unit increase in SVR was associated with 0.6-mL decrease in RVESV, 1.7-mL decrease in RVEDV, and 0.4-g decrease in RV mass. A 1% increase in AI was associated with 0.2-mL decrease in RVEDV. We found significant effect modification by age, sex, and race for some of these relationships, with males, whites, and younger individuals having greater decreases in RV volumes and mass. Conclusions-Markers of increased systemic arterial load were associated with smaller RV volumes and lower RV mass in a population of adults without clinical cardiovascular disease. C1 [Al-Naamani, Nadine; Roberts, Kari E.] Tufts Med Ctr, Dept Med, Boston, MA USA. [Al-Naamani, Nadine; Ruthazer, Robin; Paulus, Jessica K.] Tufts Med Ctr, Clin & Translat Sci Inst, Boston, MA USA. [Chirinos, Julio A.; Zamani, Payman; Kawut, Steven M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Barr, R. Graham] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Lima, Joao A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Kronmal, Richard] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Kawut, SM (reprint author), Univ Penn, Perelman Sch Med, 727 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@exchange.upenn.edu FU National Center for Advancing Translational Sciences (NCATS); National Institutes of Health (NIH) [R01-HL086719, R01-HL098382-01A1, K24-HL103844, N01-HC95159, N01-HC95167, UL1-TR001064, TL1-TR001062, N01-HC95160, N01-HC95161, N01-HC95162, N01-HC95163, N01-HC95164, N01-HC95165] FX This research was supported by the National Center for Advancing Translational Sciences (NCATS) and the National Institutes of Health (NIH; R01-HL086719, R01-HL098382-01A1, K24-HL103844, N01-HC95159 through HC95165, N01-HC95167, UL1-TR001064, and TL1-TR001062). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 54 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD DEC PY 2016 VL 5 IS 12 AR e004162 DI 10.1161/JAHA.116.004162 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EG1JF UT WOS:000390787700017 ER PT J AU Jackson, JD Moy, B Evans, MK AF Jackson, Jonathan D. Moy, Beverly Evans, Michele K. TI The Elimination of Cancer Health Disparities: Are We Ready to Do the Heavy Lifting? SO ONCOLOGIST LA English DT Editorial Material ID AFRICAN-AMERICAN MEN; CLINICAL-TRIALS; RACE; WILLINGNESS; PARTICIPATE; BARRIERS; RISK C1 [Jackson, Jonathan D.; Moy, Beverly] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. RP Jackson, JD (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM jjackson31@partners.org NR 21 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 21 IS 12 BP 1411 EP 1413 DI 10.1634/theoncologist.2016-0327 PG 3 WC Oncology SC Oncology GA EG6DZ UT WOS:000391135800004 PM 27821795 ER PT J AU Hopfner, F Haubenberger, D Galpern, WR Gwinn, K Van't Veer, A White, S Bhatia, K Adler, CH Eidelberg, D Ondo, W Stebbins, GT Tanner, CM Helmich, RC Lenz, FA Sillitoe, RV Vaillancourt, D Vitek, JL Louis, ED Shill, HA Frosch, MP Foroud, T Kuhlenbaumer, G Singleton, A Testa, CM Hallett, M Elble, R Deuschl, G AF Hopfner, Franziska Haubenberger, Dietrich Galpern, Wendy R. Gwinn, Katrina Van't Veer, Ashlee White, Samantha Bhatia, Kailash Adler, Charles H. Eidelberg, David Ondo, William Stebbins, Glenn T. Tanner, Caroline M. Helmich, Rick C. Lenz, Fred A. Sillitoe, Roy V. Vaillancourt, David Vitek, Jerrold L. Louis, Elan D. Shill, Holly A. Frosch, Matthew P. Foroud, Tatiana Kuhlenbaeumer, Gregor Singleton, Andrew Testa, Claudia M. Hallett, Mark Elble, Rodger Deuschl, Guenther TI Knowledge gaps and research recommendations for essential tremor SO PARKINSONISM & RELATED DISORDERS LA English DT Review DE Essential tremor; Common data elements; Genetic association studies; Neuropathology ID PURKINJE-CELL LOSS; PARKINSONS-DISEASE; HEARING IMPAIRMENT; INCREASED NUMBER; CEREBELLUM; LINGO-1; MOTOR; BRAIN; GENE; MUTATIONS AB Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hopfner, Franziska; Kuhlenbaeumer, Gregor; Deuschl, Guenther] Univ Hosp Schleswig Holstein, Dept Neurol, Kiel, Germany. [Haubenberger, Dietrich; Galpern, Wendy R.; Gwinn, Katrina; Van't Veer, Ashlee; White, Samantha; Hallett, Mark] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bhatia, Kailash] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1E 6BT, England. [Adler, Charles H.] Mayo Clin, Coll Med, Scottsdale, AZ USA. [Eidelberg, David] Feinstein Inst Med Res, Manhasset, NY USA. [Ondo, William] Methodist Neurol Inst, Houston, TX USA. [Stebbins, Glenn T.] Rush Univ, Dept Neurol Sci, Med Ctr, Chicago, IL 60612 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Parkinsons Dis Res Educ & Clin Ctr, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Helmich, Rick C.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands. [Lenz, Fred A.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Hopkins Hosp, Baltimore, MD 21205 USA. [Sillitoe, Roy V.] Baylor Coll Med, Dept Pathol & Immunol, Dept Neurosci, Program Dev Biol, Houston, TX 77030 USA. [Vaillancourt, David] Univ Florida, Dept Biomed Engn, Ctr Movement Disorders & Neurorestorat, Dept Appl Physiol & Kinesiol, Gainesville, FL USA. [Vitek, Jerrold L.] Univ Minnesota, Sch Med, Dept Neurol, Minneapolis, MN 55455 USA. [Louis, Elan D.] Yale Univ, Dept Neurol, Dept Chron Dis Epidemiol, Ctr Neuroepidemiol & Clin Neurol Res,Yale Sch Med, New Haven, CT USA. [Shill, Holly A.] Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Parkinsons & Movement Disorders Ctr, Richmond, VA USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Elble, Rodger] 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,Rm 6-5700, Bethesda, MD 20892 USA. EM dietrich.haubenberger@nih.gov RI Helmich, Rick/R-6333-2016; OI Helmich, Rick/0000-0003-4035-6573; Gwinn, Katrina/0000-0002-8277-651X FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke NR 91 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 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD DEC PY 2016 VL 33 BP 27 EP 35 DI 10.1016/j.parkreldis.2016.10.002 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EG0SR UT WOS:000390743000004 PM 27769649 ER PT J AU McCrea, E Sissung, TM Price, DK Chau, CH Figg, WD AF McCrea, Edel Sissung, Tristan M. Price, Douglas K. Chau, Cindy H. Figg, William D. TI Androgen receptor variation affects prostate cancer progression and drug resistance SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Androgen receptor; Prostate cancer; AR-V7; Pharmacology; Mutation ID LIGAND-BINDING DOMAIN; MOLECULAR-DYNAMICS SIMULATIONS; GROWTH-FACTOR-I; SPLICE VARIANTS; ANTITUMOR-ACTIVITY; ENZALUTAMIDE RESISTANCE; ABIRATERONE ACETATE; BIOLOGICAL-ACTIVITY; CYP17A1 INHIBITOR; XENOGRAFT MODEL AB Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment. We address how these AR splice variants and mutations affect tumor progression and therapeutic resistance and discuss potential novel therapeutic strategies under development. It is hoped that these therapies can be administered with increasing precision as tumor genotyping methods become more sophisticated, thereby lending clinicians a better understanding of the underlying biology of prostate tumors in individual patients. Published by Elsevier Ltd. C1 [McCrea, Edel; Price, Douglas K.; Chau, Cindy H.; Figg, William D.] NCI, Mol Pharmacol Sect, Genitourinary Malignancies Branch, Bethesda, MD 20892 USA. [Sissung, Tristan M.; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Off Clin Director, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov FU Intramural Research Program of National Institutes of Health, National Cancer Institute, Bethesda, MD, USA FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA. NR 93 TC 1 Z9 1 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 DEC PY 2016 VL 114 BP 152 EP 162 DI 10.1016/j.phrs.2016.10.001 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EG5HQ UT WOS:000391075300017 PM 27725309 ER PT J AU Mertan, F Turkbey, B AF Mertan, Francesca Turkbey, Baris TI Incorporating imaging into personalized medicine for the detection of prostate cancer Pharmacological research-Urogenital pharmacology SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Prostate; Prostate cancer; MRI; mpMRI; Personalized medicine; Imaging ID ULTRASOUND-GUIDED BIOPSY; LOCALIZATION; MRI AB Imaging has played an important role in the administration of personalized medicine. From diagnosing diseases to guiding therapies, imaging has become an all-encompassing modality. With respect to prostate cancer, personalized management of the disease has been transformed by imaging. Specifically, multiparametric magnetic resonance imaging has emerged as a vital player in the detection, characterization, and localization of the disease thus making the incorporation of imaging in personalized prostate cancer management integral. In this review, the current role of imaging in personalized medicine for the management of prostate cancer is discussed. (C) 2016 Published by Elsevier Ltd. C1 [Mertan, Francesca; Turkbey, Baris] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 16 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 114 BP 163 EP 165 DI 10.1016/j.phrs.2016.10.020 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EG5HQ UT WOS:000391075300018 PM 27777131 ER PT J AU Shah, J Sikdar, S Gerber, L AF Shah, Jay Sikdar, Siddhartha Gerber, Lynn TI Re: "Dry Needling Alters Trigger Points in the Upper Trapezius Muscle and Reduces Pain in Subjects with Chronic Myofascial Pain" Reply SO PM&R LA English DT Letter C1 [Shah, Jay] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. [Sikdar, Siddhartha] George Mason Univ, Bioengn Dept, Fairfax, VA 22030 USA. [Gerber, Lynn] George Mason Univ, Ctr Chron Illness & Disabil, Fairfax, VA 22030 USA. RP Shah, J (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. NR 2 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 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD DEC PY 2016 VL 8 IS 12 BP 1226 EP 1227 DI 10.1016/j.pmrj.2016.08.003 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EG5LS UT WOS:000391085900014 PM 27989420 ER PT J AU Wolfe, F Clauw, DJ Fitzcharles, MA Goldenberg, DL Hauser, W Katz, RL Mease, PJ Russell, AS Russell, IJ Walitt, B AF Wolfe, Frederick Clauw, Daniel J. Fitzcharles, Mary-Ann Goldenberg, Don L. Haeuser, Winfried Katz, Robert L. Mease, Philip J. Russell, Anthony S. Russell, Irwin Jon Walitt, Brian TI 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE Fibromyalgia; Criteria; Diagnosis; Classification ID OF-RHEUMATOLOGY CRITERIA; SYMPTOM SEVERITY SCALE; GENERAL-POPULATION; WIDESPREAD PAIN; CLASSIFICATION CRITERIA; TENDER POINTS; PREVALENCE; RELIABILITY; VALIDATION; VERSION AB Objectives: The provisional criteria of the American College of Rheumatology (ACR) 2010 and the 2011 self-report modification for survey and clinical research are widely used for fibromyalgia diagnosis. To determine the validity, usefulness, potential problems, and modifications required for the criteria, we assessed multiple research reports published in 2010-2016 in order to provide a 2016 update to the criteria. Methods: We reviewed 14 validation studies that compared 2010/2011 criteria with ACR 1990 classification and clinical criteria, as well as epidemiology, clinical, and databank studies that addressed important criteria-level variables. Based on definitional differences between 1990 and 2010/2011 criteria, we interpreted 85% sensitivity and 90% specificity as excellent agreement. Results: Against 1990 and clinical criteria, the median sensitivity and specificity of the 2010/2011 criteria were 86% and 90%, respectively. The 2010/2011 criteria led to misclassification when applied to regional pain syndromes, but when a modified widespread pain criterion (the "generalized pain criterion") was added misclassification was eliminated. Based on the above data and clinic usage data, we developed a (2016) revision to the 2010/2011 fibromyalgia criteria. Fibromyalgia may now be diagnosed in adults when all of the following criteria are met: (1) Generalized pain, defined as pain in at least 4 of 5 regions, is present. (2) Symptoms have been present at a similar level for at least 3 months. (3) Widespread pain index (WPI) >= 7 and symptom severity scale (SSS) score >= 5 OR WPI of 4-6 and SSS score >= 9. (4) A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses. Conclusions: The fibromyalgia criteria have good sensitivity and specificity. This revision combines physician and questionnaire criteria, minimizes misclassification of regional pain disorders, and eliminates the previously confusing recommendation regarding diagnostic exclusions. The physician based criteria are valid for individual patient diagnosis. The self-report version of the criteria is not valid for clinical diagnosis in individual patients but is valid for research studies. These changes allow the criteria to function as diagnostic criteria, while still being useful for classification. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wolfe, Frederick] Natl Data Bank Rheumat Dis, 1035 N Emporia,Ste 288, Wichita, KS 67214 USA. [Wolfe, Frederick] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Clauw, Daniel J.] Univ Michigan, Sch Med, Chron Pain & Fatigue Res Ctr, Ann Arbor, MI USA. [Fitzcharles, Mary-Ann] McGill Univ, Div Rheumatol, Ctr Hlth, Montreal, PQ, Canada. [Goldenberg, Don L.] Oregon Hlth & Sci Univ, Portland, OR USA. [Goldenberg, Don L.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Haeuser, Winfried] Dept Internal Med 1, Saarbrucken, Germany. [Haeuser, Winfried] Tech Univ Munich, Dept Psychosomat Med & Psychotherapy, Munich, Germany. [Katz, Robert L.] Rush Med Coll, Rheumatol, Chicago, IL USA. [Mease, Philip J.] Swedish Med Ctr, Seattle, WA USA. [Mease, Philip J.] Univ Washington, Seattle, WA 98195 USA. [Russell, Anthony S.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Russell, Irwin Jon] Fibromyalgia Res & Consulting, San Antonio, TX USA. [Walitt, Brian] NINR, NIH, Bethesda, MD 20892 USA. RP Wolfe, F (reprint author), Natl Data Bank Rheumat Dis, 1035 N Emporia,Ste 288, Wichita, KS 67214 USA.; Wolfe, F (reprint author), Univ Kansas, Sch Med, Wichita, KS 67214 USA. EM fwolfe@arthritis-research.org NR 49 TC 1 Z9 1 U1 10 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 EI 1532-866X J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD DEC PY 2016 VL 46 IS 3 BP 319 EP 329 DI 10.1016/j.semarthrit.2016.08.012 PG 11 WC Rheumatology SC Rheumatology GA EG3XY UT WOS:000390979200009 PM 27916278 ER PT J AU Podbilewicz, B Chernomordik, LV AF Podbilewicz, Benjamin Chernomordik, Leonid V. TI Membrane fusion: Conserved and diverse SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Editorial Material C1 [Podbilewicz, Benjamin] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. [Chernomordik, Leonid V.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Rockville, MD 20847 USA. RP Podbilewicz, B (reprint author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel.; Chernomordik, LV (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Rockville, MD 20847 USA. EM podbilew@tx.technion.ac.il; chernoml@mail.nih.gov OI Podbilewicz, Benjamin/0000-0002-0411-4182 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD DEC PY 2016 VL 60 BP 63 EP 64 DI 10.1016/j.semcdb.2016.11.009 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EG5IJ UT WOS:000391077200009 PM 27979329 ER PT J AU Moss, B AF Moss, Bernard TI Membrane fusion during poxvirus entry SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Vaccinia virus; Membrane fusion; Virus entry; Hemifusion; Endocytosis ID VACCINIA-VIRUS ENTRY; INTRACELLULAR MATURE VIRION; CELL-CELL-FUSION; SERINE-PROTEASE INHIBITOR; SURFACE HEPARAN-SULFATE; OPEN READING FRAME; L1 PROTEIN; ENVELOPE PROTEIN; NEUTRALIZING ANTIBODY; ENTRY/FUSION COMPLEX AB Poxviruses comprise a large family of enveloped DNA viruses that infect vertebrates and invertebrates. Poxviruses, unlike most DNA viruses, replicate in the cytoplasm and encode enzymes and other proteins that enable entry, gene expression, genome replication, virion assembly and resistance to host defenses. Entry of vaccinia virus, the prototype member of the family, can occur at the plasma membrane or following endocytosis. Whereas many viruses encode one or two proteins for attachment and membrane fusion, vaccinia virus encodes four proteins for attachment and eleven more for membrane fusion and core entry. The entry-fusion proteins are conserved in all poxviruses and form a complex, known as the Entry Fusion Complex (EFC), which is embedded in the membrane of the mature virion. An additional membrane that encloses the mature virion and is discarded prior to entry is present on an extracellular form of the virus. The EFC is held together by multiple interactions that depend on nine of the eleven proteins. The entry process can be divided into attachment, hemifusion and core entry. All eleven EFC proteins are required for core entry and at least eight for hemifusion. To mediate fusion the virus particle is activated by low pH, which removes one or more fusion repressors that interact with EFC components. Additional EFC-interacting fusion repressors insert into cell membranes and prevent secondary infection. The absence of detailed structural information, except for two attachment proteins and one EFC protein, is delaying efforts to determine the fusion mechanism. Published by Elsevier Ltd. C1 [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 Division of Intramural Research, NIAID, NIH FX I thank Jason Laliberte and Andrea Weisberg for help with illustrations. This work was supported by the Division of Intramural Research, NIAID, NIH. NR 94 TC 2 Z9 2 U1 4 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD DEC PY 2016 VL 60 BP 89 EP 96 DI 10.1016/j.semcdb.2016.07.015 PG 8 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EG5IJ UT WOS:000391077200012 PM 27423915 ER PT J AU Dodd, KW Berman, A Brown, J Carr, BG Dunn, P Escobedo, M Gayer, C Grieser, M Carpenter, CR Hess, EP Grudzen, CR AF Dodd, Kenneth W. Berman, Amy Brown, Jeremy Carr, Brendan G. Dunn, Patrick Escobedo, Marcus Gayer, Christopher Grieser, Mira Carpenter, Christopher R. Hess, Erik P. Grudzen, Corita R. TI Funding Research in Emergency Department Shared Decision Making: A Summary of the 2016 Academic Emergency Medicine Consensus Conference Panel Discussion SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Academic Emergency Medicine Consensus Conference on Shared Decision Making in the Emergency Department - Development of a Policy-Relevant Patient-Centered Research Agenda CY MAY 10, 2016 CL New Orleans, LA AB As part of the 2016 Academic Emergency Medicine Consensus Conference, Shared Decision Making in the Emergency Department: Development of a Policy-relevant Patient-centered Research Agenda, a panel of representatives from the Office of Emergency Care Research, the Patient-Centered Outcomes Research Institute, the American Heart Association, the John A. Hartford Foundation, and the Emergency Care Coordination Center were assembled to discuss funding opportunities for future research in this field. This article summarizes their discussion of funding priorities and examples of successfully funded projects related to shared decision making in emergency medicine. (C) 2016 by the Society for Academic Emergency Medicine C1 [Dodd, Kenneth W.] Hennepin Cty Med Ctr, Dept Emergency Med, Minneapolis, MN 55415 USA. [Berman, Amy; Escobedo, Marcus] John A Hartford Fdn, New York, NY USA. [Brown, Jeremy] NIH, Off Emergency Care Res, Bldg 10, Bethesda, MD 20892 USA. [Carr, Brendan G.] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA. [Carr, Brendan G.] US Dept HHS, Emergency Care Coordinat Ctr, Washington, DC 20201 USA. [Dunn, Patrick] Amer Heart Assoc, Dallas, TX USA. [Gayer, Christopher; Grieser, Mira] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Carpenter, Christopher R.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO USA. [Hess, Erik P.] Mayo Clin, Rochester, MN USA. [Grudzen, Corita R.] NYU, Sch Med, Ronald O Perelman Dept Emergency Med, New York, NY USA. [Grudzen, Corita R.] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. RP Grudzen, CR (reprint author), NYU, Sch Med, Ronald O Perelman Dept Emergency Med, New York, NY USA.; Grudzen, CR (reprint author), NYU, Sch Med, Dept Populat Hlth, New York, NY USA. EM corita.grudzen@nyumc.org OI Grudzen, Corita/0000-0003-3039-8497 FU Agency for Healthcare Research and Quality [1R13HS024172-01]; NIMHD NIH HHS [1R13MD010171-01] NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2016 VL 23 IS 12 BP 1340 EP 1345 DI 10.1111/acem.13063 PG 6 WC Emergency Medicine SC Emergency Medicine GA EF8ES UT WOS:000390562300006 PM 27474887 ER PT J AU Eitan, E Suire, C Zhang, S Mattson, MP AF Eitan, Erez Suire, Caitlin Zhang, Shi Mattson, Mark P. TI Impact of lysosome status on extracellular vesicle content and release SO AGEING RESEARCH REVIEWS LA English DT Review DE Alzheimer's disease; HIV AIDS; Niemann pick disease; Parkinson's disease ID CHEDIAK-HIGASHI-SYNDROME; OUTER-MEMBRANE VESICLES; HEPATITIS-C VIRUS; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; MULTIVESICULAR BODIES; PARKINSONS-DISEASE; EXOSOME SECRETION; CARCINOMA CELLS; ESCRT FUNCTIONS AB Extracellular vesicles (EVs) are nanoscale size bubble-like membranous structures released from cells. EVs contain RNA, lipids and proteins and are thought to serve various roles including intercellular communication and removal of misfolded proteins. The secretion of misfolded and aggregated proteins in EVs may be a cargo disposal alternative to the autophagy-lysosomal and ubiquitin-proteasome pathways. In this review we will discuss the importance of lysosome functionality for the regulation of EV secretion and content. Exosomes are a subtype of EVs that are released by the fusion of multivesicular bodies (MVB) with the plasma membrane. MVBs can also fuse with lysosomes, and the trafficking pathway of MVBs can therefore determine whether or not exosomes are released from cells. Here we summarize data from studies of the effects of lysosome inhibition on the secretion of EVs and on the possibility that cells compensate for lysosome malfunction by disposal of potentially toxic cargos in EVs. A better understanding of the molecular mechanisms that regulate trafficking of MVBs to lysosomes and the plasma membrane may advance an understanding of diseases in which pathogenic proteins, lipids or infectious agents accumulate within or outside of cells. (C) 2016 Published by Elsevier B.V. C1 [Eitan, Erez; Suire, Caitlin; Zhang, Shi; Mattson, Mark P.] NIA, Lab Neurosci, Baltimore, MD 21224 USA. RP Eitan, E (reprint author), NIA, Lab Neurosci, Baltimore, MD 21224 USA. EM erez.eitan@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 122 TC 3 Z9 3 U1 8 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD DEC PY 2016 VL 32 SI SI BP 65 EP 74 DI 10.1016/j.arr.2016.05.001 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA EF9AP UT WOS:000390623400007 PM 27238186 ER PT J AU Fink, E Fuller, K Agan, B Berger, EA Saphire, A Quinnan, GV Elder, JH AF Fink, Elizabeth Fuller, Katherine Agan, Brian Berger, Edward A. Saphire, Andrew Quinnan, Gerald V. Elder, John H. TI Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article DE HIV; envelope; ADCC; HIV clinical outcomes research ID IMMUNODEFICIENCY-VIRUS-INFECTION; CELL-MEDIATED CYTOTOXICITY; PBL-SCID MICE; MONOCLONAL-ANTIBODIES; DISEASE PROGRESSION; ANTIIDIOTYPIC ANTIBODIES; ANTI-CD4 AUTOANTIBODIES; NEUTRALIZING ANTIBODY; PASSIVE-IMMUNIZATION; ENVELOPE AB The purpose of this study was to assess humoral antibody responses as a function of disease progression (DP) in a well-defined HIV+ cohort. We quantified antibodies to HIV-1 gp120, Gag, and CD4 receptor by enzyme-linked immunosorbent assay in sera from a cohort of 97 HIV+ subjects at defined stages of DP. We also measured antibody-dependent cellular cytotoxicity (ADCC) as a function of the clinical status of the patients. We purified antibodies to CD4 and gp120 and assessed them for specificity, ability to block gp120 binding to target cells, ability to block virus infection, and ability to facilitate ADCC. All of the HIV+ patient samples were positive for antibodies to HIV gp120 and p24 and 80% showed evidence of hypergammaglobulinemia. Approximately 10% of cohort members were positive for antibodies to CD4, but we noted no significant correlation relevant to DP. There were statistically significant differences between the groups concerning the level of humoral response to gp120 and Gag. However, we observed no distinction in ability of anti-gp120 antibodies purified from each group to neutralize infection. In addition, there was a statistically significant difference in ADCC, with elite controllers exhibiting significantly lower levels of ADCC than the other five groups. We detected IgA anti-gp120 antibodies, but did not correlate their presence with either DP or ADCC levels. The results are consistent with the interpretation that the humoral antibody response to the antigens assessed here represents a signature of the level of viremia but does not correlate with clinical status of HIV infection. C1 [Fink, Elizabeth; Fuller, Katherine; Saphire, Andrew; Elder, John H.] Scripps Res Inst, Dept Immunol & Microbial Sci, 10466 North Torrey Pines Rd IMM215, La Jolla, CA 92037 USA. [Agan, Brian] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Agan, Brian] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Quinnan, Gerald V.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biostat, Bethesda, MD 20814 USA. RP Elder, JH (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, 10466 North Torrey Pines Rd IMM215, La Jolla, CA 92037 USA. EM jelder@scripps.edu NR 48 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 32 IS 12 BP 1187 EP 1197 DI 10.1089/aid.2016.0182 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF8PZ UT WOS:000390592600007 PM 27771962 ER PT J AU Lovell, JP Zerbe, CS Olivier, KN Claypool, RJ Frein, C Anderson, VL Freeman, AF Holland, SM AF Lovell, Jana P. Zerbe, Christa S. Olivier, Kenneth N. Claypool, Reginald J. Frein, Cathleen Anderson, Victoria L. Freeman, Alexandra F. Holland, Steven M. TI Mediastinal and Disseminated Mycobacterium kansasii Disease in GATA2 Deficiency SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Rationale: Mycobacterium kansasii usually causes chronic pulmonary infections in immunocompetent patients. In contrast, disseminated M. kansasii disease is commonly associated with advanced human immunodeficiency virus infection, but is reported infrequently in other immunocompromised patients. Objectives: To identify common clinical manifestations and potential risk factors for M. kansasii infection in patients with GATA2 deficiency. Methods: We reviewed M. kansasii disease associated with GATA2 deficiency at one institution and disease associated with primary and other immunodeficiencies reported in the literature. Measurements and Main Results: Nine patients with GATA2 deficiency developed M. kansasii infections. Six patients developed disseminated disease. All patients presented with significant mediastinal lymphadenopathy or abscesses. Seven patients had pulmonary risk factors, including six smokers. The majority of patients had low numbers of neutrophils, monocytes, B cells, CD4(+) T cells, and natural killer cells. Other conditions associated with disseminated M. kansasii disease were thymic disorders and IFN-gamma/IL-12 defects. Conclusions: Disseminated M. kansasii disease involving mediastinal lymph nodes is surprisingly common in GATA2 deficiency, but also occurs in defects of IFN-gamma synthesis and response. Disseminated M. kansasii should be considered a marker indicating a need to evaluate for immunodeficiency syndromes. C1 [Lovell, Jana P.; Zerbe, Christa S.; Claypool, Reginald J.; Anderson, Victoria L.; Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Frein, Cathleen] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Holland, SM (reprint author), Bldg 10-11N248,MSC 1960, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E]; NIH Medical Research Scholars Program - NIH FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health (NIH). This project was also funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. J.P.L. was funded through the NIH Medical Research Scholars Program, a public-private partnership supported by the NIH, and by generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, American Association for Dental Research, Howard Hughes Medical Institute, and Colgate-Palmolive Co., as well as alumni of student research programs and other individual sources of support. For a complete list, please visit the Foundation website at http://www.fnih.org/education-training-0/medical-research-scholars-progr am. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. government. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 13 IS 12 BP 2169 EP 2173 DI 10.1513/AnnalsATS.201603-207BC PG 5 WC Respiratory System SC Respiratory System GA EF9OF UT WOS:000390658800013 PM 27607353 ER PT J AU Young, LR Trapnell, BC Mandl, KD Swarr, DT Wambach, JA Blaisdell, CJ AF Young, Lisa R. Trapnell, Bruce C. Mandl, Kenneth D. Swarr, Daniel T. Wambach, Jennifer A. Blaisdell, Carol J. TI Accelerating Scientific Advancement for Pediatric Rare Lung Disease Research Report from a National Institutes of Health-NHLBI Workshop, September 3 and 4, 2015 SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD. C1 [Young, Lisa R.] Vanderbilt Univ, Dept Pediat Med & Cell & Dev Biol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Trapnell, Bruce C.] Univ Cincinnati, Sch Med, Dept Med, Cincinnati, OH USA. [Trapnell, Bruce C.] Univ Cincinnati, Dept Pediat, Sch Med, Cincinnati, OH USA. [Mandl, Kenneth D.] Harvard Med Sch, Computat Hlth Informat Program, Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Mandl, Kenneth D.] Harvard Med Sch, Computat Hlth Informat Program, Boston Childrens Hosp, Dept Biomed Informat, Boston, MA USA. [Swarr, Daniel T.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Wambach, Jennifer A.] Washington Univ, Sch Med, Edward Mallinckrodt Dept Pediat, St Louis, MO 63110 USA. [Blaisdell, Carol J.] NHLBI, Div Lung Dis, Bldg 10, Bethesda, MD 20892 USA. RP Blaisdell, CJ (reprint author), NHLBI, Div Lung Dis, NIH, Two Rockledge Ctr, Suite 10042,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM carol.blaisdell@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 13 IS 12 BP S385 EP S393 DI 10.1513/AnnalsATS.201605-402OT PG 9 WC Respiratory System SC Respiratory System GA EF9OF UT WOS:000390658800001 ER PT J AU Masuda, J Kawamoto, H Strober, W Takayama, E Mizutani, A Murakami, H Ikawa, T Kitani, A Maeno, N Shigehiro, T Satoh, A Seno, A Arun, V Kasai, T Fuss, IJ Katsura, Y Seno, M AF Masuda, Junko Kawamoto, Hiroshi Strober, Warren Takayama, Eiji Mizutani, Akifumi Murakami, Hiroshi Ikawa, Tomokatsu Kitani, Atsushi Maeno, Narumi Shigehiro, Tsukasa Satoh, Ayano Seno, Akimasa Arun, Vaidyanath Kasai, Tomonari Fuss, Ivan J. Katsura, Yoshimoto Seno, Masaharu TI Transient Tcf3 Gene Repression by TALE-Transcription Factor Targeting SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE TCF3 (E2A); Artificial transcription factor; TALE technology ID PLURIPOTENT STEM-CELLS; ZINC-FINGER PROTEINS; UMBILICAL-CORD BLOOD; EX-VIVO EXPANSION; HEMATOPOIETIC STEM; LYMPHOCYTE DEVELOPMENT; PROGENITOR CELLS; LENTIVIRAL VECTORS; DNA; EXPRESSION AB Transplantation of hematopoietic stem and progenitor cells (HSCs) i.e., self-renewing cells that retain multipotentiality, is now a widely performed therapy for many hematopoietic diseases. However, these cells are present in low number and are subject to replicative senescence after extraction; thus, the acquisition of sufficient numbers of cells for transplantation requires donors able to provide repetitive blood samples and/or methods of expanding cell numbers without disturbing cell multipotentiality. Previous studies have shown that HSCs maintain their multipotentiality and self-renewal activity if TCF3 transcription function is blocked under B cell differentiating conditions. Taking advantage of this finding to devise a new approach to HSC expansion in vitro, we constructed an episomal expression vector that specifically targets and transiently represses the TCF3 gene. This consisted of a vector encoding a transcription activator-like effector (TALE) fused to a Kruppel-associated box (KRAB) repressor. We showed that this TALE-KRAB vector repressed expression of an exogenous reporter gene in HEK293 and COS-7 cell lines and, more importantly, efficiently repressed endogenous TCF3 in a human B lymphoma cell line. These findings suggest that this vector can be used to maintain multipotentiality in HSC being subjected to a long-term expansion regimen prior to transplantation. C1 [Masuda, Junko; Mizutani, Akifumi; Murakami, Hiroshi; Maeno, Narumi; Shigehiro, Tsukasa; Satoh, Ayano; Seno, Akimasa; Arun, Vaidyanath; Kasai, Tomonari; Seno, Masaharu] Okayama Univ, Grad Sch Nat Sci & Technol, Div Med Bioengn, Okayama 7008530, Japan. [Masuda, Junko; Strober, Warren; Kitani, Atsushi; Fuss, Ivan J.] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Kawamoto, Hiroshi; Ikawa, Tomokatsu; Katsura, Yoshimoto] RIKEN Res Ctr Allergy & Immunol, Lab Lymphocyte Dev, Yokohama, Kanagawa 2300045, Japan. [Kawamoto, Hiroshi] Kyoto Univ, Inst Frontier Med Sci, Dept Immunol, Kyoto 6068507, Japan. [Takayama, Eiji] Asahi Univ, Sch Dent, Dept Oral Biochem, Hozumi 1851, Gifu 5010296, Japan. [Ikawa, Tomokatsu] RIKEN Ctr Integrat Med Sci, Lab Immune Regenerat, Yokohama, Kanagawa 2300045, Japan. [Katsura, Yoshimoto] Nihon Univ, Sch Med, Adv Med Res Ctr, Div Cell Regenerat & Transplantat, Tokyo 1738610, Japan. RP Masuda, J (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Div Med Bioengn, Okayama 7008530, Japan.; Masuda, J (reprint author), NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. EM junkomasuda@okayama-u.ac.jp OI SATOH, Ayano/0000-0003-3736-1283 FU Japan Society for the Promotion of Science (JSPS) KAKENHI [25860797]; Okayama Foundation for Science and Technology FX This work was supported in part by Japan Society for the Promotion of Science (JSPS) KAKENHI, grant numbers 25860797, and Okayama Foundation for Science and Technology. NR 60 TC 0 Z9 0 U1 5 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 EI 1559-0291 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD DEC PY 2016 VL 180 IS 8 BP 1559 EP 1573 DI 10.1007/s12010-016-2187-4 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA EE8RA UT WOS:000389892200008 PM 27406037 ER PT J AU Plazyo, O Romero, R Unkel, R Balancio, A Mial, TN Xu, Y Dong, Z Hassan, SS Gomez-Lopez, N AF Plazyo, Olesya Romero, Roberto Unkel, Ronald Balancio, Amapola Mial, Tara N. Xu, Yi Dong, Zhong Hassan, Sonia S. Gomez-Lopez, Nardhy TI HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome SO BIOLOGY OF REPRODUCTION LA English DT Article DE AIM2; alarmins; caspase-1; DAMPs; interleukin-1 beta; interleukin-6; MMP-9; NLRP3; NOD2; parturition; pregnancy; preterm birth; preterm labor; RAGE; sterile inflammation; sterile intra-amniotic inflammation; TLR-2 ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; HUMAN MYOMETRIAL CELLS; NECROSIS-FACTOR-ALPHA; GROUP BOX-1 PROTEIN; TOLL-LIKE RECEPTOR; NOD-LIKE RECEPTORS; PRETERM PREMATURE RUPTURE; PLASMA CYTOKINE PROFILE; HUMAN FETAL MEMBRANES; INNATE IMMUNE-SYSTEM AB Spontaneous preterm labor occurs in two subsets of patients with sterile intra-amniotic inflammation, a process induced by alarmins such as high-mobility group box-1 (HMGB1). Inflammasomes are implicated in the process of spontaneous preterm labor. Therefore, we investigated whether HMGB1 initiates an inflammasome-associated inflammatory response in the chorioamniotic membranes. Incubation of the chorioamniotic membranes with HMGB1 1) induced the release of mature IL-1beta and IL-6; 2) upregulated the mRNA expression of the pro-inflammatory mediators NFKB1, IL6, TNF, IL1A, IFNG, and HMGB1 receptors RAGE and TLR2; 3) upregulated the mRNA expression of the inflammasome components NLRP3 and AIM2 as well as NOD proteins (NOD1 and NOD2); 4) increased the protein concentrations of NLRP3 and NOD2; 5) increased the concentration of caspase-1 and the quantity of its active form (p20); and 6) upregulated the mRNA expression and active form of MMP-9. In addition, HMGB1 concentrations in chorioamniotic membrane extracts from women who underwent spontaneous preterm labor were greater than in those from women who had undergone spontaneous labor at term. Collectively, these results show that HMGB1 can induce an inflammatory response in the chorioamniotic membranes, which is partially mediated by the inflammasome. These results provide insight into the mechanisms whereby HMGB1 induces preterm labor and birth in mice and explain why the concentration of this alarmin is increased in women who undergo spontaneous preterm labor. C1 [Plazyo, Olesya; Romero, Roberto; Unkel, Ronald; Balancio, Amapola; Mial, Tara N.; Xu, Yi; Dong, Zhong; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch,Program Perinatal Res & Obst, Div Intramural Res,Eunice Kennedy Shriver Natl In, NIH,DHHS, Bethesda, MD USA. [Plazyo, Olesya; Romero, Roberto; Unkel, Ronald; Balancio, Amapola; Mial, Tara N.; Xu, Yi; Dong, Zhong; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch,Program Perinatal Res & Obst, Div Intramural Res,Eunice Kennedy Shriver Natl In, NIH,DHHS, Detroit, MI USA. [Plazyo, Olesya; Unkel, Ronald; Balancio, Amapola; Mial, Tara N.; Xu, Yi; Dong, Zhong; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Sch Med,Perinatol Res Branch, NICHD,NIH,DHHS, Detroit, MI 48201 USA. EM ngomezlo@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); NICHD/NIH/DHHS [HHSN275201300006C]; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), and, in part, with federal funds from the NICHD/NIH/DHHS under Contract No. HHSN275201300006C. This research was also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. Presented, in part, at the 63rd Annual Scientific Meeting of the Society for Reproductive Investigation, March 16-19, 2016, Montreal, QC, Canada. NR 152 TC 1 Z9 1 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD DEC 1 PY 2016 VL 95 IS 6 AR 130 DI 10.1095/biolreprod.116.144139 PG 14 WC Reproductive Biology SC Reproductive Biology GA EG1PJ UT WOS:000390804400017 PM 27806943 ER PT J AU Ramnarayanan, S Kyathanahalli, C Ingles, J Park-York, M Jeyasuria, P Condon, JC AF Ramnarayanan, Saiprasad Kyathanahalli, Chandrashekara Ingles, Judith Park-York, MieJung Jeyasuria, Pancharatnam Condon, Jennifer C. TI The Unfolded Protein Response Regulates Uterine Myocyte Antioxidant Responsiveness During Pregnancy SO BIOLOGY OF REPRODUCTION LA English DT Article DE oxidative stress; pregnancy; unfolded protein response; uterus ID ENDOPLASMIC-RETICULUM STRESS; OXIDATIVE STRESS; VITAMINS C; CELL-DEATH; ER STRESS; SUPEROXIDE-DISMUTASE; ALZHEIMERS-DISEASE; PREECLAMPSIA; APOPTOSIS; NRF2 AB There is considerable evidence that implicates oxidative stress in the pathophysiology of human pregnancy complications. However, the role and the mechanism of maintaining an antioxidant prosurvival uterine environment during normal pregnancy is largely unresolved. Herein we report that the highly active uterine unfolded protein response plays a key role in promoting antioxidant activity in the uterine myocyte across gestation. The unfolded protein response (UPR) senses the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and activates a signaling network that consists of the transmembrane protein kinase eukaryotic translation initiation factor 2 alpha kinase 3/PKR-like-ER kinase (EIF2AK3), which acts to decrease protein translation levels, allowing for a lowered need for protein folding during periods of ER stress. However, independent of its translational regulatory capacity, EIF2AK3dependent signals elicit the activation of the transcription factor, nuclear factor erythroid 2-like 2 (NFE2L2) in response to oxidative stress. NFE2L2 binds to antioxidant response elements in the promoters of a variety of antioxidant genes that minimize the opportunities for generation of reactive oxygen intermediates. Our analysis demonstrates that in the absence of EIF2AK3, the uterine myocyte experiences increased levels of reactive oxygen species due to decreased NFE2L2 activation. Elevated levels of intracellular reactive oxygen species were observed in the EIF2AK3 null cells, and this was associated with the onset of apoptotic cell death. These findings confirm the prosurvival and antioxidant role of UPR-mediated EIF2AK3 activation in the context of the human uterine myocyte. C1 [Ramnarayanan, Saiprasad; Kyathanahalli, Chandrashekara; Park-York, MieJung; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, 275 East Hancock St, Detroit, MI 48201 USA. [Ingles, Judith; Jeyasuria, Pancharatnam; Condon, Jennifer C.] Wayne State Univ, Sch Med, Dept Physiol, 275 East Hancock St, Detroit, MI 48201 USA. [Jeyasuria, Pancharatnam; Condon, Jennifer C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Bethesda, MD USA. RP Condon, JC (reprint author), Wayne State Univ, CS Mott Ctr, 275 East Hancock St, Detroit, MI 48201 USA. EM jcondon@med.wayne.edu FU March of Dimes [21 FY2012-152]; NICHD [1R01HD065011] FX This work was supported by the March of Dimes #21 FY2012-152 and the NICHD 1R01HD065011. NR 46 TC 0 Z9 0 U1 1 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD DEC 1 PY 2016 VL 95 IS 6 AR 120 DI 10.1095/biolreprod.116.141804 PG 9 WC Reproductive Biology SC Reproductive Biology GA EG1PJ UT WOS:000390804400007 PM 27733380 ER PT J AU Chen, SC Kim, SYH AF Chen, Stephanie C. Kim, Scott Y. H. TI A framework for analysis of research risks and benefits to participants in standard of care pragmatic clinical trials SO CLINICAL TRIALS LA English DT Article DE Comparative effectiveness randomized control trials; pragmatic randomized control trials; informed consent; research risk analysis; research ethics ID RECURRENT ERYSIPELAS; SESSION LENGTH; BREAST-CANCER; MORTALITY; HEMODIALYSIS; ETHICS; ASSOCIATIONS; PROPHYLAXIS; PENICILLIN; CONSENT AB Background/Aims: Standard of care pragmatic clinical trials that compare treatments already in use could improve care and reduce costs, but there is considerable debate about the research risks of standard of care pragmatic clinical trials and how to apply informed consent regulations to such trials. We sought to develop a framework integrating the insights from opposing sides of the debate. Methods: We developed a formal risk benefit analysis framework for standard of care pragmatic clinical trials and then applied it to key provisions of the US federal regulations. Results: Our formal framework for standard of care pragmatic clinical trial risk benefit analysis takes into account three key considerations: the ex ante estimates of risks and benefits of the treatments to be compared in a standard of care pragmatic clinical trial, the allocation ratios of treatments inside and outside such a trial, and the significance of some participants receiving a different treatment inside a trial than outside the trial. The framework provides practical guidance on how the research ethics regulations on informed consent should be applied to standard of care pragmatic clinical trials. Conclusion: Our proposed formal model makes explicit the relationship between the concepts used by opposing sides of the debate about the research risks of standard of care pragmatic clinical trials and can be used to clarify the implications for informed consent. C1 [Chen, Stephanie C.; Kim, Scott Y. H.] NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,IC118, Bethesda, MD 20892 USA. [Kim, Scott Y. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,IC118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov FU Intramural Research Program at 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 at the National Institutes of Health. NR 31 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2016 VL 13 IS 6 BP 605 EP 611 DI 10.1177/1740774516656945 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG0KZ UT WOS:000390723000007 PM 27365010 ER PT J AU Fay, MP Follmann, DA AF Fay, Michael P. Follmann, Dean A. TI Non-inferiority tests for anti-infective drugs using control group quantiles SO CLINICAL TRIALS LA English DT Article DE Difference in proportions; exact test; non-inferiority margin; variable margin ID PROPORTIONS; PNEUMONIA AB Background/Aims: In testing for non-inferiority of anti-infective drugs, the primary endpoint is often the difference in the proportion of failures between the test and control group at a landmark time. The landmark time is chosen to approximately correspond to the qth historic quantile of the control group, and the non-inferiority margin is selected to be reasonable for the target level q. For designing these studies, a troubling issue is that the landmark time must be pre-specified, but there is no guarantee that the proportion of control failures at the landmark time will be close to the target level q. If the landmark time is far from the target control quantile, then the pre-specified non-inferiority margin may not longer be reasonable. Exact variable margin tests have been developed by Rohmel and Kieser to address this problem, but these tests can have poor power if the observed control failure rate at the landmark time is far from its historic value. Methods: We develop a new variable margin non-inferiority test where we continue sampling until a pre-specified proportion of failures, q, have occurred in the control group, where q is the target quantile level. The test does not require any assumptions on the failure time distributions, and hence, no knowledge of the true qth control quantile for the study is needed. Results: Our new test is exact and has power comparable to (or greater than) its competitors when the true control quantile from the study equals (or differs moderately from) its historic value. Our nivm R package performs the test and gives confidence intervals on the difference in failure rates at the true target control quantile. The tests can be applied to time to cure or other numeric variables as well. Conclusion: A substantial proportion of new anti-infective drugs being developed use non-inferiority tests in their development, and typically, a pre-specified landmark time and its associated difference margin are set at the design stage to match a specific target control quantile. If through changing standard of care or selection of a different population the target quantile for the control group changes from its historic value, then the appropriateness of the pre-specified margin at the landmark time may be questionable. Our proposed test avoids this problem by sampling until a pre-specified proportion of the controls have failed. C1 [Fay, Michael P.; Follmann, Dean A.] NIAID, Biostat Res Branch, 5601 Fishers Lane,MSC 9820, Rockville, MD 20892 USA. RP Fay, MP (reprint author), NIAID, Biostat Res Branch, 5601 Fishers Lane,MSC 9820, Rockville, MD 20892 USA. EM mfay@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 11 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 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2016 VL 13 IS 6 BP 632 EP 640 DI 10.1177/1740774516654861 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG0KZ UT WOS:000390723000010 PM 27430709 ER PT J AU Korn, EL Freidlin, B AF Korn, Edward L. Freidlin, Boris TI Non-factorial analyses of two-by-two factorial trial designs SO CLINICAL TRIALS LA English DT Article DE Factorial design; factorial analysis; Hochberg procedure; interaction; multiple comparisons; 2 x 2 trial design ID ASSESS CHELATION-THERAPY; HIGH-DOSE MULTIVITAMINS; CLINICAL-TRIALS; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; COMBINATION; TESTS; MINERALS; TACT AB Background/aims Factorial analyses of 2 x 2 trial designs are known to be problematic unless one can be sure that there is no interaction between the treatments (A and B). Instead, we consider non-factorial analyses of a factorial trial design that addresses clinically relevant questions of interest without any assumptions on the interaction. Primary questions of interest are as follows: (1) is A better than the control treatment C, (2) is B better than C, (3) is the combination of A and B (AB) better than C, and (4) is AB better than A, B, and C. Methods A simple three-step procedure that tests the first three primary questions of interest using a Bonferroni adjustment at the first step is proposed. A Hochberg procedure on the four primary questions is also considered. The two procedures are evaluated and compared in limited simulations. Published results from three completed trials with factorial designs are re-evaluated using the two procedures. Results Both suggested procedures (that answer multiple questions) require a 50%-60% increase in per arm sample size over a two-arm design asking a single question. The simulations suggest a slight advantage to the three-step procedure in terms of power (for the primary and secondary questions). The proposed procedures would have formally addressed the questions arising in the highlighted published trials arguably more simply than the pre-specified factorial analyses used. Conclusion Factorial trial designs are an efficient way to evaluate two treatments, alone and in combination. In situations where a statistical interaction between the treatment effects cannot be assumed to be 0, simple non-factorial analyses are possible that directly assess the questions of interest without the zero interaction assumption. C1 [Korn, Edward L.; Freidlin, Boris] NCI, Biometr Res Program, MSC 9735, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Program, MSC 9735, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 27 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2016 VL 13 IS 6 BP 651 EP 659 DI 10.1177/1740774516659472 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG0KZ UT WOS:000390723000012 PM 27439306 ER PT J AU Sheehan, J Hirschfeld, S Foster, E Ghitza, U Goetz, K Karpinski, J Lang, L Moser, RP Odenkirchen, J Reeves, D Rubinstein, Y Werner, E Huerta, M AF Sheehan, Jerry Hirschfeld, Steven Foster, Erin Ghitza, Udi Goetz, Kerry Karpinski, Joanna Lang, Lisa Moser, Richard P. Odenkirchen, Joanne Reeves, Dianne Rubinstein, Yaffa Werner, Ellen Huerta, Michael TI Improving the value of clinical research through the use of Common Data Elements SO CLINICAL TRIALS LA English DT Article DE Common Data Elements; data collection; data sharing; interoperability; data standards ID TRIALS AB The use of Common Data Elements can facilitate cross-study comparisons, data aggregation, and meta-analyses; simplify training and operations; improve overall efficiency; promote interoperability between different systems; and improve the quality of data collection. A Common Data Element is a combination of a precisely defined question (variable) paired with a specified set of responses to the question that is common to multiple datasets or used across different studies. Common Data Elements, especially when they conform to accepted standards, are identified by research communities from variable sets currently in use or are newly developed to address a designated data need. There are no formal international specifications governing the construction or use of Common Data Elements. Consequently, Common Data Elements tend to be made available by research communities on an empiric basis. Some limitations of Common Data Elements are that there may still be differences across studies in the interpretation and implementation of the Common Data Elements, variable validity in different populations, and inhibition by some existing research practices and the use of legacy data systems. Current National Institutes of Health efforts to support Common Data Element use are linked to the strengthening of National Institutes of Health Data Sharing policies and the investments in data repositories. Initiatives include cross-domain and domain-specific resources, construction of a Common Data Element Portal, and establishment of trans-National Institutes of Health working groups to address technical and implementation topics. The National Institutes of Health is seeking to lower the barriers to Common Data Element use through greater awareness and encourage the culture change necessary for their uptake and use. As National Institutes of Health, other agencies, professional societies, patient registries, and advocacy groups continue efforts to develop and promote the responsible use of Common Data Elements, particularly if linked to accepted data standards and terminologies, continued engagement with and feedback from the research community will remain important. C1 [Sheehan, Jerry; Foster, Erin; Karpinski, Joanna; Lang, Lisa; Huerta, Michael] NIH, Natl Lib Med, 38 Ctr Dr,Rm 2S20,MSC 3811, Bethesda, MD 20894 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Ghitza, Udi] NIDA, NIH, Bethesda, MD 20892 USA. [Goetz, Kerry] NEI, NIH, Bethesda, MD 20892 USA. [Moser, Richard P.; Reeves, Dianne] NCI, NIH, Bethesda, MD 20892 USA. [Odenkirchen, Joanne] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Rubinstein, Yaffa] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Werner, Ellen] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Huerta, M (reprint author), NIH, Natl Lib Med, 38 Ctr Dr,Rm 2S20,MSC 3811, Bethesda, MD 20894 USA. EM mike.huerta@nih.hhs.gov FU Intramural NIH HHS [Z99 HD999999] NR 11 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 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2016 VL 13 IS 6 BP 671 EP 676 DI 10.1177/1740774516653238 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG0KZ UT WOS:000390723000015 PM 27311638 ER PT J AU Szczesna, E Kasprzak, AA AF Szczesna, Ewa Kasprzak, Andrzej A. TI Insights into the process of EB1-dependent tip-tracking of kinesin-14 Ncd. The role of the microtubule SO EUROPEAN JOURNAL OF CELL BIOLOGY LA English DT Article DE EB1; Kinesin-14; Ncd; Tip-tracking; Microtubule plus end; +TIPs ID PLUS-END-TRACKING; IN-VITRO; LOCALIZATION SIGNAL; EB1; PROTEIN; RECONSTITUTION; MICROSCOPY; DYNAMICS; CLIP-170; CAP AB End-binding proteins are capable of tracking the plus-ends of growing microtubules (MTs). The motor protein Ncd, a member of the kinesin-14 family, interacts with EB1 protein and becomes a non-autonomous tip-tracker. Here, we attempted to find out whether at least for Ncd, the efficient EB1-ediated tip-tracking involves the interaction of the kinesin with the MT surface. We prepared a series of Ncd tail mutants in which the MT-binding sites were altered or eliminated. Using TIRF microscopy, we characterized their behavior as tip-trackers and measured the dwell times of single molecules of EB1 and Ncd tail or its mutated forms. The mutated forms of Ncd tail exhibited tip-tracking in the presence of EB1 and the effectiveness of this process was proportional to the affinity of the mutant's tail to MT. Even though the interaction of Ncd with EB1 was weak (K-d similar to 9 mu M) the half saturating concentration of EB1 for tip-tracking was 7 nM. The dwell time of Ncd tail in the presence of EB1 was similar to 1 s. The dwell time of EB1 alone was shorter (similar to 0.3 s) and increased considerably in the presence of a large excess of Ncd tail. We demonstrated that tip-tracking of kinesin-14 occurs through several concurrent mechanisms: binding of kinesin only to EB1 located at the MT end, interaction of the kinesin molecules with a composite site formed by EB1 and the MT tip, and probably surface diffusion of the tail along MT. The second mechanism seems to play a crucial role in efficient tip-tracking. (C) 2016 Elsevier GmbH. All rights reserved. C1 [Szczesna, Ewa; Kasprzak, Andrzej A.] Polish Acad Sci, Nencki Inst Expt Biol, Dept Biochem, 3 Pasteur St, PL-02093 Warsaw, Poland. [Szczesna, Ewa] NINDS, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Kasprzak, AA (reprint author), Polish Acad Sci, Nencki Inst Expt Biol, Dept Biochem, 3 Pasteur St, PL-02093 Warsaw, Poland. EM e.szczesna@nencki.gov.pl; a.kasprzak@nencki.gov.pl RI Kasprzak, Andrzej/R-4476-2016 FU National Science Centre [DEC-2012/05/N/NZ1/00020] FX We thank Krzysztof Skowronek and Seweryn Bajer for reagents and helpful discussions and Michal Szkop and Beata Kliszcz for critically reading the manuscript. The study was supported in part by National Science Centre grant DEC-2012/05/N/NZ1/00020. NR 40 TC 0 Z9 0 U1 6 U2 6 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 DEC PY 2016 VL 95 IS 12 BP 521 EP 530 DI 10.1016/j.ejcb.2016.08.004 PG 10 WC Cell Biology SC Cell Biology GA EF9CU UT WOS:000390629100001 PM 27608966 ER PT J AU Price, AJ Travis, RC Appleby, PN Albanes, D Gurrea, AB Bjorge, T Bueno-de-Mesquita, HB Chen, C Donovan, J Gislefoss, R Goodman, G Gunter, M Hamdy, FC Johansson, M King, IB Kuhn, T Mannisto, S Martin, RM Meyer, K Neal, DE Neuhouser, ML Nygard, O Stattin, P Tell, GS Trichopoulou, A Tumino, R Ueland, PM Ulvik, A de Vogel, S Vollset, SE Weinstein, SJ Key, TJ Allen, NE AF Price, Alison J. Travis, Ruth C. Appleby, Paul N. Albanes, Demetrius Gurrea, Aurelio Barricarte Bjorge, Tone Bueno-de-Mesquita, H. Bas Chen, Chu Donovan, Jenny Gislefoss, Randi Goodman, Gary Gunter, Marc Hamdy, Freddie C. Johansson, Mattias King, Irena B. Kuehn, Tilman Mannisto, Satu Martin, Richard M. Meyer, Klaus Neal, David E. Neuhouser, Marian L. Nygard, Ottar Stattin, Par Tell, Grethe S. Trichopoulou, Antonia Tumino, Rosario Ueland, Per Magne Ulvik, Arve de Vogel, Stefan Vollset, Stein Emil Weinstein, Stephanie J. Key, Timothy J. Allen, Naomi E. TI Circulating Folate and Vitamin B-12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls SO EUROPEAN UROLOGY LA English DT Article DE Folate; Vitamin B-12; Prostate cancer; High grade; Prospective cohort; Pooled data meta-analysis ID ONE-CARBON METABOLISM; FOLIC-ACID; SERUM FOLATE; CLOT CONTACT; HOMOCYSTEINE; BIOMARKERS; ASSOCIATION; POPULATION; STABILITY; NUTRITION AB Background: Folate and vitamin B-12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. Objective: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. Design, setting, and participants: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. Outcome measurements and statistical analysis: Incident PCa and subtype by stage and grade. Results and limitations: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], p(trend) = 0.018, for folate and 1.12 [95% CI, 1.01-1.25], p(trend) = 0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (p(heterogeneity) < 0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend = 0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (p(heterogeneity) > 0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. Conclusions: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. Patient summary: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease. (C) 2016 European Association of Urology. Published by Elsevier B.V. C1 [Price, Alison J.; Travis, Ruth C.; Appleby, Paul N.; Key, Timothy J.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. [Price, Alison J.] London Sch Hyg & Trop Med, London, England. [Albanes, Demetrius; Weinstein, Stephanie J.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gurrea, Aurelio Barricarte] Navarra Publ Hlth Inst, Pamplona, Spain. [Gurrea, Aurelio Barricarte] Navarra Inst Hlth Res IdiSNA, Pamplona, Spain. [Gurrea, Aurelio Barricarte] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain. [Bjorge, Tone; Tell, Grethe S.; de Vogel, Stefan; Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Bjorge, Tone; Gislefoss, Randi] Canc Registry Norway, Oslo, Norway. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. Bas; Gunter, Marc] Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Bueno-de-Mesquita, H. Bas] Univ Malaya, Dept Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [Chen, Chu; Goodman, Gary; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Donovan, Jenny; Martin, Richard M.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg, Oxford, England. [Johansson, Mattias] Int Agcy Res Canc, Lyon, France. [Johansson, Mattias] Umea Univ, Dept Biobank Res, Umea, Sweden. [King, Irena B.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Kuehn, Tilman] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Martin, Richard M.] Univ Bristol, MRC, Integrat Epidemiol Unit, Bristol, Avon, England. [Martin, Richard M.] Natl Inst Hlth Res, Bristol Biomed Res Unit Nutr, Bristol, Avon, England. [Meyer, Klaus; Ulvik, Arve] Bevital AS, Bergen, Norway. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge, England. [Nygard, Ottar; Ueland, Per Magne] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Nygard, Ottar] Haukeland Hosp, Dept Heart Dis, Bergen, Norway. [Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Trichopoulou, Antonia] Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Trichopoulou, Antonia] Hellen Hlth Fdn, Athens, Greece. [Tumino, Rosario] ASP Ragusa, Canc Registry & Histopathol Unit, Civ MP Arezzo Hosp, Ragusa, Italy. [Vollset, Stein Emil] Norwegian Inst Publ Hlth, Bergen, Norway. [Gislefoss, Randi] Inst Populat Based Res, Oslo, Norway. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Clin Trial Serv Unit, Oxford, England. [Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Epidemiol Studies Unit, Oxford, England. RP Price, AJ (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford OX3 7LF, England. EM alison.price@ceu.ox.ac.uk OI Price, Alison/0000-0002-3891-3337 FU Cancer Research UK [C570/ A16491, C8221/A19170, 14136]; Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health; U.S. Public Health Service from the National Cancer Institute [HHSN261201500005C]; Department of Health and Human Services; CARET: NIH [UM1CA167462, U01CA63673, R01CA96789]; European Commission (DG-SANCO); International Agency for Research on Cancer; Danish Cancer Society (Denmark); German Cancer Aid; German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (BMBF); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy; National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports; Netherlands Cancer Registry; LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Health Research Fund (FIS) [PI13/01162, PI13/00061]; Regional Governments of Andalucia, Asturias; Basque Country; Murcia and Navarra; ISCIII RETIC (Spain) [RD06/0020]; Swedish Cancer Society; Swedish Research Council; County Council of Skane (Sweden); County Council of Vasterbotten (Sweden); Medical Research Council [1000143, MR/M012190/1]; Norwegian Cancer Society [107335-PR-2007-0153]; Swedish Cancer Society [4620]; Lions Research Foundation, Umea, Sweden; Medical Faculty, Umea University; World Cancer Research Fund UK [2007/07]; National Cancer Research Institute; UK NIHR Health Technology Assessment Programme [96/20/06, 96/20/99]; NIHR through the Biomedical Research Centre; CRUK programme grant (the Integrative Cancer Epidemiology Programme) [C18281/A19169]; National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust; University of Bristol FX This work was supported by Cancer Research UK (grant numbers C570/ A16491 and C8221/A19170). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The authors in the writing team had full access to the all data in the study. The corresponding author had the final responsibility for the decision to submit for publication. Funding for the collaborating studies was as follows: ATBC: The ATBC Study is supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health, and by U.S. Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. CARET: NIH grants UM1CA167462, U01CA63673, and R01CA96789. EPIC: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada;, PI13/01162 to EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/ A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Janus: Norwegian Cancer Society (Grant Number 107335-PR-2007-0153). NSHDC: The Swedish Cancer Society (Grant Number 4620), the Lions Research Foundation, Umea, Sweden and Medical Faculty, Umea University. ProtecT: funded through the World Cancer Research Fund UK (grant number: 2007/07). The National Cancer Research Institute (administered by the Medical Research Council) provided support for the development of the ProtecT epidemiologic database through the Prostate Mechanisms of Progression and Treatment collaborative. The ProtecT study is supported by the UK NIHR Health Technology Assessment Programme (projects 96/20/06, 96/20/99). Support for the ProtecT bio-repository in Cambridge is provided by NIHR through the Biomedical Research Centre. Richard Martin is supported by a CRUK programme grant, number C18281/A19169 (the Integrative Cancer Epidemiology Programme) and by the National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. NR 36 TC 2 Z9 2 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD DEC PY 2016 VL 70 IS 6 BP 941 EP 951 DI 10.1016/j.eururo.2016.03.029 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA EF8FA UT WOS:000390563100020 PM 27061263 ER PT J AU Velho, RV De Pace, R Tidow, H Braulke, T Pohl, S AF Velho, Renata Voltolini De Pace, Raffaella Tidow, Henning Braulke, Thomas Pohl, Sandra TI Identification of the interaction domains between alpha- and gamma-subunits of GlcNAc-1-phosphotransferase SO FEBS LETTERS LA English DT Article DE hexameric GlcNAc-1-phosphotransferase complex; lysosomal enzymes; mannose 6-phosphate; MRH domain; mucolipidosis II and III; pull-down interaction approach ID GLCNACLYSOSOMAL ENZYME N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE; LYSOSOMAL-ENZYMES; PROTEIN; MUTATIONS; RECOGNITION; REGIONS AB The disease-associated hexameric N-acetylglucosamine (GlcNAc)-1-phosphotransferase complex ((222)) catalyzes the formation of mannose 6-phosphate residues on lysosomal enzymes required for efficient targeting to lysosomes. Using pull-down experiments and mutant subunits, we identified a potential loop-like region in the -subunits comprising residues 535-588 and 645-698 involved in the binding to -subunits. The interaction is independent of the mannose 6-phosphate receptor homology domain but requires the N-terminal unstructured part of the -subunit consisting of residues 26-69. These studies provide new insights into structural requirements for the assembly of the GlcNAc-1-phosphotransferase complex, and the functions of distinct domains of the - and -subunits. C1 [Velho, Renata Voltolini; De Pace, Raffaella; Braulke, Thomas; Pohl, Sandra] Univ Med Ctr Hamburg Eppendorf, Childrens Hosp, Biochem Sect, Martinistr 52, D-20246 Hamburg, Germany. [Tidow, Henning] Univ Hamburg, Inst Biochem & Mol Biol, Hamburg, Germany. [De Pace, Raffaella] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD USA. RP Pohl, S (reprint author), Univ Med Ctr Hamburg Eppendorf, Childrens Hosp, Biochem Sect, Martinistr 52, D-20246 Hamburg, Germany. EM s.pohl@uke.de FU Deutsche Forschungsgemeinschaft [GRK1459, SFB877-B3] FX This study was supported by Deutsche Forschungsgemeinschaft (GRK1459 and SFB877-B3). NR 26 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 DEC PY 2016 VL 590 IS 23 BP 4287 EP 4295 DI 10.1002/1873-3468.12456 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EF5ST UT WOS:000390390600014 PM 27736005 ER PT J AU Sarrel, PM Sullivan, SD Nelson, LM AF Sarrel, Philip M. Sullivan, Shannon D. Nelson, Lawrence M. TI Hormone replacement therapy in young women with surgical primary ovarian insufficiency SO FERTILITY AND STERILITY LA English DT Review DE Premenopausal oophorectomy; ovarian insufficiency; surgical menopause; estrogen therapy ID BILATERAL SALPINGO-OOPHORECTOMY; RECENTLY POSTMENOPAUSAL WOMEN; TERM HEALTH CONSEQUENCES; LONG-TERM; EARLY MENOPAUSE; CARDIOVASCULAR-DISEASE; VASOMOTOR SYMPTOMS; BREAST-CANCER; HOT FLASHES; PROPHYLACTIC OOPHORECTOMY AB Bilateral oophorectomy performed in women before they are menopausal induces surgical primary ovarian insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E-2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical primary ovarian insufficiency is clearly indicated. (C) 2016 by American Society for Reproductive Medicine. C1 [Sarrel, Philip M.] Yale Univ, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Sarrel, Philip M.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Sullivan, Shannon D.] US FDA, Silver Spring, MD USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, CAPT US Publ Hlth Serv, Intramural Res Program, NIH, Bethesda, MD USA. RP Nelson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, CAPT US Publ Hlth Serv, Intramural Res Program, NIH,CRC, Room 1-3330,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM Lawrence_Nelson@nih.gov FU Intramural Research Program, National Institutes of Health, Bethesda, MD FX Supported in part by the Intramural Research Program, National Institutes of Health, Bethesda, MD. NR 76 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2016 VL 106 IS 7 BP 1580 EP 1587 DI 10.1016/j.fertnstert.2016.09.018 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400007 PM 27793381 ER PT J AU Sullivan, SD Sarrel, PM Nelson, LM AF Sullivan, Shannon D. Sarrel, Philip M. Nelson, Lawrence M. TI Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause SO FERTILITY AND STERILITY LA English DT Review DE Primary ovarian insufficiency; premature ovarian failure; premature menopause; early menopause; estrogen; progestin; androgen; hormone replacement therapy; menopausal hormone therapy; management; morbidity; mortality ID BONE-MINERAL DENSITY; CLINICAL-PRACTICE GUIDELINE; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; MEIBOMIAN GLAND SECRETIONS; SEX STEROID REPLACEMENT; ISCHEMIC-HEART-DISEASE; POSTMENOPAUSAL WOMEN; ESTROGEN-REPLACEMENT; TURNER-SYNDROME AB Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, similar to 50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. (C) 2016 by American Society for Reproductive Medicine. C1 [Sullivan, Shannon D.] US FDA, Silver Spring, MD USA. [Sarrel, Philip M.] Yale Univ, Obstet Gynecol & Reprod Sci & Psychiat, New Haven, CT USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA. RP Nelson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Publ Hlth Serv, Intramural Res Program, NIH,CRC, Room 1-3330,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM lawrence_nelson@nih.gov FU Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported in part by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (L.M.N.). NR 116 TC 1 Z9 1 U1 14 U2 14 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 DEC PY 2016 VL 106 IS 7 BP 1588 EP 1599 DI 10.1016/j.fertnstert.2016.09.046 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400008 PM 27912889 ER PT J AU Chin, HB Howards, PP Kramer, MR Mertens, AC Spencer, JB AF Chin, Helen B. Howards, Penelope P. Kramer, Michael R. Mertens, Ann C. Spencer, Jessica B. TI Which female cancer patients fail to receive fertility counseling before treatment in the state of Georgia? SO FERTILITY AND STERILITY LA English DT Article DE Cancer survivors; fertility counseling; female fertility ID BREAST-CANCER; YOUNG-WOMEN; AMERICAN-SOCIETY; PRESERVATION; CHEMOTHERAPY; PREGNANCY; SURVIVORS; DISPARITIES; PARENTHOOD; ADOLESCENT AB Objective: To assess which characteristics are associated with failure to receive fertility counseling among a cohort of young women diagnosed with cancer. Design: Population-based cohort study. Setting: Not applicable. Patient(s): A total of 1,282 cancer survivors, of whom 1,116 met the inclusion criteria for the analysis. Intervention(s): None. Main Outcome Measure(s): The main outcome in this study was whether or not women reported receiving any information at the time of their cancer diagnosis on how cancer treatment might affect their ability to become pregnant. Result(s): Forty percent of cancer survivors reported that they did not receive fertility counseling at the time of cancer diagnosis. Women were more likely to fail to receive counseling if they had only a high school education or less or if they had given birth. Cancer-related variables that were associated with a lack of counseling included not receiving chemotherapy as part of treatment and diagnosis with certain cancer types. Conclusion(s): Counseling about the risk of infertility and available fertility preservation options is important to cancer patients. Additionally, counseling can make women aware of other adverse reproductive outcomes, such as early menopause and its associated symptoms. Less-educated women and parous women are at particular risk of not getting fertility-related information. Programs that focus on training not just the oncologist, but also other health care providers involved with cancer care, to provide fertility counseling may help to expand access. (C) 2016 by American Society for Reproductive Medicine. C1 [Chin, Helen B.; Howards, Penelope P.; Kramer, Michael R.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pediat, Aflac Canc Ctr, Atlanta, GA USA. Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA. RP Chin, HB (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,Mailstop A3-05, Res Triangle Pk, NC 27709 USA. EM helen.chin@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development grant [1R01HD066059]; Reproductive, Perinatal, and Pediatric Training Grant [T32HD052460]; Health Resources, and Service Administration Training Grant [T03MC07651-06]; Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX Supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant 1R01HD066059, Reproductive, Perinatal, and Pediatric Training Grant T32HD052460, Health Resources, and Service Administration Training Grant T03MC07651-06, and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 41 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2016 VL 106 IS 7 BP 1763 EP + DI 10.1016/j.fertnstert.2016.08.034 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400033 PM 27678034 ER PT J AU Duan, LQ Davis, JS Woolbright, BL Du, K Cahkraborty, M Weemhoff, J Jaeschke, H Bourdi, M AF Duan, Luqi Davis, John S. Woolbright, Benjamin L. Du, Kuo Cahkraborty, Mala Weemhoff, James Jaeschke, Hartmut Bourdi, Mohammed TI Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Acetaminophen hepatotoxicity; C57BL/6 sub-strains; Mitochondrial dysfunction; Protein adducts; DNA fragmentation ID INDUCED HEPATIC-NECROSIS; CULTURED MOUSE HEPATOCYTES; PARA-BENZOQUINONE IMINE; INDUCED OXIDANT STRESS; INDUCED HEPATOTOXICITY; TERMINAL KINASE; CELL-DEATH; PROTEIN ADDUCTS; MITOCHONDRIAL DYSFUNCTION; PERMEABILITY TRANSITION AB Mouse models of acetaminophen (APAP) hepatotoxicity are considered relevant for the human pathophysiology. The C57BL/6 strain is most popular because it is the background strain of gene knock-out mice. However, conflicting results in the literature may have ben caused by sub-strain mismatches, e.g. C57BL/6J and C57BL/6N. This study was initiated to determine the mechanism behind the sub-strain susceptibility to APAP toxicity. C57BL/6N and C57BL/6J mice were dosed with 200 mg/kg APAP and sacrificed at different time points. C57BL/6N mice developed significantly more liver injury as measured by plasma ALT activities and histology. Although there was no difference in glutathione depletion or cytochrome P450 activity between groups, C57BL/6N had a higher glutathione disulfide-to-glutathione ratio and more APAP protein adducts. C57BL/6N showed more mitochondrial translocation of phospho-JNK and BAX, and more release of mitochondrial intermembrane proteins apoptosis-inducing factor (AIF), second mitochondria-derived activator of caspases (SMAC), which caused more DNA fragmentation. The increased mitochondrial dysfunction was confirmed in vitro as C57BL/6N hepatocytes had a more precipitous drop in JC-1 fluorescence after APAP exposure. Conclusion: C57BL/6N mice are more susceptible to APAP-induced hepatotoxicity, likely due to increased formation of APAP-protein adducts and a subsequent enhancement of mitochondrial dysfunction associated with aggravated nuclear DNA fragmentation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Duan, Luqi; Woolbright, Benjamin L.; Du, Kuo; Weemhoff, James; Jaeschke, Hartmut] Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Davis, John S.; Cahkraborty, Mala; Bourdi, Mohammed] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD USA. [Davis, John S.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cahkraborty, Mala] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bourdi, Mohammed] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Jaeschke, H (reprint author), Univ Kansas, Dept Pharmacol Toxicol & Therapeut, Med Ctr, 3901 Rainbow Blvd,MS 1018, Kansas City, KS 66160 USA. EM lduan@kumc.edu; John.Davis@nih.gov; bwoolbright@kmc.edu; kdu@kumc.edu; cahkraborty@nih.gov; jweemhoff@kumc.edu; hjaeschke@kumc.edu; mohammed.bourdi@nih.gov FU National Institutes of Health [R01 AA12916, R01 DK102142]; National Center for Research Resources of the National Institutes of Health [5P20RR021940-07]; National Institute of General Medical Sciences of the National Institutes of Health [8 P20 GM103549-07]; National Institute of Environmental Health Sciences [T32 ES007079-26A2] FX This work was supported in part by the National Institutes of Health grants R01 AA12916, and R01 DK102142 and by grants from the National Center for Research Resources (5P20RR021940-07) and the National Institute of General Medical Sciences (8 P20 GM103549-07) of the National Institutes of Health. Additional support came from the "Training Program in Environmental Toxicology" T32 ES007079-26A2 (to B.L.W.) from the National Institute of Environmental Health Sciences. NR 60 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 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 BP 107 EP 118 DI 10.1016/j.fct.2016.10.021 PN B PG 12 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EF7JH UT WOS:000390505400003 PM 27773698 ER PT J AU Catlin, NR Herbert, R Janardhan, K Hejtmancik, MR Fomby, LM Vallant, M Kissling, GE DeVito, MJ AF Catlin, Natasha R. Herbert, Ron Janardhan, Kyathanahalli Hejtmancik, Milton R. Fomby, Laurene M. Vallant, Molly Kissling, Grace E. DeVito, Michael J. TI Dose-response assessment of the dermal toxicity of Virginia cedarwood oil in F344/N rats and B6C3F1/N mice SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Cedarwood oil; Benchmark dose; Skin ID ALPHA-CEDRENE; ANIMAL-MODELS; IN-VIVO; SKIN; DERMATITIS; ABSORPTION; PERFUMES AB Virginia cedarwood oil is widely used as a fragrance material in household and personal products and as a naturally derived pesticide alternative. Due to conflicting literature on dermal exposures in animals and humans, concern for safe levels of human exposure remains. The present study evaluated the toxicity of cedarwood oil applied dermally to F344/N rats and B6C3F1/N mice for 13 weeks. Groups of 10 male and female rats and mice received no treatment (untreated control) or were administered cedarwood oil in 95% aqueous ethanol dermally at concentrations ranging from 0% (vehicle control), 6.25%, 12.5%, 25%, 50%, and 100% (undiluted). Rats and mice developed extensive skin lesions at the site of application. Benchmark dose modeling (BMD) was performed for the significantly increased skin lesions observed in the rat, to provide perspective for risk assessment applications. Benchmark dose modeling levels (BMDL) of 0.65 to 2.1% and 1.2 to 4.4% (equivalent to 13 to 42 mg/Kg and 24 to 48 mg/kg, respectively) cedarwood oil were calculated for the most sensitive endpoint of epidermal hyperplasia in female rats and chronic active inflammation in male rats, respectively. These BMDL levels coincide with reported use levels in cosmetics and pesticides, raising the concern for human exposure. Published by Elsevier Ltd. C1 [Catlin, Natasha R.; Herbert, Ron; Vallant, Molly; Kissling, Grace E.; DeVito, Michael J.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli] Integrated Lab Syst Inc, Morrisville, NC 27560 USA. [Hejtmancik, Milton R.; Fomby, Laurene M.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Catlin, NR (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM natasha.catlin@nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, United States Department of Health and Human Services [N01-ES-65406] FX This work was performed for the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, United States Department of Health and Human Services, under contract No. N01-ES-65406. Prior to submission this work was reviewed by Drs. Vicki Sutherland and Matthew Stout. NR 32 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 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 BP 159 EP 168 DI 10.1016/j.fct.2016.10.016 PN B PG 10 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EF7JH UT WOS:000390505400008 PM 27769849 ER PT J AU Nagababu, E AF Nagababu, Enika TI Ferriheme catalyzes nitric oxide reaction with glutathione to form S-nitrosoglutathione: A novel mechanism for formation of S-nitrosothiols SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE S-nitrosothiols; S-nitrosoglutathione; Nitric oxide; Ferriheme; Glutathione ID RED-CELL MEMBRANE; REDUCTIVE NITROSYLATION; HEME; PROTEIN; NITROSATION; KINETICS; OXYGEN; IRON; DEOXYHEMOGLOBIN; DEGRADATION AB S-nitrosothiols (SNO) perform many important functions in biological systems, but the mechanism by which they are generated in vivo remains a contentious issue. Nitric oxide (NO) reacts with thiols to form SNO only in the presence of a molecule that will accept an electron from either NO or the thiol. In this study, we present evidence that ferriheme accepts an electron from NO or glutathione (GSH) to generate S-nitrosoglutathione (GSNO) in vitro under anaerobic or hypoxic (2% O-2) conditions. Ferriheme formed charge transfer-stable complexes with NO to form ferriheme-NO (heme-Fe(II)-NO+) and with GSH to form ferriheme-GS (heme-Fe(II)-GS(center dot))under anaerobic conditions. The reaction between GSH and the heme-Fe(II)-NO+ complex or between NO and the heme-Fe(II)-GS(center dot) complex resulted in simultaneous reductive ferriheme nitrosylation (heme-Fe(II) NO) and the generation of GSNO. Thus, ferriheme is readily reduced to ferroheme in the presence of NO and GSH together, but not with either individually. The reaction between NO and the heme-Fe(II)-GS(center dot) complex to generate GSNO occurred more rapidly than NO was consumed by endothelial cells, but not red blood cells. In addition, pretreatment of endothelial cells with ferriheme or the ferriheme-GS complex generated SNO upon addition of NO under hypoxic conditions. The results of this study raise the possibility that in vivo, ferriheme can complex with GSH to form ferriheme-GS complex (heme-Fe(II)-GS(center dot)), which rapidly reacts with NO to generate GSNO under intracellular oxygen levels. The GSNO formation by this mechanism is more efficient than any other in vitro mechanism(s) reported so far. C1 [Nagababu, Enika] Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Integrated Vasc Biol Lab, 720 Rutland Ave,Ross 1150, Baltimore, MD 21205 USA. [Nagababu, Enika] NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. RP Nagababu, E (reprint author), Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Integrated Vasc Biol Lab, 720 Rutland Ave,Ross 1150, Baltimore, MD 21205 USA.; Nagababu, E (reprint author), NIA, Baltimore, MD 21224 USA. EM nenika1@JHMI.edu FU Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland; Intramural Research Program of The National Institute on Aging, National Institutes of Health, USA FX This research was supported by the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland and the Intramural Research Program of The National Institute on Aging, National Institutes of Health, USA. NR 51 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC PY 2016 VL 101 BP 296 EP 304 DI 10.1016/j.freeradbiomed.2016.09.015 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EG0DN UT WOS:000390701300026 PM 27693379 ER PT J AU Fernandez Nunez, L Ocampo, J Gottlieb, AM Rossi, S Moreno, S AF Fernandez Nunez, Lucas Ocampo, Josefina Gottlieb, Alexandra M. Rossi, Silvia Moreno, Silvia TI Multiple isoforms for the catalytic subunit of PICA in the basal fungal lineage Mucor circinelloides SO FUNGAL BIOLOGY LA English DT Article DE cAMP; Differentiation; Orthologs; Paralogs; Pseudokinase; Zygomycetes ID PROTEIN-KINASE-A; ROUXII SPORANGIOSPORES; ASPERGILLUS-NIDULANS; REGULATORY SUBUNIT; SIGNALING PATHWAY; CAMP; VIRULENCE; GROWTH; GENES; EXPRESSION AB Protein kinase A (PICA) activity is involved in dimorphism of the basal fungal lineage Mucor. From the recently sequenced genome of Mucor circinelloides we could predict ten catalytic subunits of PKA. From sequence alignment and structural prediction we conclude that the catalytic core of the isoforms is conserved, and the difference between them resides in their amino termini. This high number of isoforms is maintained in the subdivision Mucoromycotina. Each paralogue, when compared to the ones form other fungi is more homologous to one of its orthologs than to its paralogs. All of these fungal isoforms cannot be included in the class I or II in which fungal protein kinases have been classified. mRNA levels for each isoform were measured during aerobic and anaerobic growth. The expression of each isoform is differential and associated to a particular growth stage. We reanalyzed the sequence of PKAC (GI 20218944), the only cloned sequence available until now for a catalytic subunit of M. circinelloides. PKAC cannot be classified as a PKA because of its difference in the conserved C-tail; it shares with PKB a conserved C2 domain in the N-terminus. No catalytic activity could be measured for this protein nor predicted bioinformatically. It can thus be classified as a pseudokinase. Its importance can not be underestimated since it is expressed at the mRNA level in different stages of growth, and its deletion is lethal. (C) 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved. C1 [Fernandez Nunez, Lucas; Ocampo, Josefina; Rossi, Silvia; Moreno, Silvia] Univ Buenos Aires, Facu Ciencias Exactas & Nat, Dept Quim Biol, IQUIBICEN CONICET, Intendente Guiraldes 2160,Ciudad Univ,C1428EGA, Buenos Aires, DF, Argentina. [Gottlieb, Alexandra M.] Univ Buenos Aires, Facu Ciencias Exactas & Nat, Dept Ecol Genet & Evolut, IEGEBA CONICET, Intendente Guiraldes 2160,Ciudad Univ,C1428EGA, Buenos Aires, DF, Argentina. [Ocampo, Josefina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Dev Biol, NIH, Bethesda, MD USA. RP Moreno, S (reprint author), Univ Buenos Aires, Facu Ciencias Exactas & Nat, Intendente Guiraldes 2160,Ciudad Univ,C1428EGA, Buenos Aires, DF, Argentina. EM smoreno@qb.fcen.uba.ar FU Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2010-0128]; Universidad de Buenos Aires [X461]; Consejo Nacional de Investigaciones Cientificas y Tecnicas (PIP) [11220110100826] FX This study was supported by the following grants: PICT 2010-0128 Agencia Nacional de Promocion Cientifica y Tecnologica, Universidad de Buenos Aires (X461) and Consejo Nacional de Investigaciones Cientificas y Tecnicas (PIP-2012-2014, 11220110100826). LFN and JO were at the time doctoral and postdoctoral fellows from CONICET. NR 61 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 1878-6146 EI 1878-6162 J9 FUNGAL BIOL-UK JI Fungal Biol. PD DEC PY 2016 VL 120 IS 12 BP 1493 EP 1508 DI 10.1016/j.funbio.2016.07.013 PG 16 WC Mycology SC Mycology GA EG0KG UT WOS:000390721100002 PM 27890086 ER PT J AU Wei, YH Reveal, B Cai, WL Lilly, MA AF Wei, Youheng Reveal, Brad Cai, Weili Lilly, Mary A. TI The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster SO G3-GENES GENOMES GENETICS LA English DT Article DE TORC1; Nprl2; Nprl3; Iml1; metabolism ID AMINO-ACID SUFFICIENCY; RAG GTPASES; FAT-BODY; GROWTH-CONTROL; CELL-GROWTH; AUTOPHAGY; MTOR; RAPAMYCIN; TORC1; DISEASE AB TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionarily conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here, we characterize null mutants of the GATOR1 components nprl2, nprl3, and iml1 in Drosophila melanogaster. We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability. Consistent with increased TORC1 activity, GATOR1 mutants exhibit a cell autonomous increase in cell growth. Notably, escaper nprl2 and nprl3 mutant adults have a profound locomotion defect. In line with a nonautonomous role in the regulation of systemic metabolism, expressing the Nprl3 protein in the fat body, a nutrient storage organ, and hemocytes but not muscles and neurons rescues the motility of nprl3 mutants. Finally, we show that nprl2 and nprl3 mutants fail to activate autophagy in response to amino acid limitation and are extremely sensitive to both amino acid and complete starvation. Thus, in Drosophila, in addition to maintaining baseline levels of TORC1 activity, the GATOR1 complex has retained a critical role in the response to nutrient stress. In summary, the TORC1 inhibitor GATOR1 contributes to multiple aspects of the development and physiology of Drosophila. C1 [Wei, Youheng; Reveal, Brad; Cai, Weili; Lilly, Mary A.] NICHHD, Cell Biol & Neurobiol Branch, NIH, Bldg 35 1C-917, Bethesda, MD 20892 USA. RP Lilly, MA (reprint author), NICHHD, Cell Biol & Neurobiol Branch, NIH, Bldg 35 1C-917, Bethesda, MD 20892 USA. EM lillym@helix.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [ZIA HD001613 16] FX We thank members of the Lilly laboratory for comments on the manuscript. Multiple stocks used in this study were obtained from the Bloomington Stock Center. We thank Thomas Neufeld (University of Minnesota) for providing the TorA948V/CyO stock. This work was supported by grant ZIA HD001613 16 from the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 62 TC 0 Z9 0 U1 2 U2 2 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC PY 2016 VL 6 IS 12 BP 3859 EP 3867 DI 10.1534/g3.116.035337 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EF8PN UT WOS:000390591400008 PM 27672113 ER PT J AU McClendon, TB Mainpal, R Amrit, FRG Krause, MW Ghazi, A Yanowitz, JL AF McClendon, T. Brooke Mainpal, Rana Amrit, Francis R. G. Krause, Michael W. Ghazi, Arjumand Yanowitz, Judith L. TI X Chromosome Crossover Formation and Genome Stability in Caenorhabditis elegans Are Independently Regulated by xnd-1 SO G3-GENES GENOMES GENETICS LA English DT Article DE meiosis; ATM; Tip60; ionizing radiation; genome instability ID DAMAGE-INDUCED APOPTOSIS; DOUBLE-STRAND BREAKS; HISTONE H3 METHYLATION; DNA-DAMAGE; C-ELEGANS; MEIOTIC RECOMBINATION; CHECKPOINT PROTEIN; GENE-EXPRESSION; GERMLINE IMMORTALITY; TUMOR-SUPPRESSOR AB The germ line efficiently combats numerous genotoxic insults to ensure the high fidelity propagation of unaltered genomic information across generations. Yet, germ cells in most metazoans also intentionally create double-strand breaks (DSBs) to promote DNA exchange between parental chromosomes, a process known as crossing over. Homologous recombination is employed in the repair of both genotoxic lesions and programmed DSBs, and many of the core DNA repair proteins function in both processes. In addition, DNA repair efficiency and crossover (CO) distribution are both influenced by local and global differences in chromatin structure, yet the interplay between chromatin structure, genome integrity, and meiotic fidelity is still poorly understood. We have used the xnd-1 mutant of Caenorhabditis elegans to explore the relationship between genome integrity and crossover formation. Known for its role in ensuring X chromosome CO formation and germ line development, we show that xnd-1 also regulates genome stability. xnd-1 mutants exhibited a mortal germ line, high embryonic lethality, high incidence of males, and sensitivity to ionizing radiation. We discovered that a hypomorphic allele of mys-1 suppressed these genome instability phenotypes of xnd-1, but did not suppress the CO defects, suggesting it serves as a separation-of-function allele. mys-1 encodes a histone acetyltransferase, whose homolog Tip60 acetylates H2AK5, a histone mark associated with transcriptional activation that is increased in xnd-1 mutant germ lines, raising the possibility that thresholds of H2AK5ac may differentially influence distinct germ line repair events. We also show that xnd-1 regulated him-5 transcriptionally, independently of mys-1, and that ectopic expression of him-5 suppressed the CO defects of xnd-1. Our work provides xnd-1 as a model in which to study the link between chromatin factors, gene expression, and genome stability. C1 [McClendon, T. Brooke; Yanowitz, Judith L.] Univ Pittsburgh, Sch Med, Mol Genet & Dev Biol Grad Program, Pittsburgh, PA 15224 USA. [Amrit, Francis R. G.; Ghazi, Arjumand] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15224 USA. [McClendon, T. Brooke; Mainpal, Rana; Yanowitz, Judith L.] Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Serv, Pittsburgh, PA 15213 USA. [Krause, Michael W.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Yanowitz, JL (reprint author), Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Magee Womens Res Inst, 204 Craft Ave, Pittsburgh, PA 15213 USA. EM jly@alum.mit.edu RI Ghazi, Arjumand/D-9373-2017; Rana, Mainpal/Q-7646-2016 OI Ghazi, Arjumand/0000-0002-5859-4206; Rana, Mainpal/0000-0003-2458-7259 FU National Institutes of Health (NIH) Office of Research Infrastructure Programs [P40 OD010440]; Ellison Medical Foundation [AG-NS-0879-12]; State of Pennsylvania Formula Funds; National Institute of General Medical Sciences [R01GM104007] FX We thank Cynthia Wagner and Zebulin Kessler for their assistance in the construction and bombardment of the Ppie-1::him-5::gfp trans-gene, and Tetsu Fukushige and Weiping Chen for assistance with the microarrays. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). The anti-E7 tubulin antibody developed by M. McCutcheon and S. Carroll and was obtained from the Developmental Studies Hybridoma Bank, created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH and maintained at the Department of Biology The University of Iowa. Sequencing of trans genic constructs and the ced-3(n717) allele was performed in the Genomics Research Core at the University of Pittsburgh. Funding for these studies was provided by A New Scholar in Aging award from the Ellison Medical Foundation (AG-NS-0879-12) to A.G., State of Pennsylvania Formula Funds to J.L.Y., and an R01 from the National Institute of General Medical Sciences (R01GM104007) to J.L.Y. NR 65 TC 0 Z9 0 U1 3 U2 3 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC PY 2016 VL 6 IS 12 BP 3913 EP 3925 DI 10.1534/g3.116.035725 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EF8PN UT WOS:000390591400013 PM 27678523 ER PT J AU Lin, YZ Chen, ZX Oliver, B Harbison, ST AF Lin, Yanzhu Chen, Zhen-Xia Oliver, Brian Harbison, Susan T. TI Microenvironmental Gene Expression Plasticity Among Individual Drosophila melanogaster SO G3-GENES GENOMES GENETICS LA English DT Article DE microenvironmental plasticity; plasticity; Drosophila; interindividual variation; RNA-Seq ID MONOZYGOTIC TWINS DISCORDANT; ODOR-GUIDED BEHAVIOR; DEVELOPMENTAL STABILITY; ENVIRONMENTAL VARIATION; PHENOTYPIC PLASTICITY; VARIANCE HETEROGENEITY; RESIDUAL VARIANCE; BIPOLAR DISORDER; IDENTICAL-TWINS; REFERENCE PANEL AB Differences in phenotype among genetically identical individuals exposed to the same environmental condition are often noted in genetic studies. Despite this commonplace observation, little is known about the causes of this variability, which has been termed microenvironmental plasticity. One possibility is that stochastic or technical sources of variance produce these differences. A second possibility is that this variation has a genetic component. We have explored gene expression robustness in the transcriptomes of 730 individual Drosophila melanogaster of 16 fixed genotypes, nine of which are infected with Wolbachia. Three replicates of flies were grown, controlling for food, day/night cycles, humidity, temperature, sex, mating status, social exposure, and circadian timing of RNA extraction. Despite the use of inbred genotypes, and carefully controlled experimental conditions, thousands of genes were differentially expressed, revealing a unique and dynamic transcriptional signature for each individual fly. We found that 23% of the transcriptome was differentially expressed among individuals, and that the variability in gene expression among individuals is influenced by genotype. This transcriptional variation originated from specific gene pathways, suggesting a plastic response to the microenvironment; but there was also evidence of gene expression differences due to stochastic fluctuations. These observations reveal previously unappreciated genetic sources of variability in gene expression among individuals, which has implications for complex trait genetics and precision medicine. C1 [Lin, Yanzhu; Harbison, Susan T.] NHLBI, Lab Syst Genet, NIH, Bethesda, MD 20892 USA. [Chen, Zhen-Xia; Oliver, Brian] NIDDK, Sect Dev Genom, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Harbison, ST (reprint author), NHLBI, Lab Syst Genet, Bldg 10,Room 7D13,10 Ctr Dr, Bethesda, MD 20892 USA. EM susan.harbison@nih.gov FU Intramural Research Program of the National Institutes of Health; National Heart Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases FX The authors H. Yang for technical assistance. This work utilized the computational resources of the National Institutes of Health High Performance Computing Biowulf cluster (http://hpc.nih.gov). This research was supported by the Intramural Research Program of the National Institutes of Health, The National Heart Lung and Blood Institute, and The National Institute of Diabetes and Digestive and Kidney Diseases. NR 99 TC 0 Z9 0 U1 9 U2 9 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC PY 2016 VL 6 IS 12 BP 4197 EP 4210 DI 10.1534/g3.116.035444 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EF8PN UT WOS:000390591400038 PM 27770026 ER PT J AU Morgan, AP Didion, JP Doran, AG Holt, JM McMillan, L Keane, TM de Villena, FPM AF Morgan, Andrew P. Didion, John P. Doran, Anthony G. Holt, James M. McMillan, Leonard Keane, Thomas M. de Villena, Fernando Pardo-Manuel TI Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers SO G3-GENES GENOMES GENETICS LA English DT Article DE inbred mouse strains; wild-derived mouse strains; Robertsonian translocations; karyotype evolution ID HOUSE MOUSE; HAPLOTYPE DIVERSITY; LABORATORY MOUSE; CONSOMIC STRAINS; COMPLEX TRAITS; MICE; GENE; DUPLICATION; SPECIATION; KARYOTYPE AB Wild-derived mouse inbred strains are becoming increasingly popular for complex traits analysis, evolutionary studies, and systems genetics. Here, we report the whole-genome sequencing of two wild-derived mouse inbred strains, LEWES/EiJ and ZALENDE/EiJ, of Mus musculus domesticus origin. These two inbred strains were selected based on their geographic origin, karyotype, and use in ongoing research. We generated 14x and 18x coverage sequence, respectively, and discovered over 1.1 million novel variants, most of which are private to one of these strains. This report expands the number of wild-derived inbred genomes in the Mus genus from six to eight. The sequence variation can be accessed via an online query tool; variant calls (VCF format) and alignments (BAM format) are available for download from a dedicated ftp site. Finally, the sequencing data have also been stored in a lossless, compressed, and indexed format using the multi-string Burrows-Wheeler transform. All data can be used without restriction. C1 [Morgan, Andrew P.; Didion, John P.; de Villena, Fernando Pardo-Manuel] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Holt, James M.; McMillan, Leonard] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Doran, Anthony G.; Keane, Thomas M.] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Didion, John P.] NHGRI, NIH, Bethesda, MD 20892 USA. RP de Villena, FPM (reprint author), Univ N Carolina, Dept Genet, 120 Mason Farm Rd,CB 7264, Chapel Hill, NC 27599 USA. EM fernando@med.unc.edu OI Doran, Anthony/0000-0003-3061-4102 FU National Institutes of Health (NIH) [F30MH103925, T32GM067553, P50GM076468, U19AI100625]; Medical Research Council [MR/L007428/1]; Biotechnology and Biological Sciences Research Council [BB/M000281/1]; Wellcome Trust FX We wish to thank Timothy A. Bell for help preparing the DNA. This work was supported in part by National Institutes of Health (NIH) grants F30MH103925 (A.P.M.), T32GM067553 (A.P.M. and J.P.D.), P50GM076468, and U19AI100625 (F.P.-M.dV.). T.M.K. and A.G.D. are supported by the Medical Research Council (MR/L007428/1), the Biotechnology and Biological Sciences Research Council (BB/M000281/1), and the Wellcome Trust. NR 41 TC 0 Z9 0 U1 5 U2 5 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC PY 2016 VL 6 IS 12 BP 4211 EP 4216 DI 10.1534/g3.116.034751 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EF8PN UT WOS:000390591400039 PM 27765810 ER PT J AU Mensah, GA AF Mensah, George A. TI New Partnerships to Advance Global Health Research for NCD SO GLOBAL HEART LA English DT Editorial Material ID AFRICA; WORLD; FUND C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mensah, George A.] NHLBI, Div Cardiovasc Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA.; Mensah, GA (reprint author), NHLBI, Div Cardiovasc Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 18 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 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD DEC PY 2016 VL 11 IS 4 BP 473 EP 478 DI 10.1016/j.gheart.2016.10.022 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6PT UT WOS:000390453700028 PM 27938846 ER PT J AU Mensah, GA AF Mensah, George A. TI NCD Research in the Post-2015 Global Health Agenda Perspectives from the NHLBI Strategic Vision SO GLOBAL HEART LA English DT Editorial Material ID INEQUITIES; DIVERSITY; PROGRAM; NETWORK; OBESITY; HEART C1 [Mensah, George A.] NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. EM George.Mensah@nih.gov NR 46 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 2211-8160 EI 2211-8179 J9 GLOB HEART JI Glob. Heart PD DEC PY 2016 VL 11 IS 4 BP 479 EP 483 DI 10.1016/j.gheart.2016.11.002 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6PT UT WOS:000390453700029 PM 27938847 ER PT J AU Wang, XM Bassig, BA Wen, JJ Li, GD Liu, ZB Yao, WX Hu, W Wang, Y Li, JM Wang, XD Gan, MZ Wang, CS Xu, G Rothman, N Lan, Q Xu, CG AF Wang, Xue-mei Bassig, Bryan A. Wen, Jing-jing Li, Gan-di Liu, Zhi-bin Yao, Wen-xiu Hu, Wei Wang, Ying Li, Ji-man Wang, Xiao-dong Gan, Mao-zhou Wang, Chun-sen Xu, Gang Rothman, Nathaniel Lan, Qing Xu, Cai-gang TI Clinical analysis of 1629 newly diagnosed malignant lymphomas in current residents of Sichuan province, China SO HEMATOLOGICAL ONCOLOGY LA English DT Article DE lymphoma; China; geographical variation; descriptive epidemiology ID B-CELL LYMPHOMA; UNITED-STATES; SUBTYPE; CLASSIFICATION; SHANGHAI AB Previous studies in other provinces of China (Beijing, Xinjiang, Shanxi, Jiangxi, Shanghai, Guangdong, and Taiwan) suggest that the distributions of lymphoma subtypes differ compared with Western populations. In order to evaluate the characteristics of malignant lymphoma in Sichuan, China, we analyzed case series data from incident lymphoma patients diagnosed in 2008 from three hospitals, including a total of 1629 cases and including only current residents of Sichuan. The median age of diagnosis for cases was 54years, with a higher proportion of male cases compared with female cases. The most commonly diagnosed subtypes included diffuse large B-cell lymphoma (40.4%), NK/T-cell lymphoma (NKTCL; 11.8%), mixed cellularity Hodgkin lymphoma (7.0%), mantle cell lymphoma (4.8%), and marginal zone B-cell lymphoma (3.9%). Differences in demographic characteristics between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cases were apparent for median age at diagnosis (HL: 34years; NHL: 57years), and NHLs accounted for nearly all (99.3%) of the 931 cases of extranodal lymphoma. These findings indicate a higher proportion of NKTCL cases and a lower proportion of follicular lymphoma cases (2.3%) in these hospitals in Sichuan, relative to reports from some other provinces within China (e.g., Shanghai and Shanxi) and the USA. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Wang, Xue-mei; Wen, Jing-jing; Li, Gan-di; Liu, Zhi-bin; Xu, Cai-gang] Sichuan Univ, Dept Hematol, Hematol Res Lab & Pathol, West China Hosp, Chengdu 610041, Sichuan, Peoples R China. [Bassig, Bryan A.; Hu, Wei; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Yao, Wen-xiu; Wang, Ying; Li, Ji-man] Sichuan Prov Tumour Hosp, Dept Internal Med & Pathol, Chengdu, Sichuan, Peoples R China. [Wang, Xiao-dong; Gan, Mao-zhou; Wang, Chun-sen; Xu, Gang] Sichuan Prov Peoples Hosp, Dept Hematol & Pathol, Chengdu, Sichuan, Peoples R China. [Wang, Xue-mei] Luzhou Med Coll, Affiliated Hosp, Dept Hematol, Luzhou, Peoples R China. RP Xu, CG (reprint author), Sichuan Univ, Dept Hematol, Hematol Res Lab & Pathol, West China Hosp, Chengdu 610041, Sichuan, Peoples R China. EM xucg@cd120.com NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0278-0232 EI 1099-1069 J9 HEMATOL ONCOL JI Hematol. Oncol. PD DEC PY 2016 VL 34 IS 4 BP 193 EP 199 DI 10.1002/hon.2202 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA EF8RC UT WOS:000390595800003 PM 25824105 ER PT J AU Makowsky, R Lhaki, P Wiener, HW Bhatta, MP Cullene, M Johnson, DC Perry, RT Lama, M Boland, JF Yeager, M Ghimire, S Broker, TR Shrestha, S AF Makowsky, Robert Lhaki, Pema Wiener, Howard W. Bhatta, Madhav P. Cullene, Michael Johnson, Derek C. Perry, Rodney T. Lama, Mingma Boland, Joseph F. Yeager, Meredith Ghimire, Sarita Broker, Thomas R. Shrestha, Sadeep TI Genomic diversity and phylogenetic relationships of human papillomavirus 16 (HPV16) in Nepal SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE HPV16 sequence; Nepal; Phylogenetic tree; HSIL; HPV16 lineage ID CERVICAL-CANCER; E6; VARIANTS; CLASSIFICATION; PERSISTENCE; NEOPLASIA; SEQUENCE; LESIONS; WOMEN AB Objectives/Background: Sequence variants in HPV16 confer differences in oncogenic potential; however, to date there have not been any HPV sequence studies performed in Nepal. The objective of this study was to characterize HPV16 viral genome sequences from Nepal compared to a reference sequence in order to determine their lineages. Additionally, we sought to determine if five High-grade Squamous Intraepithelial Lesion (HSIL) subjects were genetically distinct from the non-HSIL subjects. Methods: DNA was isolated from exfoliated cervical cells from 17 individuals in Nepal who were previously identified to be HPV16-positive. A custom HPV16 Ion Ampliseq panel of multiplexed degenerate primers was designed that generated 47 overlapping amplicons and covered 99% of the viral genome for all known HPV16 variant lineages. All sequence data were processed through a custom quality control and analysis pipeline of sequence comparisons and phylogenetic analysis. Results: There were high similarities across the genomes, with two major indels observed in the non-coding region between E5 and L2. Compared to the PAVE reference HPV16 genome, there were up to 9, 4, 38, 27, 8, 7, 52, and 32 nucleotide variants in the E6, E7, E1, E2, E4, E5, L2, and L1 genes in the Nepalese samples, respectively. Based on sequence variation, HPV16 from Nepal falls across the A, C, and D lineages in this study. We found no evidence of genetic distinctness between HSIL and non-HSIL subjects. Conclusions: The evolutionary and pathological characteristics of the representative HPV16 genomes from Nepal seem similar to results from other parts of the world and provide the basis for further studies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Makowsky, Robert] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL USA. [Lhaki, Pema; Lama, Mingma] NFCC Int, Kathmandu, Nepal. [Wiener, Howard W.; Johnson, Derek C.; Perry, Rodney T.; Shrestha, Sadeep] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Ryals Rm217L,1720 2nd Ave S, Birmingham, AL 35294 USA. [Bhatta, Madhav P.] Kent State Univ, Coll Publ Hlth, Dept Biostat Environm Hlth Sci & Epidemiol, Kent, OH 44242 USA. [Cullene, Michael; Boland, Joseph F.; Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Cullene, Michael; Boland, Joseph F.; Yeager, Meredith] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Genom Res Lab, Gaithersburg, MD USA. [Ghimire, Sarita] Nepal Canc Care Fdn, Canc Screening Ctr, Lalitpur, Nepal. [Broker, Thomas R.] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL USA. RP Shrestha, S (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Ryals Rm217L,1720 2nd Ave S, Birmingham, AL 35294 USA. EM sshrestha@uab.edu FU Department of Epidemiology, School of Public Health, University of Alabama at Birmingham; College of Public Health, Kent State University; National Institutes of Health Cancer Prevention and Control Training Grant [R25CA47888] FX We thank the study participants and the staff at Nepal Fertility Care Center (NFCC) who helped with the sample collection, particularly Pankaj Bhattarai who was instrumental in the health camps. The Family Health Division, within the Nepal ministry of health also assisted with the logistics of the health camp and data collection. The study was supported in part by the pilot fund from the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham and College of Public Health, Kent State University. Derek Johnson was supported by a National Institutes of Health Cancer Prevention and Control Training Grant (R25CA47888). NR 27 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 EI 1567-7257 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD DEC PY 2016 VL 46 BP 7 EP 11 DI 10.1016/j.meegid.2016.10.004 PG 5 WC Infectious Diseases SC Infectious Diseases GA EF6QP UT WOS:000390456000002 PM 27725301 ER PT J AU Pereira, TA Syn, WK Pereira, FEL Lambertucci, JR Secor, WE Diehl, AM AF Pereira, Thiago Almeida Syn, Wing-Kin Pereira, Fausto E. L. Lambertucci, Jose Roberto Secor, William Evan Diehl, Anna Mae TI Serum osteopontin is a biomarker of severe fibrosis and portal hypertension in human and murine schistosomiasis mansoni SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Osteopontin; Schistosomiasis mansoni; Liver fibrosis; Portal hypertension; Biomarker ID IMMUNE-RESPONSES; PATHOLOGICAL SYNDROMES; CBA/J MICE; INFECTIONS; IMMUNOPATHOGENESIS; IMMUNOREGULATION; ACTIVATION; CELLS AB Schistosomiasis is a major cause of fibrosis and portal hypertension. The reason 4-10% of infected subjects develops hepatosplenic schistosomiasis remains unclear. Chronically infected male CBA/J mice reproduce the dichotomic forms of human schistosomiasis. Most mice (80%) develop moderate splenomegaly syndrome (similar to hepatointestinal disease in humans) and 20% present severe hypersplenomegaly syndrome (analogous to human hepatosplenic disease). We demonstrated that the profibrogenic molecule osteopontin discriminates between mice with severe and mild disease and could be a novel morbidity biomarker in murine and human schistosomiasis. Failure to downregulate osteopontin during the chronic phase may explain why hepatosplenic subjects develop severe fibrosis. (C) 2016 Published by Elsevier Ltd on behalf of Australian Society for Parasitology. C1 [Pereira, Thiago Almeida; Diehl, Anna Mae] Duke Univ, Med Ctr, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Pereira, Thiago Almeida; Lambertucci, Jose Roberto] Univ Fed Minas Gerais, Fac Med, Lab Doencas Infecciosas & Parasitarias, Dept Clin Med, Belo Horizonte, MG, Brazil. [Pereira, Thiago Almeida] NIAID, Immunopathogesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Syn, Wing-Kin] Fdn Liver Res, Inst Hepatol, Liver Regenerat & Repair Res Grp, London, England. [Syn, Wing-Kin] Med Univ South Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Syn, Wing-Kin] Ralph H Johnson Vet Affairs Med Ctr, Gastroenterol Sect, Charleston, SC USA. [Pereira, Fausto E. L.] Univ Fed Espirito Santo, Nucleo Doengas Infecciosas, Vitoria, ES, Spain. [Secor, William Evan] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Diehl, AM (reprint author), Duke Univ, Med Ctr, Dept Med, Duke Liver Ctr,Div Gastroenterol, 905 S LaSalle St,GSRB1 Snyderman Bldg,Suite 1073, Durham, NC 27710 USA. EM diehl004@mc.duke.edu FU National Institutes of Health (NIH), USA [R01-DK-077794]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), USA; Duke University Endowment, USA; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Ministry of Science, Technology and Innovation of Brazil (CNPq); Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil FX We thank Mr Carl Stone for administrative support. This work was supported by: National Institutes of Health (NIH), USA (grant number R01-DK-077794 (to AMD); Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), USA (to TAP)); the Duke University Endowment, USA (the Florence McAlister Professorship) (to AMD), the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Ministry of Science, Technology and Innovation of Brazil (CNPq) (to TAP, FEP and JRL); and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil (to JRL). NR 25 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 0020-7519 EI 1879-0135 J9 INT J PARASITOL JI Int. J. Parasit. PD DEC PY 2016 VL 46 IS 13-14 BP 829 EP 832 DI 10.1016/j.ijpara.2016.08.004 PG 4 WC Parasitology SC Parasitology GA EG0ML UT WOS:000390726800001 PM 27729270 ER PT J AU Kaur, S Roberts, DD AF Kaur, Sukhbir Roberts, David D. TI Divergent modulation of normal and neoplastic stem cells by thrombospondin-1 and CD47 signaling SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Review DE Self-renewal; c-Myc; Tumor initiating cells; Cancer; Extracellular matrix; Matricellular proteins ID REGULATORY PROTEIN-ALPHA; HEMATOPOIETIC PROGENITOR CELLS; LEUKEMIA-INITIATING CELLS; ADVERSE PROGNOSTIC-FACTOR; ISCHEMIC TISSUE SURVIVAL; SIRP-ALPHA; THERAPEUTIC TARGET; BREAST-CANCER; NEUTROPHIL TRANSMIGRATION; HEPATOCELLULAR-CARCINOMA AB Thrombospondin-1 is a secreted matricellular protein that regulates the differentiation and function of many cell types. Thrombospondin-1 is not required for embryonic development, but studies using lineage-committed adult stem cells have identified positive and negative effects of thrombospondin-1 on stem cell differentiation and self-renewal and identified several thrombospondin-1 receptors that mediate these responses. Genetic studies in mice reveal a broad inhibitory role of thrombospondin-1 mediated by its receptor CD47. Cells and tissues lacking thrombospondin-1 or CD47 exhibit an increased capacity for self-renewal associated with increased expression of the stem cell transcription factors c-Myc, Sox2, Klf4, and Oct4. Thrombospondin-1 inhibits expression of these transcription factors in a CD47dependent manner. However, this regulation differs in some neoplastic cells. Tumor initiating/cancer stem cells express high levels of CD47, but in contrast to nontransformed stem cells CD47 signaling supports cancer stem cells. Suppression of CD47 expression in cancer stem cells or ligation of CD47 by function blocking antibodies or thrombospondin-1 results in loss of self-renewal. Therefore, the therapeutic CD47 antagonists that are in clinical development for stimulating innate anti-tumor immunity may also inhibit tumor growth by suppressing cancer stem cells. These and other therapeutic modulators of thrombospondin-1 and CD47 signaling may also have applications in regenerative medicine to enhance the function of normal stem cells. Published by Elsevier Ltd. C1 [Kaur, Sukhbir; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), Bldg 10 Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 119 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 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD DEC PY 2016 VL 81 BP 184 EP 194 DI 10.1016/j.biocel.2016.05.005 PN A PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EF9HO UT WOS:000390641500024 PM 27163531 ER PT J AU Sun, C Gao, J Couzens, L Tian, X Farooqui, MZ Eichelberger, MC Wiestner, A AF Sun, Clare Gao, Jin Couzens, Laura Tian, Xin Farooqui, Mohammed Z. Eichelberger, Maryna C. Wiestner, Adrian TI Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib SO JAMA ONCOLOGY LA English DT Letter ID INFECTIONS C1 [Sun, Clare; Farooqui, Mohammed Z.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. [Gao, Jin; Couzens, Laura; Eichelberger, Maryna C.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Room 3-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD DEC 1 PY 2016 VL 2 IS 12 BP 1656 EP 1657 DI 10.1001/jamaoncol.2016.2437 PG 2 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900028 PM 27533065 ER PT J AU Blake, KD Portnoy, DB Kaufman, AR Lin, CTJ Lo, SC Backlund, E Cantor, D Hicks, L Lin, A Caporaso, A Davis, T Moser, RP Hesse, BW AF Blake, Kelly D. Portnoy, David B. Kaufman, Annette R. Lin, Chung-Tung Jordan Lo, Serena C. Backlund, Eric Cantor, David Hicks, Lloyd Lin, Amy Caporaso, Andrew Davis, Terisa Moser, Richard P. Hesse, Bradford W. TI Rationale, Procedures, and Response Rates for the 2015 Administration of NCI's Health Information National Trends Survey: HINTS-FDA 2015 SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID TOBACCO PRODUCTS; FOOD AB The National Cancer Institute (NCI) developed the Health Information National Trends Survey (HINTS) to monitor population trends in cancer communication practices, information preferences, health risk behaviors, attitudes, and cancer knowledge. The U.S. Food and Drug Administration (FDA) recognized HINTS as a unique data resource for informing its health communication endeavors and partnered with NCI to field HINTS-FDA 2015. HINTS-FDA 2015 was a self-administered paper instrument sent by mail May 29 to September 8, 2015, using a random probability-based sample of U.S. postal addresses stratified by county-level smoking rates, with an oversampling of high and medium-high smoking strata to increase the yield of current smokers responding to the survey. The response rate for HINTS-FDA 2015 was 33% (N=3,738). The yield of current smokers (n=495) was lower than expected, but the sampling strategy achieved the goal of obtaining more former smokers (n=1,132). Public-use HINTS-FDA 2015 data and supporting documentation have been available for download and secondary data analyses since June 2016 at http://hints.cancer.gov. NCI and FDA encourage the use of HINTS-FDA for health communication research and practice related to tobacco-related communications, public knowledge, and behaviors as well as beliefs and actions related to medical products and dietary supplements. C1 [Blake, Kelly D.; Hesse, Bradford W.] NCI, NIH, Hlth Commun & Informat Res Branch, Behav Res Program,Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E222,MSC 9671, Bethesda, MD 20892 USA. [Portnoy, David B.; Backlund, Eric] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Kaufman, Annette R.] NCI, NIH, Tobacco Control Res Branch, Behav Res Program,Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lin, Chung-Tung Jordan; Lo, Serena C.] US FDA, Off Analyt & Outreach, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Cantor, David; Hicks, Lloyd; Lin, Amy; Caporaso, Andrew; Davis, Terisa] Westat Corp, Rockville, MD USA. [Moser, Richard P.] NCI, NIH, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Blake, KD (reprint author), NCI, NIH, Hlth Commun & Informat Res Branch, Behav Res Program,Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E222,MSC 9671, Bethesda, MD 20892 USA. EM kelly.blake@nih.gov FU National Cancer Institute (NCI); U.S. Food and Drug Administration's Center for Tobacco Products, Office of the Commissioner; Center for Food Safety and Applied Nutrition; NCI [HHSN261201000064C] FX HINTS-FDA (Health Information National Trends Survey-U.S. Food and Drug Administration) was funded by the National Cancer Institute (NCI) and the U.S. Food and Drug Administration's Center for Tobacco Products, Office of the Commissioner, and Center for Food Safety and Applied Nutrition via interagency agreements with NCI and by contract from NCI to Westat, Inc. (HHSN261201000064C). NR 17 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD DEC PY 2016 VL 21 IS 12 BP 1269 EP 1275 DI 10.1080/10810730.2016.1242672 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EF6BQ UT WOS:000390415100008 PM 27892827 ER PT J AU Bedda, M Chattopadhyay, PK Kao, SF Foulds, K Roederer, M AF Bedda, Margaret Chattopadhyay, Pratip K. Kao, Shing-Fen Foulds, Kathy Roederer, Mario TI A simple tube adapter to expedite and automate thawing of viably frozen cells SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Immunoassay; T-cells; flow cytometry; Cryopreservation ID BIOBANKING AB Although cryopreserved cell specimens are used throughout biomedical research, the process for thawing samples is labor-intensive and prone to error. Here we describe a small laboratory device that couples an uncapped vial of frozen cells to a conical tube containing warm cell culture media. The entire complex is loaded directly into a centrifuge; within 5 min, cells are thawed and diluted out of toxic cryopreservation medium. The recovery and viability of cells are slightly reduced compared to the common (traditional) method. However, antigen-specific T-cell function is not affected. Since no technician time is required (beyond uncapping of vials), our device allows the parallel processing of as many samples as a centrifuge can hold (up to 96, in some models). Moreover, since the samples are not thawed manually in a water bath, the problems associated with technician-to-technician differences in sample handling are minimized, as is the potential for contamination. Importantly, the elimination of substantial labor involving subjective decisions standardizes this process and can reduce variability in results from cryopreserved specimens. (C) 2016 Published by Elsevier B.V. C1 [Bedda, Margaret; Chattopadhyay, Pratip K.; Kao, Shing-Fen; Foulds, Kathy; Roederer, Mario] NIH, ImmunoTechnol Sect, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. RP Chattopadhyay, PK (reprint author), NIH, ImmunoTechnol Sect, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. EM pchattop@mail.nih.gov OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural Research Program of the Vaccine Research Center, NIH FX The authors wish to acknowledge Robert Clary and Howard Metger at the NIH Mechanical Instrument Design and Fabrication Service for making initial variations of the device. PC is a Marylou Ingram Scholar in the International Society for the Advancement of Cytometry. This work was supported by the Intramural Research Program of the Vaccine Research Center, NIH. NR 8 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD DEC PY 2016 VL 439 BP 74 EP 78 DI 10.1016/j.jim.2016.08.009 PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA EF7IC UT WOS:000390502300011 PM 27594593 ER PT J AU Heldreth, CM Guardino, CM Wong, LH Schetter, CD Shapiro, JR Schafer, P Shalowitz, M Lanzi, RG Thorp, J Raju, T AF Heldreth, Courtney M. Guardino, Christine M. Wong, Lauren H. Schetter, Christine Dunkel Shapiro, Jenessa R. Schafer, Peter Shalowitz, Madeleine Lanzi, Robin Gaines Thorp, John, Jr. Raju, Tonse CA CCHN TI CHILDHOOD RACISM EXPERIENCES AND POSTPARTUM DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN MOTHERS SO JOURNAL OF SOCIAL AND CLINICAL PSYCHOLOGY LA English DT Article DE Racial discrimination; childhood racism; early adversity; mental health ID LOW-BIRTH-WEIGHT; MENTAL-HEALTH; BLOOD-PRESSURE; PERCEIVED DISCRIMINATION; POSTNATAL DEPRESSION; PHYSICAL HEALTH; SEXUAL-ABUSE; RISK-FACTORS; STRESS; DISPARITIES AB In the present research, we examined the effects of childhood experiences of racism-both directly and vicariously experienced when directed at family members or close others-on postpartum depressive symptoms one month after the birth of a child. The sample included 1,349 African American women, who were predominantly low-income. Data were collected by an NIH network in five different regions of the United States using community-based participatory research methods. Participants completed interview measures of childhood experiences of racism, current everyday experiences of discrimination, and postpartum depressive symptoms at one month after birth. We also assessed adult everyday experiences of discrimination as a potential mediator of the association between childhood racism and depressive symptoms. Direct and vicarious childhood racism experiences were each independently associated with greater postpartum depressive symptoms. Furthermore, when adult everyday experiences of racism were included in the models, the effects of childhood racism were no longer significant, suggesting mediation. Consistent with this hypothesis, associations between both childhood direct and indirect racism experiences and postpartum depressive symptoms were partially mediated by the participant's everyday experiences of racism as an adult. Our findings suggest that childhood racism experiences, even those that are observed rather than directly experienced, may have implications for future mental health. C1 [Heldreth, Courtney M.; Guardino, Christine M.; Schetter, Christine Dunkel; Shapiro, Jenessa R.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Wong, Lauren H.] St Louis Coll Pharm, St Louis, MO USA. [Schafer, Peter] New York Acad Med, New York, NY USA. [Shalowitz, Madeleine] North Shore Univ Hlth Syst, Evanston, IL USA. [Shalowitz, Madeleine] Univ Chicago, Chicago, IL 60637 USA. [Lanzi, Robin Gaines] Univ Alabama Birmingham, Birmingham, AL USA. [Thorp, John, Jr.] Univ N Carolina, Chapel Hill, NC USA. [Raju, Tonse; CCHN] Eunice Kennedy Shriver Natl Inst Child & Hlth Dev, Rockville, MD USA. RP Heldreth, CM; Schetter, CD (reprint author), Univ Calif Los Angeles, Los Angeles, CA 90095 USA. EM courtneymariel.h@gmail.com; dunkel@psych.ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-o5S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research (NINR) [U NR008929] FX The Community Child Health Network (CCHN) is supported through cooperative agreements with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-o5S1, U HD44245-06S1, R03 HD59584) and the National Institute for Nursing Research (NINR; U NR008929). NR 83 TC 0 Z9 0 U1 2 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0736-7236 J9 J SOC CLIN PSYCHOL JI J. Soc. Clin. Psychol. PD DEC PY 2016 VL 35 IS 10 BP 840 EP 864 PG 25 WC Psychology, Clinical; Psychology, Social SC Psychology GA EF8EC UT WOS:000390560500003 ER PT J AU Braun, LM Rodriguez, DA Song, Y Meyer, KA Lewis, CE Reis, JP Gordon-Larsen, P AF Braun, Lindsay M. Rodriguez, Daniel A. Song, Yan Meyer, Katie A. Lewis, Cora E. Reis, Jared P. Gordon-Larsen, Penny TI Changes in walking, body mass index, and cardiometabolic risk factors following residential relocation: Longitudinal results from the CARDIA study SO JOURNAL OF TRANSPORT & HEALTH LA English DT Article DE Built environment; Walkability; Walking; fixed effects; Residential self-selection ID YOUNG-ADULTS CARDIA; PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; NEIGHBORHOOD WALKABILITY; CARDIORESPIRATORY FITNESS; AUSTRALIAN ADULTS; BLOOD-PRESSURE; LAND-USE; ASSOCIATION; BEHAVIOR AB Background: While many studies have found the built environment to be associated with walking, most have used cross-sectional research designs and few have examined more distal cardiometabolic outcomes. This study contributes longitudinal evidence based on changes in walking, body mass index (BMI), and cardiometabolic risk following residential relocation. Methods: We examined 1079 participants in the CARDIA study who moved residential locations between 2000 and 2006 (ages 32-46 in 2000, 49% white/51% black, 55% female). We created a walkability index from measures of population density, street connectivity, and food and physical activity resources, measured at participants' pre- and post-move residential locations. Outcomes measured before and after the move included walking, BMI, waist circumference, blood pressure, insulin resistance, triglycerides, cholesterol, atherogenic dyslipidemia, and C-reactive protein. Fixed effects (FE) models were used to estimate associations between within-person change in walkability and within-person change in each outcome. These estimates were compared to those from random effects (RE) models to assess the implications of unmeasured confounding. Results: In FE models, a one-SD increase in walkability was associated with a 0.81 mmHg decrease in systolic blood pressure [95% CI: ( 1.55, 0.07)] and a 7.36 percent increase in C-reactive protein [95% CI: (0.60,14.57)]. Although several significant associations were observed in the RE models, Hausman tests suggested that these estimates were biased for most outcomes. RE estimates were most commonly biased away from the null or in the opposite direction of effect as the FE estimates. Conclusions: Greater walkability was associated with lower blood pressure and higher C-reactive protein in FE models, potentially reflecting competing health risks and benefits in dense, walkable environments. RE models tended to overstate or otherwise misrepresent the relationship between walkability and health. Approaches that base estimates on variation between individuals may be subject to bias from unmeasured confounding, such as residential self-selection. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Braun, Lindsay M.; Song, Yan] Univ North Carolina Chapel Hill, Dept City & Reg Planning, Campus Box 3140,New East Bldg, Chapel Hill, NC 27599 USA. [Rodriguez, Daniel A.] Univ Calif Berkeley, Dept City & Reg Planning, Berkeley, CA 94720 USA. [Meyer, Katie A.; Gordon-Larsen, Penny] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL USA. [Reis, Jared P.] NHLBI, Prevent & Populat Sci Program, Bldg 10, Bethesda, MD 20892 USA. [Gordon-Larsen, Penny] Univ North Carolina Chapel Hill, Carolina Populat Ctr, Chapel Hill, NC USA. RP Braun, LM (reprint author), Univ North Carolina Chapel Hill, Dept City & Reg Planning, Campus Box 3140,New East Bldg, Chapel Hill, NC 27599 USA. EM maurerbraun@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [R01HL104580, R01HL114091]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] [P2C HD050924]; National Institute for Diabetes and Digestive and Kidney Diseases [NIDDK] [P30DK56350]; National Institute of Environmental Health Sciences [NIEHS] [P30ES010126]; NHLBI [AG0005, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C] FX The authors have no financial or other conflicts of interest to disclose. L.M. Braun had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis. We are grateful to Mr. Marc Peterson of the Carolina Population Center Spatial Analysis Unit for the underlying Geographic Information Systems data. This work was funded by the National Heart, Lung, and Blood Institute (NHLBI) grants R01HL104580 and R01HL114091. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the NHLBI, the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). For general support, the authors are grateful to the Carolina Population Center, University of North Carolina at Chapel Hill (grant P2C HD050924 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD]), the Nutrition Obesity Research Center (NORC), University of North Carolina (grant P30DK56350 from the National Institute for Diabetes and Digestive and Kidney Diseases [NIDDK]), and the UNC Center for Environmental Health and Susceptibility (CEHS), University of North Carolina (grant P30ES010126 from the National Institute of Environmental Health Sciences [NIEHS]). The National Heart, Lung, and Blood Institute had input into design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript, and decision to submit the manuscript for publication. NR 60 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2214-1405 J9 J TRANSP HEALTH JI J. Transp. Health PD DEC PY 2016 VL 3 IS 4 SI SI BP 426 EP 439 DI 10.1016/j.jth.2016.08.006 PG 14 WC Public, Environmental & Occupational Health; Transportation SC Public, Environmental & Occupational Health; Transportation GA EG0SP UT WOS:000390742800002 PM 28163997 ER PT J AU Beigi, M Wilkinson, L Gobet, F Parton, A Jahanshahi, M AF Beigi, M. Wilkinson, L. Gobet, F. Parton, A. Jahanshahi, M. TI Levodopa medication improves incidental sequence learning in Parkinson's disease SO NEUROPSYCHOLOGIA LA English DT Article DE Parkinson's disease; Incidental sequence learning; Serial reaction time; Levodopa medication; Striatum; Basal ganglia ID BASAL GANGLIA; COGNITIVE FUNCTION; IMPLICIT; STRIATUM; MEMORY; MODULATION; ATTENTION; TASK; PET AB Empirical evidence suggests that levodopa medication used to treat the motor symptoms of Parkinson's disease (PD) may either improve, impair or not affect specific cognitive processes. This evidence led to the 'dopamine overdose' hypothesis that levodopa medication impairs performance on cognitive tasks if they recruit fronto-striatal circuits which are not yet dopamine-depleted in early PD and as a result the medication leads to an excess of dopamine. This hypothesis has been supported for various learning tasks including conditional associative learning, reversal learning, classification learning and intentional deterministic sequence learning, on all of which PD patients demonstrated significantly worse performance when tested on relative to off dopamine medication. Incidental sequence learning is impaired in PD, but how such learning is affected by dopaminergic therapy remains undetermined. The aim of the current study was to investigate the effect of dopaminergic medication on incidental sequence learning in PD. We used a probabilistic serial reaction time task (SRTT), a sequence learning paradigm considered to make the sequence less apparent and more likely to be learned incidentally rather than intentionally. We compared learning by the same group of PD patients (n=15) on two separate occasions following oral administration of levodopa medication (on state) and after overnight withdrawal of medication (off state). Our results demonstrate for the first time that levodopa medication enhances incidental learning of a probabilistic sequence on the serial reaction time task in PD. However, neither group significantly differed from performance of a control group without a neurological disease, which indicates the importance of within group comparisons for identifying deficits. Levodopa medication enhanced incidental learning by patients with PD on a probabilistic sequence learning paradigm even though the patients were not aware of the existence of the sequence or their acquired knowledge. The results suggest a role in acquiring incidental motor sequence learning for dorsal striatal areas strongly affected by dopamine depletion in early PD. C1 [Beigi, M.; Wilkinson, L.; Jahanshahi, M.] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Queen Sq, London WC1N 3BG, England. [Beigi, M.; Parton, A.] Brunel Univ, Div Psychol, Dept Life Sci, Uxbridge UB8 3PH, Middx, England. [Wilkinson, L.] NINDS, Behav Neurol Unit, 10 Ctr Dr, Bethesda, MD USA. [Gobet, F.] Univ Liverpool, Dept Psychol Sci, Liverpool L69 7ZA, Merseyside, England. RP Jahanshahi, M (reprint author), UCL Inst Neurol, 33 Queen Sq, London WC1N 3BG, England. EM m.jahanshahi@ucl.ac.uk OI Gobet, Fernand/0000-0002-9317-6886 FU ESRC [R84003]; Parkinson's UK FX This work was funded by the ESRC (R84003) and Parkinson's UK. NR 52 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 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD DEC PY 2016 VL 93 BP 53 EP 60 DI 10.1016/j.neuropsychologia.2016.09.019 PN A PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA EG0LC UT WOS:000390723300006 PM 27686948 ER PT J AU Giles, AJ Chien, CD Reid, CM Fry, TJ Park, DM Kaplan, RN Gilbert, MR AF Giles, Amber J. Chien, Christopher D. Reid, Caitlin M. Fry, Terry J. Park, Deric M. Kaplan, Rosandra N. Gilbert, Mark R. TI The functional interplay between systemic cancer and the hematopoietic stem cell niche SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Stem cell niche; Hematopoiesis; Microenvironment; Cancer ID COLONY-STIMULATING FACTOR; BONE-MARROW MICROENVIRONMENT; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; PROGENITOR CELLS; ENDOTHELIAL-CELLS; SELF-RENEWAL; OSTEOBLASTIC CELLS; STEM/PROGENITOR CELLS; RAPID MOBILIZATION AB Hematopoietic cells are increasingly recognized as playing key roles in tumor growth and metastatic progression. Although many studies have focused on the functional interaction of hematopoietic cells with tumor cells, few have examined the regulation of hematopoiesis by the hematopoietic stem cell (HSC) niche in the setting of cancer. Hematopoiesis occurs primarily in the bone marrow, and processes including expansion, mobilization, and differentiation of hematopoietic progenitors are tightly regulated by the specialized stem cell niche. Loss of niche components or the ability of stem cells to localize to the stem cell niche relieves HSCs of the restrictions imposed under normal homeostasis. In this review, we discuss how tumor-derived factors and therapeutic interventions disrupt structural and regulatory properties of the stem cell niche, resulting in niche invasion by hematopoietic malignancies, extramedullary hematopoiesis, myeloid skewing by peripheral tissue microenvironments, and lymphopenia. The key regulatory roles played by the bone marrow niche in hematopoiesis has implications for therapy-related toxicity and the successful development of immune-based therapies for cancer. Published by Elsevier Inc. C1 [Giles, Amber J.; Reid, Caitlin M.; Park, Deric M.; Gilbert, Mark R.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Chien, Christopher D.; Fry, Terry J.; Kaplan, Rosandra N.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giles, AJ (reprint author), 37 Convent Dr,Bldg 37 Rm 1142B, Bethesda, MD 20892 USA. EM amber.giles@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 92 TC 0 Z9 0 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD DEC PY 2016 VL 168 BP 53 EP 60 DI 10.1016/j.pharmthera.2016.09.006 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EF9FE UT WOS:000390635300006 PM 27595927 ER PT J AU Baseler, WA Davies, LC Quigley, L Ridnour, LA Weiss, JM Hussain, SP Wink, DA McVicar, DW AF Baseler, Walter A. Davies, Luke C. Quigley, Laura Ridnour, Lisa A. Weiss, Jonathan M. Hussain, S. Perwez Wink, David A. McVicar, Daniel W. TI Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production SO REDOX BIOLOGY LA English DT Article ID DENDRITIC CELL ACTIVATION; ALTERNATIVE ACTIVATION; METABOLIC-REGULATION; INHIBITION; INTERLEUKIN-10; BIOSYNTHESIS; INFLAMMATION; HIF-1-ALPHA; RESPONSES; SYNTHASE AB Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes. (C) 2016 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. C1 [Baseler, Walter A.; Davies, Luke C.; Quigley, Laura; Ridnour, Lisa A.; Weiss, Jonathan M.; Wink, David A.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Davies, Luke C.] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff, S Glam, Wales. [Hussain, S. Perwez] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov FU Intramural Research Program of the National Cancer Institute; Welcome Trust, UK FX This work was funded in part by the Intramural Research Program of the National Cancer Institute. LCD is funded in part by the Welcome Trust, UK. NR 29 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD DEC PY 2016 VL 10 BP 12 EP 23 DI 10.1016/j.redox.2016.09.005 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF8SD UT WOS:000390598800002 PM 27676159 ER PT J AU Salmon, AB Kim, G Liu, C Wren, JD Georgescu, C Richardson, A Levine, RL AF Salmon, Adam B. Kim, Geumsoo Liu, Chengyu Wren, Jonathan D. Georgescu, Constantin Richardson, Arlan Levine, Rodney L. TI Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice SO REDOX BIOLOGY LA English DT Article DE Redox; Oxidative stress; Longevity; Metabolism; Proteostasis ID PROTEINS; DISEASE; CELLS; OVEREXPRESSION; LOCALIZATION; PROTEOSTASIS; OXIDATION; RESIDUES; MAMMALS AB Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA) repairs oxidation of free-and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity. Here we test the effects of increasing MsrA on longevity and healthy aging in two transgenic mouse models. We show that elevated expression of MsrA targeted specifically to the cytosol reduces the rate of age-related death in female mice when assessed by Gompertz analysis. However, neither cytosolic nor mitochondrial MsrA overexpression extends lifespan when measured by log-rank analysis. In mice with MsrA overexpression targeted to the mitochondria, we see evidence for improved insulin sensitivity in aged female mice. With these and our previous data, we conclude that the increasing MsrA expression in mice has differential effects on aging and healthy aging that are dependent on the target of its subcellular localization. C1 [Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Bldg 10, Bethesda, MD 20892 USA. [Wren, Jonathan D.; Georgescu, Constantin] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK USA. [Richardson, Arlan] Oklahoma City VA Med Ctr, Oklahoma City, OK USA. RP Salmon, AB (reprint author), UTHSCSA, 15355 Lambda Dr, San Antonio, TX 78245 USA.; Levine, RL (reprint author), NIH, Bldg 50 Room 2351, Bethesda, MD 20892 USA. EM salmona@uthscsa.edu; rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU National Institute of Health [R01AG050797]; American Federation of Aging Research; American Heart Association [15BGIA23220016]; Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System; Intramural Research Program of the National, Heart, Lung, and Blood Institute FX The authors have no potential conflicts of interest to disclose. The laboratory of ABS is supported by a grant from the National Institute of Health (R01AG050797), a grant from the American Federation of Aging Research, a grant from the American Heart Association (15BGIA23220016) and the Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System. Body composition was measured through the San Antonio Nathan Shock Center Healthspan and Functional Assessment core facility (P30AG013319). Statistical analysis of lifespan was performed by the Discovery Bioinformatics Core of the Oklahoma Nathan Shock Center (P30AG050911). The work of KM, CL, and RLL was supported by the Intramural Research Program of the National, Heart, Lung, and Blood Institute. This material is the result of work supported with resources and the use of facilities at South Texas Veterans Health Care System, San Antonio, Texas. The contents do not necessarily represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 30 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD DEC PY 2016 VL 10 BP 251 EP 256 DI 10.1016/j.redox.2016.10.012 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF8SD UT WOS:000390598800026 PM 27821326 ER PT J AU Proctor, LM AF Proctor, Lita M. TI The National Institutes of Health Human Microbiome Project SO SEMINARS IN FETAL & NEONATAL MEDICINE LA English DT Review DE Microbiome; DNA sequence; Metagenomics; Metabolomics; Metatranscriptomics; Resources ID DIVERSITY; GUT; PERIODONTITIS; BACTERIA AB This overview describes the impetus for and the goals of the National Institutes of Health (NIH)'s Human Microbiome Project (HMP) and the research resources available through the HMI? As the HMP also serves as a catalyst for human microbiome research at the NIH, NIH Institutes and Centers support for this field is also briefly addressed. Published by Elsevier Ltd. C1 [Proctor, Lita M.] NHGRI, Human Microbiome Project, NIH, 5635 Fisher Lane,Suite 4076, Bethesda, MD 20852 USA. RP Proctor, LM (reprint author), NHGRI, Human Microbiome Project, NIH, 5635 Fisher Lane,Suite 4076, Bethesda, MD 20852 USA. EM lita.proctor@nih.gov NR 25 TC 3 Z9 3 U1 10 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1744-165X EI 1878-0946 J9 SEMIN FETAL NEONAT M JI Semin. Fetal Neonatal Med. PD DEC PY 2016 VL 21 IS 6 BP 368 EP 372 DI 10.1016/j.siny.2016.05.002 PG 5 WC Pediatrics SC Pediatrics GA EF7LA UT WOS:000390509900002 PM 27350143 ER PT J AU Burks, S Nagle, M Kim, S Milo, B Frank, J AF Burks, S. Nagle, M. Kim, S. Milo, B. Frank, J. TI Pulsed Focused Ultrasound Preconditions Tissues To Increase Potency Of Intravenously-infused Mesenchymal Stem Cells SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Burks, S.; Nagle, M.; Kim, S.; Milo, B.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 355 BP S93 EP S93 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200350 ER PT J AU Burks, SR Nagle, ME Kim, S Milo, B Frank, J AF Burks, S. R. Nagle, M. E. Kim, S. Milo, B. Frank, J. TI Low Intensity Ultrasound Prolongs Lifetimes Of Transplanted Mesenchymal Stem Cells In Situ SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Burks, S. R.; Nagle, M. E.; Kim, S.; Milo, B.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 356 BP S93 EP S94 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200351 ER PT J AU Burks, SR Nagle, ME Kim, S Milo, B Frank, J AF Burks, S. R. Nagle, M. E. Kim, S. Milo, B. Frank, J. TI Pulsed Focused Ultrasound Mechanically Activates Trpc1 Channels To Enhance Local Stem Cell Homing SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Burks, S. R.; Nagle, M. E.; Kim, S.; Milo, B.; Frank, J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 279 BP S74 EP S74 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200275 ER PT J AU Frank, JA Burks, SR Kim, S AF Frank, J. A. Burks, S. R. Kim, S. TI Restoring Perfusion In Critical Hindlimb Ischemia Model Using Pulsed Focused Ultrasound And Mesenchymal Stromal Cells (MSC) In An Aged Mouse Model SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Frank, J. A.; Burks, S. R.; Kim, S.] NIH, Frank Lab, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 98 BP S27 EP S27 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200097 ER PT J AU Kim, SJ Lin, Y Milo, B Burks, S Nagel, M Frank, JA AF Kim, S. J. Lin, Y. Milo, B. Burks, S. Nagel, M. Frank, J. A. TI Investigating Cellular Response of Mesenchymal Stromal Cells to Therapeutic Ultrasound in 3D Scaffold SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Kim, S. J.; Milo, B.; Burks, S.; Nagel, M.; Frank, J. A.] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Lin, Y.] Georgetown Univ, Radiol & Imaging Sci, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 572 BP S149 EP S149 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200558 ER PT J AU West, KA Eder, AF AF West, Kamille A. Eder, Anne F. TI Accepting hereditary hemochromatosis blood donors: ask not why, ask why not SO TRANSFUSION LA English DT Editorial Material ID DONATION C1 [West, Kamille A.; Eder, Anne F.] NIH, Dept Transfus Med, Blood Serv Sect, Ctr Clin, Bethesda, MD 20892 USA. RP West, KA (reprint author), NIH, Dept Transfus Med, Blood Serv Sect, Ctr Clin, Bethesda, MD 20892 USA. EM kamille.west@nih.gov NR 9 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 DEC PY 2016 VL 56 IS 12 BP 2907 EP 2909 DI 10.1111/trf.13919 PG 3 WC Hematology SC Hematology GA EF8KS UT WOS:000390578300001 PM 27933629 ER PT J AU Srivastava, K Lee, E Owens, E Rujirojindakul, P Flegel, WA AF Srivastava, Kshitij Lee, Eunah Owens, Eric Rujirojindakul, Pairaya Flegel, Willy A. TI Full-length nucleotide sequence of ERMAP alleles encoding Scianna (SC) antigens SO TRANSFUSION LA English DT Article ID BLOOD-GROUP SYSTEM; AFRICAN-AMERICANS; GENETIC-VARIATION; ANTIBODY; PROTEIN; HAPLOTYPES; PHENOTYPES AB BACKGROUNDScianna (SC) blood group system comprises two antithetical antigens, Sc1 and Sc2, and five additional antigens. The antigens reside on a glycoprotein encoded by the erythroblast membrane-associated protein (ERMAP) gene. For the common ERMAP alleles, we determined the full-length nucleotide sequence that encodes the Scianna glycoprotein. STUDY DESIGN AND METHODSBlood donor samples from five populations were analyzed including 20 African Americans, 10 Caucasians, 10 Thai, five Asians, and five Hispanics for a total of 100 chromosomes. An assay was devised to determine the genomic sequence of the ERMAP gene in one amplicon, spanning 21.4 kb and covering Exons 2 to 12 and the intervening sequence (IVS). All alleles (confirmed haplotypes) were resolved without ambiguity. RESULTSAmong 50 blood donors, we found 80 single-nucleotide polymorphisms (SNPs), including six novel SNPs, in 21,308 nucleotides covering the coding sequence of the ERMAP gene and including the introns. The noncoding sequences harbored 75 SNPs (68 in the introns and seven in the 3-UTR). No SNP indicative of a nonfunctional allele was detected. The nucleotide sequences for 48 ERMAP alleles (confirmed haplotypes) were determined by allele-specific polymerase chain reaction and sequencing in 100 chromosomes. CONCLUSIONSWe documented 48 ERMAP alleles of 21,308 nucleotides each. The two nucleotide sequences available in GenBank for ERMAP alleles of similar length have not been found in our 100 chromosomes. Alleles determined without ambiguity can be used as templates to analyze next generation sequencing data, which will enhance the reliability in clinical diagnostics. C1 [Srivastava, Kshitij; Lee, Eunah; Owens, Eric; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Rujirojindakul, Pairaya] Prince Songkla Univ, Dept Pathol, Fac Med, Hat Yai, Thailand. RP Flegel, WA (reprint author), NIH, Lab Serv Sect, Dept Transfus Med, NIH Clin Ctr, Bethesda, MD 20892 USA. EM waf@nih.gov FU NIH Clinical Center [Z99 CL999999] FX This work was supported by the Intramural Research Program (project ID Z99 CL999999) of the NIH Clinical Center. NR 28 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 DEC PY 2016 VL 56 IS 12 BP 3047 EP 3054 DI 10.1111/trf.13801 PG 8 WC Hematology SC Hematology GA EF8KS UT WOS:000390578300022 PM 27612015 ER PT J AU Strengers, PFW Klein, HG AF Strengers, Paul F. W. Klein, Harvey G. TI Plasma is a strategic resource SO TRANSFUSION LA English DT Editorial Material ID FACTOR-VIII; BLOOD AB Plasma-derived medicinal products (PDMPs) such as immunoglobulins and clotting factors are listed by the World Health Organization as essential medicines. These and other PDMPs are crucial for the prophylaxis and treatment of patients with bleeding disorders, immune deficiencies, autoimmune and inflammatory diseases, and a variety of congenital deficiency disorders. While changes in clinical practice in developed countries have reduced the need for red blood cell transfusions thereby significantly reducing the collection volumes of whole blood and recovered plasma suitable for fractionation, the need for PDMPs worldwide continues to increase. The majority of plasma supplies for the manufacture of PDMPs is met by the US commercial plasma industry. However, geographic imbalance in the collection of plasma raises concerns that local disruptions of plasma supplies could result in regional and global shortages of essential PDMPs. Plasma, which fits the definition of a strategic resource, that is, an economically important raw material which is subject to a higher risk of supply interruption, should be considered a strategic resource comparable to energy and drinking water. Plasma collections should be increased outside the United States, including in low- and middle-income countries. The need for capacity building in these countries is an essential part to strengthen quality plasma collection. This will require changes in national and regional policies. We advocate the need for the restoration of an equitable balance of the international plasma supply to reduce the risk of supply shortages worldwide. Strategic independence of plasma should be endorsed on a global level. C1 [Strengers, Paul F. W.] Sanquin Plasma Prod, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands. [Strengers, Paul F. W.] Int Plasma Fractionat Assoc, Amsterdam, Netherlands. [Klein, Harvey G.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Strengers, PFW (reprint author), Sanquin Plasma Prod, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands. EM p.strengers@sanquin.nl NR 24 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 56 IS 12 BP 3133 EP 3137 DI 10.1111/trf.13913 PG 5 WC Hematology SC Hematology GA EF8KS UT WOS:000390578300032 PM 27861951 ER PT J AU Yao, PJ Petralia, RS Mattson, MP AF Yao, Pamela J. Petralia, Ronald S. Mattson, Mark P. TI Sonic Hedgehog Signaling and Hippocampal Neuroplasticity SO TRENDS IN NEUROSCIENCES LA English DT Review ID NEURAL STEM-CELLS; DOWN-SYNDROME; ALZHEIMERS-DISEASE; DENTATE GYRUS; UP-REGULATION; SYNAPTIC PLASTICITY; NEUROTROPHIC FACTOR; CEREBRAL-ISCHEMIA; BRAIN PLASTICITY; MEMORY DEFICITS AB Sonic hedgehog (Shh) is a secreted protein that controls the patterning of neural progenitor cells, and their neuronal and glial progeny, during development. Emerging findings suggest that Shh also has important roles in the formation and plasticity of neuronal circuits in the hippocampus, a brain region of fundamental importance in learning and memory. Shh mediates activity-dependent and injury-induced hippocampal neurogenesis. Activation of Shh receptors in the dendrites of hippocampal neurons engages a trans-neuronal signaling pathway that accelerates axon outgrowth and enhances glutamate release from presynaptic terminals. Impaired Shh signaling may contribute to the pathogenesis of several developmental and adult-onset neurological disorders that affect the hippocampus, suggesting a potential for therapeutic interventions that target Shh pathways. C1 [Yao, Pamela J.; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Yao, PJ; Mattson, MP (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA.; Mattson, MP (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. EM yaopa@grc.nia.nih.gov; mark.mattson@nih.gov FU National Institutes of Health/National Institute on Aging; National Institutes of Health/National Institute on Deafness and Other Communication Disorders FX This work was supported by the Intramural Research Programs of the National Institutes of Health/National Institute on Aging and the National Institutes of Health/National Institute on Deafness and Other Communication Disorders. The code for the Advanced Imaging Core is ZIC DC000081. We thank Kristen Alexander for help with the preparation of illustrations. NR 80 TC 2 Z9 2 U1 9 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD DEC PY 2016 VL 39 IS 12 BP 840 EP 850 DI 10.1016/j.tins.2016.10.001 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EF9DW UT WOS:000390631900005 PM 27865563 ER PT J AU Bonhoeffer, J Kochhar, S Hirschfeld, S Heath, PT Jones, CE Bauwens, J Honrado, A Heininger, U Munoz, FM Eckert, L Steinhoff, M Black, S Padula, M Sturkenboom, M Buttery, J Pless, R Zuber, P AF Bonhoeffer, Jan Kochhar, Sonali Hirschfeld, Steven Heath, Paul T. Jones, Christine E. Bauwens, Jorgen Honrado, Angel Heininger, Ulrich Munoz, Flor M. Eckert, Linda Steinhoff, Mark Black, Steven Padula, Michael Sturkenboom, Miriam Buttery, Jim Pless, Robert Zuber, Patrick CA GAIA Project Participants TI Global alignment of immunization safety assessment in pregnancy - The GAIA project SO VACCINE LA English DT Article ID EVENTS FOLLOWING IMMUNIZATION; VACCINES AB Immunization in pregnancy provides a promising contribution to globally reducing neonatal and under five childhood mortality and morbidity. Thorough assessment of benefits and risks for the primarily healthy pregnant women and their unborn babies is required. The GAIA project was formed in response to the call of the World Health Organization for a globally concerted approach to actively monitor the safety of vaccines and immunization in pregnancy programs. GAIA aims to improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMIC. In the first year of the project, a large and functional network of experts was created. The first outputs include a guidance document for clinical trials of immunization in pregnancy, a basic data collection guide, ten case definitions of key obstetric and neonatal health outcomes, an ontology of key terms and a map of pertinent disease codes. The GAIA Network is designed as an open and growing forum for professionals sharing the GAIA vision and aim. Based on the initial achievements, tools and services are developed to support investigators and strengthen immunization in pregnancy programs with specific focus on LMIC. (C) 2016 Published by Elsevier Ltd. C1 [Bonhoeffer, Jan; Bauwens, Jorgen] Brighton Collaborat Fdn, Spitalstr 33, CH-4056 Basel, Switzerland. [Bonhoeffer, Jan; Heininger, Ulrich] Univ Basel, Childrens Hosp, Basel, Switzerland. [Kochhar, Sonali] Global Healthcare Consulting, Delhi, India. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Heath, Paul T.; Jones, Christine E.] St Georges Univ London, London, England. [Honrado, Angel] Synapse Res Management Partners, Barcelona, Spain. [Munoz, Flor M.] Baylor Coll Med, Houston, TX 77030 USA. [Eckert, Linda] Univ Washington, Seattle, WA 98195 USA. [Steinhoff, Mark; Black, Steven] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Padula, Michael] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Sturkenboom, Miriam] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Buttery, Jim] Monash Univ, Melbourne, Vic, Australia. [Pless, Robert] Publ Hlth Agcy Canada, Ottawa, ON, Canada. [Zuber, Patrick] WHO, Geneva, Switzerland. RP Bonhoeffer, J (reprint author), Brighton Collaborat Fdn, Spitalstr 33, CH-4056 Basel, Switzerland. EM contact@brightoncollaboration.org FU Bill & Melinda Gates Foundation [OPP1119788] FX The GAIA project is supported by the Bill & Melinda Gates Foundation, Grant Number OPP1119788. The authors are grateful for the extraordinary effort by the many volunteering professional colleagues in the various working groups and the many additional participants providing excellent contributions, peer review or in person consultations. An updated list of GAIA Network partners and participants is available at: http://gaia-consortium.net. NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 1 PY 2016 VL 34 IS 49 SI SI BP 5993 EP 5997 DI 10.1016/j.vaccine.2016.07.006 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7MP UT WOS:000390514000002 PM 27751641 ER PT J AU Jones, CE Munoz, FM Spiegel, HML Heininger, U Zuber, PLF Edwards, KM Lambach, P Neels, P Kohl, KS Gidudu, J Hirschfeld, S Oleske, JM Khuri-Bulos, N Bauwens, J Eckert, LO Kochhar, S Bonhoeffer, J Heath, PT AF Jones, Christine E. Munoz, Flor M. Spiegel, Hans M. L. Heininger, Ulrich Zuber, Patrick L. F. Edwards, Kathryn M. Lambach, Philipp Neels, Pieter Kohl, Katrin S. Gidudu, Jane Hirschfeld, Steven Oleske, James M. Khuri-Bulos, Najwa Bauwens, Jorgen Eckert, Linda O. Kochhar, Sonali Bonhoeffer, Jan Heath, Paul T. CA Brighton Collaboration Immunizatio TI Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women SO VACCINE LA English DT Article DE Adverse event; Immunization; Pregnancy; Guidelines; Clinical trials; Vaccines; Safety ID INFLUENZA VACCINATION; STATEMENT; INFANTS; QUALITY; RECOMMENDATIONS; EPIDEMIOLOGY; PREVENTION; PROTOCOL AB Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries. (C) 2016 Published by Elsevier Ltd. C1 [Jones, Christine E.; Heath, Paul T.] St Georges Univ London, Inst Infect & Immun, Paediat Infect Dis Res Grp, Jenner Wing,Level 2,Room 2-213, London SW17 0RE, England. [Munoz, Flor M.] Baylor Coll Med, Houston, TX 77030 USA. [Spiegel, Hans M. L.] Henry Jackson Fdn, Bethesda, MD USA. [Heininger, Ulrich; Bonhoeffer, Jan] Univ Basel, Childrens Hosp, Basel, Switzerland. [Zuber, Patrick L. F.] WHO, SAV, Regulat Med & Other Hlth Technol RHT, Dept Essential Med & Hlth Prod EMP,Hlth Syst & In, Geneva, Switzerland. [Edwards, Kathryn M.] Vanderbilt Univ, Dept Pediat, Vanderbilt Vaccine Res Program, Nashville, TN USA. [Lambach, Philipp] WHO, Initiat Vaccine Res, Geneva, Switzerland. [Neels, Pieter] IABS EU, Int Alliance Biol Standardizat, Lyon, France. [Kohl, Katrin S.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Gidudu, Jane] CDC, Global Immunizat Div, Ctr Global Hlth, Atlanta, GA 30333 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Oleske, James M.] Rutgers New Jersey Med Sch, Div Pediat Allergy Immunol & Infect Dis, Newark, NJ USA. [Khuri-Bulos, Najwa] Univ Jordan, Infect Dis & Vaccine Ctr, Amman, Jordan. [Bauwens, Jorgen] Brighton Collaborat Fdn, Basel, Switzerland. [Eckert, Linda O.] Univ Washington, Seattle, WA 98195 USA. [Kochhar, Sonali] Global Healthcare Consulting, Delhi, India. RP Heath, PT (reprint author), St Georges Univ London, Inst Infect & Immun, Paediat Infect Dis Res Grp, Jenner Wing,Level 2,Room 2-213, London SW17 0RE, England. EM contact@brightoncollaboration.org FU Bill & Melinda Gates Foundation [OPP1119788] FX This work has been supported by the Bill & Melinda Gates Foundation Grant OPP1119788, Global Alignment of Immunization Safety Assessment in pregnancy (GAIA). NR 54 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 1 PY 2016 VL 34 IS 49 SI SI BP 5998 EP 6006 DI 10.1016/j.vaccine.2016.07.032 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7MP UT WOS:000390514000003 PM 27481360 ER PT J AU Simonsick, EM Meier, HCS Shaffer, NC Studenski, SA Ferrucci, L AF Simonsick, Eleanor M. Meier, Helen C. S. Shaffer, Nancy Chiles Studenski, Stephanie A. Ferrucci, Luigi TI Basal body temperature as a biomarker of healthy aging SO AGE LA English DT Article DE Aging; Body temperature; Functional performance; Excessive adiposity ID DISTANCE CORRIDOR WALK; INTACT OLDER-ADULTS; ALL-CAUSE MORTALITY; CALORIE RESTRICTION; METABOLIC-RATE; CORE TEMPERATURE; MUSCLE STRENGTH; GAIT SPEED; LONGEVITY; AGE AB Scattered evidence indicates that a lower basal body temperature may be associated with prolonged health span, yet few studies have directly evaluated this relationship. We examined cross-sectional and longitudinal associations between early morning oral temperature (95.0-98.6 A degrees F) and usual gait speed, endurance walk performance, fatigability, and grip strength in 762 non-frail men (52 %) and women aged 65-89 years participating in the Baltimore Longitudinal Study of Aging. Since excessive adiposity (body mass index ae35 kg/m(2) or waist-to-height ratio ae0.62) may alter temperature set point, associations were also examined within adiposity strata. Overall, controlling for age, race, sex, height, exercise, and adiposity, lower temperature was associated with faster gait speed, less time to walk 400 m quickly, and lower perceived exertion following 5-min of walking at 0.67 m/s (all p ae 0.02). In the non-adipose (N = 662), these associations were more robust (all p ae 0.006). Direction of association was reversed in the adipose (N = 100), but none attained significance (all p > 0.22). Over 2.2 years, basal temperature was not associated with functional change in the overall population or non-adipose. Among the adipose, lower baseline temperature was associated with greater decline in endurance walking performance (p = 0.006). In longitudinal analyses predicting future functional performance, low temperature in the non-adipose was associated with faster gait speed (p = 0.021) and less time to walk 400 m quickly (p = 0.003), whereas in the adipose, lower temperature was associated with slower gait speed (p = 0.05) and more time to walk 400 m (p = 0.008). In older adults, lower basal body temperature appears to be associated with healthy aging in the absence of excessive adiposity. C1 [Simonsick, Eleanor M.; Shaffer, Nancy Chiles; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Intramural Res Program, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. [Meier, Helen C. S.] Univ Wisconsin Madison, Joseph J Zilber Sch Publ Hlth, Wilwaukee, WI USA. RP Simonsick, EM (reprint author), NIA, Intramural Res Program, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM simonsickel@mail.nih.gov FU Intramural Research Program, National Institute on Aging, and National Institutes of Health; Intramural Research Program of the National Institute on Aging FX Funded by the Intramural Research Program, National Institute on Aging, and National Institutes of Health. The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the National Institute on Aging. NR 40 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD DEC PY 2016 VL 38 IS 5-6 BP 445 EP 454 DI 10.1007/s11357-016-9952-8 PG 10 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EF1CK UT WOS:000390062500007 PM 27785691 ER PT J AU Lamb, RJ Ginsburg, BC Schindler, CW AF Lamb, R. J. Ginsburg, Brett C. Schindler, Charles W. TI Effects of an ethanol-paired CS on responding for ethanol and food: Comparisons with a stimulus in a Truly-Random-Control group and to a food-paired CS on responding for food SO ALCOHOL LA English DT Article DE Pavlovian conditioning; Pavlovian-Instrumental-Transfer; Ethanol self-administration; Rat; Truly-Random-Control; Associative learning; Addiction; Alcoholism; Craving ID PAVLOVIAN-INSTRUMENTAL-TRANSFER; DRUG-SEEKING BEHAVIOR; CONDITIONED APPROACH; INCENTIVE SALIENCE; SIGN-TRACKING; COCAINE; RATS; ADDICTION; ALCOHOL; CUES AB Motivational increases due to exposure to alcohol-paired Conditioned Stimuli (CS) are central to some accounts of alcoholism. However, few studies isolate a stimulus's function as a CS from its other potential functions. Pavlovian-Instrumental-Transfer (PIT) procedures isolate a stimulus's function as a CS from its other functions. Though there are several relevant studies using PIT, knowledge gaps exist. Particularly, it is not clear that an alcohol-paired CS will increase alcohol seeking compared to the same stimulus in a Truly-Random-Control group, nor whether such increases are specific to alcohol seeking. To address these knowledge gaps in Experiment 1, rats responded for ethanol (0.1 ml 8% w/v) under an RI 30-sec schedule, then the lever was removed and half the rats had ethanol delivered during occasional 120 sec light presentations, while the remainder had ethanol and the light presented under independent RT schedules. Later the lever was returned and the light was presented during responding in extinction (PIT test). Following this test, levers were again removed and the light was presented without ethanol (light extinction), following again by a PIT test. Responding in the two groups during light presentations did not differ in either PIT test. Experiment 2 repeated Experiment 1 using food instead of ethanol. In Experiment 2, responding during light presentations increased in the paired group. In Experiment 3, rats were trained on a concurrent FR schedule of food and ethanol delivery. Ethanol was delivered following 5 responses and the response requirement for food adjusted so that similar numbers of food and ethanol deliveries were obtained. Subsequently, rats underwent conditioning, control and testing procedures identical to those in Experiment 1. In Experiment 3, the ethanol-paired CS increased ethanol-responding, but not food-responding. These results are most easily interpreted as changes in responding resulting from CS-elicited behavior rather than motivational changes. This interpretation is more compatible with some descriptions of the role of an alcohol-paired CS in alcoholism than others. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lamb, R. J.; Ginsburg, Brett C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Lamb, R. J.; Ginsburg, Brett C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Schindler, Charles W.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Lamb, RJ (reprint author), UTHSCSA, Psychiat, MC 7792,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM lamb@uthscsa.edu FU NIH [AA12337]; NIH/NIDA Intramural Research Program FX This work was supported by NIH grant AA12337. CWS was supported by the NIH/NIDA Intramural Research Program. The excellent technical assistance of Jonathan Chemello was instrumental in the accomplishment of this work. NR 32 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 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD DEC PY 2016 VL 57 BP 15 EP 27 DI 10.1016/j.alcohol.2016.10.009 PG 13 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA EF4KP UT WOS:000390294500003 PM 27916139 ER PT J AU Resnik, DB AF Resnik, David B. TI Moral Distress in Scientific Research SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID WHISTLEBLOWER C1 [Resnik, David B.] NIH, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), NIEHS, NIH, Mail Drop CU 03,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported by the Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or the U.S. government. I am grateful to Andrew Jameton for useful comments and for encouraging me to write about moral distress in scientific research. NR 10 TC 1 Z9 1 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD DEC PY 2016 VL 16 IS 12 BP 13 EP 15 DI 10.1080/15265161.2016.1239784 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EF1WN UT WOS:000390115900012 PM 27901443 ER PT J AU Campbell, SM Ulrich, CM Grady, C AF Campbell, Stephen M. Ulrich, Connie M. Grady, Christine TI Response to Open Peer Commentaries on "A Broader Understanding of Moral Distress" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 [Campbell, Stephen M.] Bentley Univ, Waltham, MA USA. [Ulrich, Connie M.] Univ Penn, Philadelphia, PA 19104 USA. [Grady, Christine] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Campbell, SM (reprint author), Bentley Univ, Dept Philosophy, 175 Forest St, Waltham, MA 02452 USA. EM scampbell@bentley.edu NR 14 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD DEC PY 2016 VL 16 IS 12 BP W1 EP W3 DI 10.1080/15265161.2016.1248579 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EF1WN UT WOS:000390115900001 ER PT J AU Keppler-Noreuil, KM Parker, VER Darling, TN Martinez-Agosto, JA AF Keppler-Noreuil, Kim M. Parker, Victoria E. R. Darling, Thomas N. Martinez-Agosto, Julian A. TI Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Review DE somatic mosaicism; segmental overgrowth; therapy; PI3K; AKT; mTOR pathway ID TUBEROUS SCLEROSIS COMPLEX; FOCAL CORTICAL DYSPLASIA; DEVELOPMENTAL BRAIN MALFORMATIONS; MAMMALIAN TARGET; MTOR INHIBITORS; ACTIVATING MUTATIONS; CONSENSUS CONFERENCE; PULMONARY-EMBOLISM; RAPAMYCIN PATHWAY; CLOVES SYNDROME AB The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. (c) 2016 Wiley Periodicals, Inc. C1 [Keppler-Noreuil, Kim M.] NHGRI, NIH, 49 Convent Dr 4A68, Bethesda, MD 20892 USA. [Keppler-Noreuil, Kim M.] Univ Iowa, Iowa City, IA 52242 USA. [Parker, Victoria E. R.] MedImmune Ltd, Gaithersburg, MD USA. [Parker, Victoria E. R.] Cambridge Univ Hosp NHS Trust, Cambridge, MA USA. [Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dermatol, Bethesda, MD 20814 USA. [Martinez-Agosto, Julian A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90024 USA. [Martinez-Agosto, Julian A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Med Genet, Dept Pediat, Los Angeles, CA 90024 USA. RP Keppler-Noreuil, KM (reprint author), NHGRI, NIH, 49 Convent Dr 4A68, Bethesda, MD 20892 USA. EM kim.keppler-noreuil@nih.gov OI Darling, Thomas/0000-0002-5161-1974 FU National Human Genome Research Institute; UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; March of Dimes Birth Defects Foundation [6-FY12-324]; NINDS [U54-NS092090]; NIH/NICHD [P50-HD-055784]; NIH/NCATS [UL1TR000124] FX The authors are grateful to the patients and their families who have participated in this research review. KKN is supported by intramural funding of the National Human Genome Research Institute. VERP is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. JAMA is supported by the March of Dimes Birth Defects Foundation (6-FY12-324), NINDS (U54-NS092090), NIH/NICHD (P50-HD-055784), and NIH/NCATS (UL1TR000124). NR 131 TC 1 Z9 1 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4868 EI 1552-4876 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD DEC PY 2016 VL 172 IS 4 BP 402 EP 421 DI 10.1002/ajmg.c.31531 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA EF5SO UT WOS:000390390100007 PM 27860216 ER PT J AU Gaur, L Hanna, A Bandettini, WP Fischbeck, KH Arai, AE Mankodi, A AF Gaur, Lasya Hanna, Alexander Bandettini, W. Patricia Fischbeck, Kenneth H. Arai, Andrew E. Mankodi, Ami TI Upper arm and cardiac magnetic resonance imaging in Duchenne muscular dystrophy SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID LATE-GADOLINIUM-ENHANCEMENT; VENTRICULAR SYSTOLIC FUNCTION; EXTRACELLULAR VOLUME; CARDIOMYOPATHY; MUSCLE; QUANTIFICATION; BOYS; MRI; FAT; T1 AB We analyzed quantitative maps of T-1 and T-2 relaxation times and muscle fat fraction measurements in magnetic resonance imaging of the upper arm skeletal muscles and heart in ambulatory boys with Duchenne muscular dystrophy and age-range-matched healthy volunteer boys. The cardiac-optimized sequences detected fatty infiltration and edema in the upper arm skeletal muscles but not the myocardium in these Duchenne muscular dystrophy boys who had normal ejection fraction. Imaging the heart and skeletal muscle using the same magnetic resonance imaging methods during a single scan may be useful in assessing relative disease status and therapeutic response in clinical trials of Duchenne muscular dystrophy. C1 [Gaur, Lasya; Hanna, Alexander; Bandettini, W. Patricia; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging, Bldg 10, Bethesda, MD 20892 USA. [Fischbeck, Kenneth H.; Mankodi, Ami] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA. [Gaur, Lasya] Johns Hopkins Univ Hosp, Pediat Cardiol, Baltimore, MD 21287 USA. RP Mankodi, A (reprint author), NINDS, Hereditary Muscle Dis Unit, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35,Room 2A-1002, Bethesda, MD 20892 USA. EM ami.mankodi@nih.gov FU National Institute of Neurological Disorders and Stroke FX This work was supported by National Institute of Neurological Disorders and Stroke. 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 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD DEC PY 2016 VL 3 IS 12 BP 948 EP 955 DI 10.1002/acn3.367 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EF8GH UT WOS:000390566700006 PM 28097207 ER PT J AU Scuteri, A Franco, OH Volzke, H Shin, MH Kweon, SS Rietzschel, E Ryliskyte, L Strazhesko, I Chen, CH Lakatta, EG Nilsson, PM AF Scuteri, Angelo Franco, Oscar H. Volzke, Henry Shin, Min-Ho Kweon, Sun-Seog Rietzschel, Ernst Ryliskyte, Ligita Strazhesko, Irina Chen, Chen-Huan Lakatta, Edward G. Nilsson, Peter M. CA Metabolic Syndrome Arteries Res TI The relationship between the metabolic syndrome and arterial wall thickness: A mosaic still to be interpreted SO ATHEROSCLEROSIS LA English DT Article DE Arteries; Arterial ageing; Carotid intima-media thickness; Metabolic syndrome ID INTIMA-MEDIA THICKNESS; MYOCARDIAL-INFARCTION; CAROTID-ARTERY; BLOOD-PRESSURE; RISK-FACTOR; STIFFNESS; ULTRASOUND; STATEMENT; STROKE; WOMEN AB Background and aims: We aimed to identify clusters of metabolic syndrome (MetS) components, risky for extremely high intima-media thickness. Methods: We studied 41,513 volunteers (men and women) from eleven cohorts worldwide, participating in the MARE (Metabolic syndrome and Artery REsearch) Consortium. Results: Specific clusters of MetS components - high triglycerides-high blood pressure-abdominal obesity (TBW), low HDL cholesterol-high blood pressure-abdominal obesity (HBW), high glucose-high blood pressure-abdominal obesity (GBW) - were accompanied by a 50-90% significantly greater likelihood of presenting extremely high intima-media thickness (via ultrasound of carotid artery, CCA IMT), after controlling for age, sex, smoking, non-HDL cholesterol, and presence of diabetes mellitus. This likelihood is comparable to the effect of being 7-8 years older or of being a cigarette smoker or of having non-HDL cholesterol 50 mg/dl higher. Conclusions: The consistent association of specific clusters of MetS components with extremely thick (older) large artery cross-culturally suggests that identification of those clusters in clinical practice will facilitate a personalized health care and a better - i.e. more healthy and cost-effective - prevention of major cardiovascular (CV) events. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Scuteri, Angelo] Policlin Tor Vergata, UOC Hypertens & Nephrol, Dept Med, Rome, Italy. [Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Shin, Min-Ho; Kweon, Sun-Seog] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Gwangju, South Korea. [Rietzschel, Ernst] Ghent Univ Hosp, Dept Cardiovasc Dis, Ghent, Belgium. [Rietzschel, Ernst] Univ Ghent, Ghent, Belgium. [Ryliskyte, Ligita] Vilnius Univ Hosp Santariskiu Klin, Ctr Cardiol & Angiol, Vilnius, Lithuania. [Strazhesko, Irina] Natl Res Ctr Prevent Med, Dept Aging & Age Associated Dis Prevent, Moscow, Russia. [Chen, Chen-Huan] Natl Yang Ming Univ, Cardiovasc Res Ctr, Dept Publ Hlth, Taipei, Taiwan. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Programme, NIH, Baltimore, MD 21224 USA. [Nilsson, Peter M.] Lund Univ, Univ Hosp, Dept Clin Sci, Malmo, Sweden. RP Scuteri, A (reprint author), Policlin Tor Vergata, UOC Hypertens & Nephrol, Dept Med, Rome, Italy. EM angeloelefante@interfree.it FU Fund for Scientific Research - Flanders (FWO) [G042703, G083810N]; Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; NIA [NO1-AG-1-2109]; Intramural Research Program of the NIH, National Institute on Aging (USA); Federal Ministry of Education and Research; Federal State of Mecklenburg-West Pomerania; Research Institute of Medical Sciences, Chonnam National University; Intramural Research Program of the NIH, National Institute on Aging; National Science Council (NSC) [99-2314-B-010-034-MY3]; Taipei Veterans General Hospital [V102C-119]; Intramural Research Program of the National Institute on Aging, National Institutes of Health; Swedish Research Council [K2008-65X-20752-01-3, K2011-65X-20752-04-6]; Lundstroms Foundation; Swedish Heart-Lung Foundation [2010-0244, 2013-0249]; ALF government grants [2012/1789]; [NO1-AG-1-2118] FX The Asklepios Study is supported by the Fund for Scientific Research - Flanders (FWO research grants G042703 and G083810N).; The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam.; The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (USA). SHIP is part of the Community Medicine Network of the University Medicine Greifswald. The network was initially funded by the Federal Ministry of Education and Research as well as the Federal State of Mecklenburg-West Pomerania.; The Dong-gu Study and the Namwon Study were supported by Research Institute of Medical Sciences, Chonnam National University.; The Baltimore Longitudinal Study of Aging (BLSA) is supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; The Kingmen Aging study was supported, in part, by a grant from the National Science Council (NSC 99-2314-B-010-034-MY3), an intramural grant from the Taipei Veterans General Hospital (grant V102C-119), Research and Development contract NO1-AG-1-2118, and the Intramural Research Program of the National Institute on Aging, National Institutes of Health.; The Malmoe Diet Cancer - Cardiovascular Study was supported by grants from the Swedish Research Council (K2008-65X-20752-01-3, K2011-65X-20752-04-6), the Lundstroms Foundation, the Swedish Heart-Lung Foundation (2010-0244; 2013-0249) and ALF government grants (Dnr: 2012/1789). NR 22 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 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD DEC PY 2016 VL 255 BP 11 EP 16 DI 10.1016/j.atherosclerosis.2016.10.032 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EE3QL UT WOS:000389509700026 PM 27794213 ER PT J AU Forbang, NI McClelland, RL Remigio-Baker, RA Allison, MA Sandfort, V Michos, ED Thomas, I Rifkin, DE Criqui, MH AF Forbang, Nketi I. McClelland, Robyn L. Remigio-Baker, Rosemay A. Allison, Matthew A. Sandfort, Veit Michos, Erin D. Thomas, Isac Rifkin, Dena E. Criqui, Michael H. TI Associations of cardiovascular disease risk factors with abdominal aortic calcium volume and density: The Multi-Ethnic Study of Atherosclerosis (MESA) SO ATHEROSCLEROSIS LA English DT Article DE Abdominal aortic calcium; Agatston calcium score; Cardiovascular disease risk factors; Coronary artery calcium; Density calcium score; Volume calcium score ID CORONARY-ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; ETHNIC-DIFFERENCES; MORTALITY; CALCIFICATION; ANGIOGRAPHY; MORBIDITY; EVENTS AB Background and aims: Abdominal aortic calcium (AAC) predicts future cardiovascular disease (CVD) events and all-cause mortality independent of CVD risk factors. The standard AAC score, the Agatston, up-weights for greater calcium density, and thus models higher calcium density as associated with increased CVD risk. We determined associations of CVD risk factors with AAC volume and density (separately). Methods: In a multi-ethnic cohort of community living adults, we used abdominal computed tomography scans to measure AAC volume and density. Multivariable linear regression was used to determine the period cross-sectional independent associations of CVD risk factors with AAC volume and AAC density in participants with prevalent AAC. Results: Among 1413 participants with non-zero AAC scores, the mean age was 65 +/- 9 years, 52% were men, 44% were European-, 24% were Hispanic-, 18% were African-, and 14% were Chinese Americans (EA, HA, AA, and CA respectively). Median (interquartile range, IQR) for AAC volume was 628 mm(3) (157 -1939 mm(3)), and mean AAC density was 3.0 +/- 0.6. Compared to EA, each of HA, AA, and CA had lower natural log (ln) AAC volume, but higher AAC density. After adjustments for AAC density, older age, ever smoking history, higher systolic blood pressure, elevated total cholesterol, reduced HDL cholesterol, statin and anti-hypertensive medication use, family history of myocardial infarction, and alcohol consumption were significantly associated with higher ln(AAC volume). In contrast, after adjustments for ln(AAC volume), older age, ever smoking history, higher BMI, and lower HDL cholesterol were significantly associated with lower AAC density. Conclusions: Several CVD risk factors were associated with higher AAC volume, but lower AAC density. Future studies should investigate the impact of calcium density of aortic plaques in CVD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Forbang, Nketi I.; Remigio-Baker, Rosemay A.; Allison, Matthew A.; Thomas, Isac; Rifkin, Dena E.; Criqui, Michael H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Allison, Matthew A.; Rifkin, Dena E.] Vet Adm San Diego Healthcare Syst, La Jolla, CA USA. [Sandfort, Veit] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Michos, Erin D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Forbang, NI (reprint author), 9500 Gilman Dr, La Jolla, CA 92093 USA. EM nforbang@gmail.com OI Allison, Matthew/0000-0003-0777-8272; Michos, Erin/0000-0002-5547-5084 FU National Heart, Lung, and Blood Institute [HL072403, 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]; NCRR [UL1-TR-000040, UL1-TR-001079] FX This study was supported by grant HL072403 and 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 NCRR. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 12 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD DEC PY 2016 VL 255 BP 54 EP 58 DI 10.1016/j.atherosclerosis.2016.10.036 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EE3QL UT WOS:000389509700032 PM 27816809 ER PT J AU Slominski, AT Zmijewski, MA Jetten, AM AF Slominski, Andrzej T. Zmijewski, Michal A. Jetten, Anton M. TI ROR alpha is not a receptor for melatonin SO BIOESSAYS LA English DT Editorial Material C1 [Slominski, Andrzej T.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Slominski, Andrzej T.] Univ Alabama Birmingham, Ctr Comprehens Canc, Canc Chemoprevent Program, Birmingham, AL 35294 USA. [Slominski, Andrzej T.] VA Med Ctr, Birmingham, AL 35233 USA. [Zmijewski, Michal A.] Med Univ Gdansk, Dept Histol, Gdansk, Poland. [Jetten, Anton M.] NIEHS, Immun Inflammat & Dis Lab, NIH, Durham, NC USA. RP Slominski, AT (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA.; Slominski, AT (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Canc Chemoprevent Program, Birmingham, AL 35294 USA.; Slominski, AT (reprint author), VA Med Ctr, Birmingham, AL 35233 USA. EM aslominski@uabmc.edu FU NIAMS NIH HHS [R21 AR066505, R01 AR052190, R01 AR056666] NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD DEC PY 2016 VL 38 IS 12 BP 1193 EP 1194 DI 10.1002/bies.201600204 PG 2 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EF0AL UT WOS:000389987700005 PM 27739090 ER PT J AU Sawyer, IA Sturgill, D Sung, MH Hager, GL Dundr, M AF Sawyer, Iain A. Sturgill, David Sung, Myong-Hee Hager, Gordon L. Dundr, Miroslav TI Cajal body function in genome organization and transcriptome diversity SO BIOESSAYS LA English DT Article DE Cajal bodies; chromatin; genome organization; nuclear bodies; RNA splicing; snRNPs; transcription ID RNA-POLYMERASE-II; WIDESPREAD INTRON RETENTION; HUMAN SNRNA GENES; 3' END FORMATION; NUCLEAR-BODIES; COILED BODIES; MESSENGER-RNA; INTEGRATOR COMPLEX; NONCODING RNAS; HUMAN-CELLS AB Nuclear bodies contribute to non-random organization of the human genome and nuclear function. Using a major prototypical nuclear body, the Cajal body, as an example, we suggest that these structures assemble at specific gene loci located across the genome as a result of high transcriptional activity. Subsequently, target genes are physically clustered in close proximity in Cajal body-containing cells. However, Cajal bodies are observed in only a limited number of human cell types, including neuronal and cancer cells. Ultimately, Cajal body depletion perturbs splicing kinetics by reducing target small nuclear RNA (snRNA) transcription and limiting the levels of spliceosomal snRNPs, including their modification and turnover following each round of RNA splicing. As such, Cajal bodies are capable of shaping the chromatin interaction landscape and the transcriptome by influencing spliceosome kinetics. Future studies should concentrate on characterizing the direct influence of Cajal bodies upon snRNA gene transcriptional dynamics. C1 [Sawyer, Iain A.; Dundr, Miroslav] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA. [Sawyer, Iain A.; Sturgill, David; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Sung, Myong-Hee] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Dundr, M (reprint author), Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell Biol, N Chicago, IL 60064 USA.; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM hagerg@dce41.nci.nih.gov; mirek.dundr@rosalindfranklin.edu FU National Institutes of Health, National Institute of General Medical Sciences [R01GM090156]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institute on Aging FX The authors are supported by a National Institutes of Health, National Institute of General Medical Sciences grant (R01GM090156, awarded to M.D.), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (G.L.H.), and the National Institute on Aging (M-H.S.). We thank Dr. Eric Wagner and Dr. Karen Meaburn for stimulating conversations. The authors declare no competing financial interests. Super-resolution structured illumination microscopy (SIM) images were acquired at the NCI Core Fluorescence Imaging Facility in Building 41, National Institutes of Health(Bethesda, MD) with the assistance of Dr. Tatiana Karpova. NR 134 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD DEC PY 2016 VL 38 IS 12 BP 1197 EP 1208 DI 10.1002/bies.201600144 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA EF0AL UT WOS:000389987700007 PM 27767214 ER PT J AU Zhai, HC Yu, Y Zhang, W Chen, G Jia, FC AF Zhai, Hongchang Yu, Yuan Zhang, Wei Chen, Gang Jia, Fucang TI ACC and IPL networks in the perception of the faces of parents during selective tasks SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Face perception; Mother/father's face; Functional connectivity; fMRI; Brain network ID EVENT-RELATED FMRI; SUPERIOR TEMPORAL SULCUS; PERSONALLY FAMILIAR FACES; SELF-FACE; ROMANTIC LOVE; BRAIN RESPONSES; VISUAL-CORTEX; NEURAL BASIS; RECOGNITION; MOTHERS AB The perception of the faces of parents is different from that of other faces. Mother's face perception is associated with childbearing and parenting and has specific cognitive processing properties. Yet, the underlying mechanism remains unknown. We investigated the neural network that is involved in the perception of parent's face based upon parental face selective tasks that were completed by 23 normal adults. Resting state functional magnetic resonance imaging (fMRI) and a task block design with fixation cross sign control fMRI were used. The faces activated the right inferior frontal gyrus, the left and right middle frontal gyri, and the left and right inferior parietal lobule. In addition, the parental faces task resulted in more activation than the control tasks in the left and right anterior cingulate, left middle (superior) temporal gyrus, right and left inferior frontal gyrus. The anterior cingulate cortex (ACC) and the inferior parietal lobe (IPL) are central nodes of the brain network, while the parental face perception network includes the anterior cingulate cortex and superior temporal gyrus (ACC-STG)/parahippocampal network as well as the inferior frontal and inferior parietal lobule (IFG-IPL) network. The network of father's face perception involves the left inferior parietal lobule and left middle frontal gyrus/right middle frontal gyrus/right inferior frontal gyrus, while mother's face perception involves the right inferior parietal lobe and frontal network (MFG.L/IFG.R). The experiments showed that the ACC-STG/parahippocampal network and IFG-IPL network are neural networks used in parental face perception, and the ACC and IPL are central nodes in the network. The neural pathway of parental face perception is similar to the perception of a stranger's face, as both include the STG, but is different in that the perception of the stranger's face involves a connected STG and IPL as a specific neural pathway. C1 [Zhai, Hongchang; Yu, Yuan] Guangzhou Univ, Coll Educ, Higher Educ Mega Ctr, 230 Waihuan West Rd, Guangzhou 510006, Guangdong, Peoples R China. [Zhang, Wei] South China Normal Univ, Sch Psychol, Guangzhou 510631, Guangdong, Peoples R China. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Jia, Fucang] Chinese Acad Sci, Shenzhen Inst Adv Technol, 1068 Xueyuan Ave, Shenzhen 518055, Peoples R China. RP Zhai, HC (reprint author), Guangzhou Univ, Coll Educ, Higher Educ Mega Ctr, 230 Waihuan West Rd, Guangzhou 510006, Guangdong, Peoples R China.; Jia, FC (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, 1068 Xueyuan Ave, Shenzhen 518055, Peoples R China. EM zhaihongchang@126.com; fc.jia@siat.ac.cn FU NSFC-Guangdong Union Foundation [U1201257]; Shenzhen Basic Research Project [JCYJ20150630114942306] FX This study was supported by grants from the following sources: the NSFC-Guangdong Union Foundation (Grant No. U1201257) and the Shenzhen Basic Research Project (Grant No. JCYJ20150630114942306). NR 69 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 10 IS 4 BP 1172 EP 1183 DI 10.1007/s11682-015-9486-1 PG 12 WC Neuroimaging SC Neurosciences & Neurology GA EF0LC UT WOS:000390015900023 PM 26613720 ER PT J AU Shin, JM Lee, B Cho, KH AF Shin, Jae-Min Lee, Byungkook Cho, Kwang-Hwi TI A New Efficient Conformational Search Method for ab initio Protein Folding Study: Window Growth Evolutionary Algorithm SO BULLETIN OF THE KOREAN CHEMICAL SOCIETY LA English DT Article DE Protein folding; Window growth evolutionary algorithm; Window growth; Evolutionary algorithm ID GENETIC ALGORITHMS; SIMULATIONS; BACKBONE; ENERGY; MINIMIZATION; NUCLEATION; BUILDUP; PROGRAM; MODEL; CHAIN AB A new conformational search method, WGEA (window growth evolutionary algorithm), is described. In this method, a trial conformation is selected or rejected on the basis of the energy of a selected window of w consecutive residues only; interactions between residues beyond the selected window are ignored. The position of the window is selected randomly in a Monte-Carlo procedure. The window size w is changed slowly, from a minimum of 6 to the full length of the protein. An ensemble of structures is generated at each window size from which a fixed number of conformations are selected to be used as seed conformations for the next window size. When the root-mean-square (RMS) deviation from the experimental structure is used as the energy function and six discrete dihedral angle states are used for each residue to describe the protein conformation, WGEA efficiently refolds 14 model proteins within C RMS deviation of 1.2-2.8 angstrom. C1 [Shin, Jae-Min; Cho, Kwang-Hwi] Soongsil Univ, Sch Syst Biomed Sci, Seoul 156743, South Korea. [Lee, Byungkook] NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Cho, KH (reprint author), Soongsil Univ, Sch Syst Biomed Sci, Seoul 156743, South Korea. EM chokh@ssu.ac.kr FU KREONET (Korea Research Environment Open NETwork); National Research Foundation of Korea (NRF) - Ministry of Science, ICT Future [NRF-2012M3A9D1054705] FX This work was supported by KREONET (Korea Research Environment Open NETwork) which is managed and operated by KISTI (Korea Institute of Science and Technology Information) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science, ICT & Future (NRF-2012M3A9D1054705). NR 39 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0253-2964 EI 1229-5949 J9 B KOREAN CHEM SOC JI Bull. Korean Chem. Soc. PD DEC PY 2016 VL 37 IS 12 BP 1971 EP 1976 DI 10.1002/bkcs.11006 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA EF4BT UT WOS:000390270200014 ER PT J AU Lam, S Mandrekar, SJ Gesthalter, Y Ziegler, KLA Seisler, DK Midthun, DE Mao, JT Aubry, MC McWilliams, A Sin, DD Shaipanich, T Liu, G Johnson, E Bild, A Lenburg, ME Ionescu, DN Mayo, J Yi, J Tazelaar, H Harmsen, WS Smith, J Spira, AE Beane, J Limburg, PJ Szabo, E AF Lam, Stephen Mandrekar, Sumithra J. Gesthalter, Yaron Ziegler, Katie L. Allen Seisler, Drew K. Midthun, David E. Mao, Jenny T. Aubry, Marie Christine McWilliams, Annette Sin, Don D. Shaipanich, Tawimas Liu, Gang Johnson, Evan Bild, Andrea Lenburg, Marc E. Ionescu, Diana N. Mayo, John Yi, Joanne (Eunhee) Tazelaar, Henry Harmsen, William S. Smith, Judith Spira, Avrum E. Beane, Jennifer Limburg, Paul J. Szabo, Eva CA Canc Prevention Network TI A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia SO CANCER PREVENTION RESEARCH LA English DT Article ID PREVENT COLORECTAL ADENOMAS; FEMALE A/J MICE; LUNG-CANCER; FORMER SMOKERS; LESIONS; CHEMOPREVENTION; BRONCHOSCOPY; STATISTICS; ASPIRIN; GENOME AB Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with >= 1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myoinositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. C1 [Lam, Stephen; Shaipanich, Tawimas; Ionescu, Diana N.] British Columbia Canc Agcy, 10-111 675 West 10th Ave, Vancouver, BC V5Z 4E6, Canada. [Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Seisler, Drew K.; Midthun, David E.; Aubry, Marie Christine; Yi, Joanne (Eunhee); Harmsen, William S.; Limburg, Paul J.] Mayo Clin, Rochester, MN USA. [Gesthalter, Yaron; Liu, Gang; Johnson, Evan; Lenburg, Marc E.; Spira, Avrum E.; Beane, Jennifer] Boston Univ, Med Ctr, Boston, MA 02215 USA. [Mao, Jenny T.] New Mexico Vet Hlth Care Syst, Albuquerque, NM USA. [McWilliams, Annette] Fiona Stanley Hosp, Palmyra Dc, WA, Australia. [Sin, Don D.] St Pauls Hosp, Vancouver, BC, Canada. [Bild, Andrea] Univ Utah, Salt Lake City, UT USA. [Mayo, John] Vancouver Gen Hosp, Vancouver, BC, Canada. [Tazelaar, Henry] Mayo Clin, Scottsdale, AZ USA. [Smith, Judith] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Lam, S (reprint author), British Columbia Canc Agcy, 10-111 675 West 10th Ave, Vancouver, BC V5Z 4E6, Canada. EM slam2@bccancer.bc.ca FU National Cancer Institute [N01CN35000] FX The study was supported by a contract from the National Cancer Institute (N01CN35000). NR 36 TC 1 Z9 1 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 DEC PY 2016 VL 9 IS 12 BP 906 EP 914 DI 10.1158/1940-6207.CAPR-15-0254 PG 9 WC Oncology SC Oncology GA EF1NS UT WOS:000390092200003 PM 27658890 ER PT J AU McDermott, TJ Badura-Brack, AS Becker, KM Ryan, TJ Bar-Haim, Y Pine, DS Khanna, MM Heinrichs-Graham, E Wilson, TW AF McDermott, Timothy J. Badura-Brack, Amy S. Becker, Katherine M. Ryan, Tara J. Bar-Haim, Yair Pine, Daniel S. Khanna, Maya M. Heinrichs-Graham, Elizabeth Wilson, Tony W. TI Attention training improves aberrant neural dynamics during working memory processing in veterans with PTSD SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Working memory; Prefrontal cortex; Attention; Cognitive control ID POSTTRAUMATIC-STRESS-DISORDER; RESTING-STATE MAGNETOENCEPHALOGRAPHY; SPACE SEPARATION METHOD; TEST-RETEST RELIABILITY; BIAS MODIFICATION; OSCILLATORY DYNAMICS; ALPHA-ACTIVITY; MEG; MAINTENANCE; TASK AB Posttraumatic stress disorder (PTSD) is associated with executive functioning deficits, including disruptions in working memory (WM). Recent studies suggest that attention training reduces PTSD symptomatology, but the underlying neural mechanisms are unknown. We used high-density magnetoencephalography (MEG) to evaluate whether attention training modulates brain regions serving WM processing in PTSD. Fourteen veterans with PTSD completed a WM task during a 306-sensor MEG recording before and after 8 sessions of attention training treatment. A matched comparison sample of 12 combat-exposed veterans without PTSD completed the same WM task during a single MEG session. To identify the spatiotemporal dynamics, each group's data were transformed into the time-frequency domain, and significant oscillatory brain responses were imaged using a beamforming approach. All participants exhibited activity in left hemispheric language areas consistent with a verbal WM task. Additionally, veterans with PTSD and combat-exposed healthy controls each exhibited oscillatory responses in right hemispheric homologue regions (e.g., right Broca's area); however, these responses were in opposite directions. Group differences in oscillatory activity emerged in the theta band (4-8 Hz) during encoding and in the alpha band (9-12 Hz) during maintenance and were significant in right prefrontal and right supramarginal and inferior parietal regions. Importantly, following attention training, these significant group differences were reduced or eliminated. This study provides initial evidence that attention training improves aberrant neural activity in brain networks serving WM processing. C1 [McDermott, Timothy J.; Badura-Brack, Amy S.; Ryan, Tara J.; Khanna, Maya M.] Creighton Univ, Dept Psychol, 2500 Calif Plaza, Omaha, NE 68178 USA. [Becker, Katherine M.; Heinrichs-Graham, Elizabeth; Wilson, Tony W.] UNMC, Ctr Magnetoencephalog, Omaha, NE USA. [Becker, Katherine M.] Colorado State Univ, Dept Psychol, Ft Collins, CO 80523 USA. [Ryan, Tara J.] Simon Fraser Univ, Dept Psychol, Burnaby, BC, Canada. [Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, Tel Aviv, Israel. [Bar-Haim, Yair] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Heinrichs-Graham, Elizabeth; Wilson, Tony W.] UNMC, Dept Neurol Sci, Omaha, NE USA. RP Badura-Brack, AS (reprint author), Creighton Univ, Dept Psychol, 2500 Calif Plaza, Omaha, NE 68178 USA. EM abadura@creighton.edu OI Wilson, Tony W/0000-0002-5053-8306 FU At Ease, USA; Creighton University College of Arts and Science Summer Undergraduate Research Fellowship; National Institutes of Health [R01-MH103220]; National Science Foundation [1539067] FX This research was supported by a grant from the nonprofit organization At Ease, USA (ABB), by a Creighton University College of Arts and Science Summer Undergraduate Research Fellowship (TJM), and Grants R01-MH103220 from the National Institutes of Health (TWW) and #1539067 from the National Science Foundation (TWW). 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 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD DEC PY 2016 VL 16 IS 6 BP 1140 EP 1149 DI 10.3758/s13415-016-0459-7 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EF0MJ UT WOS:000390019200014 PM 27722837 ER PT J AU Rotimi, CN Tekola-Ayele, F Baker, JL Shriner, D AF Rotimi, Charles N. Tekola-Ayele, Fasil Baker, Jennifer L. Shriner, Daniel TI The African diaspora: history, adaptation and health SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID DUFFY-BLOOD-GROUP; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIV-ASSOCIATED NEPHROPATHY; LACTASE PERSISTENCE; PLASMODIUM-VIVAX; KIDNEY-DISEASE; ETHIOPIAN POPULATION; MALARIAL INFECTION; SEQUENCING DATA; APOL1 VARIANTS AB The trans-Atlantic slave trade brought millions of Africans to the New World. Advances in genomics are providing novel insights into the history and health of Africans and the diasporan populations. Recent examples reviewed here include the unraveling of substantial hunter-gatherer and 'Eurasian' admixtures across sub-Saharan Africa, expanding our understanding of ancestral African genetics; the global ubiquity of mixed ancestry; the revealing of African ancestry in Latin Americans that likely derived from the slave trade; and understanding of the ancestral backgrounds of APOL1 and LPL found to influence kidney disease and lipid levels, respectively, providing specific insights into disease etiology and health disparities. C1 [Rotimi, Charles N.; Tekola-Ayele, Fasil; Baker, Jennifer L.; Shriner, Daniel] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047 12 South Dr, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bldg 12A,Room 4047 12 South Dr, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Intramural Research Program of the National Institutes of Health (NIH) in the Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute (NHGRI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Center for Information Technology (CIT); Office of the Director at the NIH [1ZIAHG200362] FX The study was supported by the Intramural Research Program of the National Institutes of Health (NIH) in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology (CIT), and the Office of the Director at the NIH (1ZIAHG200362). NR 77 TC 0 Z9 0 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X EI 1879-0380 J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD DEC PY 2016 VL 41 BP 77 EP 84 DI 10.1016/j.gde.2016.08.005 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA EE8ZQ UT WOS:000389915800011 PM 27644073 ER PT J AU Leung, JM Olivier, KN AF Leung, Janice M. Olivier, Kenneth N. TI Bronchiectasis and connective tissue diseases SO CURRENT PULMONOLOGY REPORTS LA English DT Article DE Bronchiectasis; Connective tissue disease; Rheumatoid arthritis; Sjogren's syndrome; Marfan syndrome; Ehlers-Danlos syndrome ID RESOLUTION COMPUTED-TOMOGRAPHY; EHLERS-DANLOS-SYNDROME; EARLY RHEUMATOID-ARTHRITIS; PRIMARY SJOGRENS-SYNDROME; NONTUBERCULOUS MYCOBACTERIAL INFECTION; PULMONARY-FUNCTION TESTS; MARFAN-SYNDROME; LUNG-DISEASE; MATRIX METALLOPROTEINASES; SYSTEMIC-SCLEROSIS AB Connective tissue diseases (CTD) encompass a range of heritable and autoimmune conditions that are well known for their systemic effects. While these conditions have been observed to impact the lung in myriad fashion, bronchiectasis remains an often overlooked pulmonary complication, despite the fact that the prevalence of bronchiectasis can be as high as 60 % in patients with rheumatoid arthritis. In this review, we cover the epidemiology and clinical findings of bronchiectasis in autoimmune CTDs such as rheumatoid arthritis and Sjogren's syndrome and heritable CTDs such as Marfan syndrome and Ehlers-Danlos syndrome. We propose that changes in the oral, gut, and lung microbiome may influence autoimmunity and the structural integrity of the airway, thus leading to bronchiectasis. C1 [Leung, Janice M.] Univ British Columbia, Div Resp Med, Dept Med, St Pauls Hosp, Room 166,1088 Burrard St, Vancouver, BC V6Z 1Y6, Canada. [Leung, Janice M.] Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Room 166,1088 Burrard St, Vancouver, BC V6Z 1Y6, Canada. [Olivier, Kenneth N.] NHLBI, Pulm Clin Med Sect, NIH, 10 Ctr Dr,MSC 1454,Bldg 10-CRC,Room 6-3130, Bethesda, MD 20892 USA. RP Leung, JM (reprint author), Univ British Columbia, Div Resp Med, Dept Med, St Pauls Hosp, Room 166,1088 Burrard St, Vancouver, BC V6Z 1Y6, Canada.; Leung, JM (reprint author), Univ British Columbia, St Pauls Hosp, Ctr Heart Lung Innovat, Room 166,1088 Burrard St, Vancouver, BC V6Z 1Y6, Canada.; Olivier, KN (reprint author), NHLBI, Pulm Clin Med Sect, NIH, 10 Ctr Dr,MSC 1454,Bldg 10-CRC,Room 6-3130, Bethesda, MD 20892 USA. EM Janice.Leung@hli.ubc.ca; Kenneth.olivier@nih.gov FU Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. NR 107 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 2199-2428 J9 CURR PULMONOL REP JI Curr. Pulmonol. Rep. PD DEC PY 2016 VL 5 IS 4 BP 169 EP 176 DI 10.1007/s13665-016-0154-8 PG 8 WC Respiratory System SC Respiratory System GA EF7XT UT WOS:000390543400001 ER PT J AU Young-Hyman, D de Groot, M Hill-Briggs, F Gonzalez, JS Hood, K Peyrot, M AF Young-Hyman, Deborah de Groot, Mary Hill-Briggs, Felicia Gonzalez, Jeffrey S. Hood, Korey Peyrot, Mark TI Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association SO DIABETES CARE LA English DT Article ID SELF-MANAGEMENT BEHAVIORS; POOR GLYCEMIC CONTROL; BARIATRIC SURGERY; WEIGHT-LOSS; TREATMENT ADHERENCE; COLLABORATIVE CARE; METABOLIC-CONTROL; CLINICAL DEPRESSION; EATING-DISORDERS; RANDOMIZED-TRIAL C1 [Young-Hyman, Deborah] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. [de Groot, Mary] Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. [Hill-Briggs, Felicia] Johns Hopkins Sch Med, Baltimore, MD USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Bronx, NY USA. [Gonzalez, Jeffrey S.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hood, Korey] Stanford Univ, Stanford, CA 94305 USA. [Peyrot, Mark] Loyola Univ Maryland, Baltimore, MD USA. RP Young-Hyman, D (reprint author), NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. EM younghyd@od.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [R18-DK-092765]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [R01-DK-104845, R18-DK-098742, P30-DK-111022] FX M.d.G. was funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases (R18-DK-092765). J.S.G. is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01-DK-104845, R18-DK-098742, and P30-DK-111022). NR 132 TC 7 Z9 7 U1 17 U2 17 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 DEC PY 2016 VL 39 IS 12 BP 2126 EP 2140 DI 10.2337/dc16-2053 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG1IF UT WOS:000390785000017 PM 27879358 ER PT J AU Dreger, DL Rimbault, M Davis, BW Bhatnagar, A Parker, HG Ostrander, EA AF Dreger, Dayna L. Rimbault, Maud Davis, Brian W. Bhatnagar, Adrienne Parker, Heidi G. Ostrander, Elaine A. TI Whole-genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic-trait mapping SO DISEASE MODELS & MECHANISMS LA English DT Article DE Population; Homozygosity; Canine; Inbreeding ID LINKAGE MAP; REVEALS ADAPTATION; CANIS-FAMILIARIS; SELECTIVE SWEEPS; WIDE SNP; ASSOCIATION; HUMANS; LOCUS; TOOL; DISEQUILIBRIUM AB In the decade following publication of the draft genome sequence of the domestic dog, extraordinary advances with application to several fields have been credited to the canine genetic system. Taking advantage of closed breeding populations and the subsequent selection for aesthetic and behavioral characteristics, researchers have leveraged the dog as an effective natural model for the study of complex traits, such as disease susceptibility, behavior and morphology, generating unique contributions to human health and biology. When designing genetic studies using purebred dogs, it is essential to consider the unique demography of each population, including estimation of effective population size and timing of population bottlenecks. The analytical design approach for genome-wide association studies (GWAS) and analysis of whole-genome sequence (WGS) experiments are inextricable from demographic data. We have performed a comprehensive study of genomic homozygosity, using high-depth WGS data for 90 individuals, and Illumina HD SNP data from 800 individuals representing 80 breeds. These datawere coupled with extensive pedigree data analyses for 11 breeds that, together, allowed us to compute breed structure, demography, and molecular measures of genome diversity. Our comparative analyses characterize the extent, formation and implication of breed-specific diversity as it relates to population structure. These data demonstrate the relationship between breedspecific genome dynamics and population architecture, and provide important considerations influencing the technological and cohort design of association and other genomic studies. C1 [Dreger, Dayna L.; Rimbault, Maud; Davis, Brian W.; Bhatnagar, Adrienne; Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. [Rimbault, Maud] Inst Genet & Dev Rennes, F-35043 Rennes, France. [Bhatnagar, Adrienne] PIC North Amer, Hendersonville, TN 37075 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural Program of the National Human Genome Research Institute FX This work was funded by the Intramural Program of the National Human Genome Research Institute. NR 61 TC 0 Z9 0 U1 37 U2 37 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD DEC 1 PY 2016 VL 9 IS 12 BP 1445 EP 1460 DI 10.1242/dmm.027037 PG 16 WC Cell Biology; Pathology SC Cell Biology; Pathology GA EF5LS UT WOS:000390372300003 PM 27874836 ER PT J AU Nakano, M Yahiro, K Yamasaki, E Kurazono, H Akada, J Yamaoka, Y Niidome, T Hatakeyama, M Suzuki, H Yamamoto, T Moss, J Isomoto, H Hirayama, T AF Nakano, Masayuki Yahiro, Kinnosuke Yamasaki, Eiki Kurazono, Hisao Akada, Junko Yamaoka, Yoshio Niidome, Takuro Hatakeyama, Masanori Suzuki, Hidekazu Yamamoto, Taro Moss, Joel Isomoto, Hajime Hirayama, Toshiya TI Helicobacter pylori VacA, acting through receptor protein tyrosine phosphatase alpha, is crucial for CagA phosphorylation in human duodenum carcinoma cell line AZ-521 SO DISEASE MODELS & MECHANISMS LA English DT Article DE Helicobacter pylori; VacA; CagA ID GASTRIC EPITHELIAL-CELLS; SRC-FAMILY KINASES; VACUOLATING CYTOTOXIN; PTP-ALPHA; C-SRC; BIOLOGICAL-ACTIVITY; IV SECRETION; RPTP-ALPHA; IN-VITRO; ACTIVATION AB Helicobacter pylori, a major cause of gastroduodenal diseases, produces vacuolating cytotoxin (VacA) and cytotoxin-associated gene A (CagA), which seem to be involved in virulence. VacA exhibits pleiotropic actions in gastroduodenal disorders via its specific receptors. Recently, we found that VacA induced the phosphorylation of cellular Src kinase (Src) at Tyr418 in AZ-521 cells. Silencing of receptor protein tyrosine phosphatase (RPTP)alpha, a VacA receptor, reduced VacA-induced Src phosphorylation. Src is responsible for tyrosine phosphorylation of CagA at its Glu-Pro-Ile-Tyr-Ala (EPIYA) variant C (EPIYA-C) motif in Helicobacter pylori-infected gastric epithelial cells, resulting in binding of CagA to SHP-2 phosphatase. Challenging AZ-521 cells with wild-type H. pylori induced phosphorylation of CagA, but this did not occur when challenged with a vacA gene-disrupted mutant strain. CagA phosphorylation was observed in cells infected with a vacA gene-disrupted mutant strain after addition of purified VacA, suggesting that VacA is required for H. pylori-induced CagA phosphorylation. Following siRNA-mediated RPTP alpha knockdown in AZ-521 cells, infection with wild-type H. pylori and treatment with VacA did not induce CagA phosphorylation. Taken together, these results support our conclusion that VacA mediates CagA phosphorylation through RPTP alpha in AZ-521 cells. These data indicate the possibility that Src phosphorylation induced by VacA is mediated through RPTP alpha, resulting in activation of Src, leading to CagA phosphorylation at Tyr972 in AZ-521 cells. C1 [Nakano, Masayuki; Hirayama, Toshiya] Nagasaki Univ, Inst Trop Med, Dept Bacteriol, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. [Nakano, Masayuki; Yamamoto, Taro] Nagasaki Univ, Inst Trop Med, Dept Int Hlth, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. [Yahiro, Kinnosuke] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. [Yamasaki, Eiki; Kurazono, Hisao] Obihiro Univ Agr & Vet Med, Div Food Hyg, Dept Anim & Food Hyg, Nishi 2-11,Inada Cho, Obihiro, Hokkaido 0808555, Japan. [Akada, Junko; Yamaoka, Yoshio] Oita Univ, Fac Med, Dept Environm & Prevent Med, Idaigaoka 1-1, Oita 8795593, Japan. [Yamaoka, Yoshio] Baylor Coll Med, Dept Med, Gastroenterol & Hepatol Sect, Houston, TX 77030 USA. [Niidome, Takuro] Kumamoto Univ, Grad Sch Sci & Technol, Dept Appl Chem & Biochem, Chuo Ku, 2-39-1 Kurokami, Kumamoto 8608555, Japan. [Hatakeyama, Masanori] Univ Tokyo, Grad Sch Med, Div Microbiol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. [Suzuki, Hidekazu] Keio Univ, Sch Med, Med Educ Ctr, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Isomoto, Hajime] Tottori Univ, Fac Med, Div Med & Clin Sci, 86 Nishi Cho, Yonago, Tottori 6838503, Japan. RP Nakano, M (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, 1-12-4 Sakamoto, Nagasaki 8528523, Japan.; Nakano, M (reprint author), Nagasaki Univ, Inst Trop Med, Dept Int Hlth, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. EM manakano@nagasaki-u.ac.jp RI Suzuki, Hidekazu/J-4396-2013 FU Takeda Science Foundation; Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [JP16K08778]; Cooperative Research Grant of Institute of Tropical Medicine, Nagasaki University (NEKKEN); Improvement of Research Environment for Young Researchers from the Japan Science and Technology Agency; Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute FX This work was supported by Takeda Science Foundation and by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP16K08778 (to M.N.); by the Cooperative Research Grant of Institute of Tropical Medicine, Nagasaki University (NEKKEN) (to K.Y. and T.H.); by Improvement of Research Environment for Young Researchers from the Japan Science and Technology Agency (to K.Y.); by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute (to J.M.). NR 56 TC 0 Z9 0 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD DEC 1 PY 2016 VL 9 IS 12 BP 1473 EP 1481 DI 10.1242/dmm.025361 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA EF5LS UT WOS:000390372300005 PM 27935824 ER PT J AU Zhang, J Wang, P Li, JY Mendola, P Sherman, S Ying, Q AF Zhang, Jie Wang, Peng Li, Jingyi Mendola, Pauline Sherman, Seth Ying, Qi TI Estimating population exposure to ambient polycyclic aromatic hydrocarbon in the United States - Part II: Source apportionment and cancer risk assessment SO ENVIRONMENT INTERNATIONAL LA English DT Review DE Cancer risk assessment; United States; Polycyclic aromatic hydrocarbon; Source apportionment; Benzo[alpha]pyrene ID SOURCE IDENTIFICATION; RADIOCARBON ANALYSIS; DIAGNOSTIC RATIOS; URBAN-ENVIRONMENT; EMISSION SOURCES; PAHS; AIR; ATMOSPHERE; MODEL; AEROSOLS AB A revised Community Multiscale Air Quality (CMAQ) model was developed to simulate the emission, reactions, transport, deposition and gas-to-particle partitioning processes of 16 priority polycyclic aromatic hydrocarbons (PAHs), as described in Part I of the two-part series. The updated CMAQ model was applied in this study to quantify the contributions of different emission sources to the predicted PAH concentrations and excess cancer risk in the United States (US) in 2011. The cancer risk in the continental US due to inhalation exposure of outdoor naphthalene (NAPH) and seven larger carcinogenic PAHs (cPAHs) was predicted to be significant. The incremental lifetime cancer risk (ILCR) exceeds 1 x 10(-5) in many urban and industrial areas. Exposure to PAHs was estimated to result in 5704 (608-10,800) excess lifetime cancer cases. Point sources not related with energy generation and the oil and gas processes account for approximately 31% of the excess cancer cases, followed by non-road engines with 18.6% contributions. Contributions of residential wood combustion (16.2%) are similar to that of transportation- related sources (mostly motor vehicles with small contributions from railway and marine vessels; 13.4%). The oil and gas industry emissions, although large contributors to high concentrations of cPAHs regionally, are only responsible of 4.3% of the excess cancer cases, which is similar to the contributions of non-US sources (6.8%) and non-point sources (7.2%). The power generation units pose the most minimal impact on excess cancer risk, with contributions of approximately 2.3%. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zhang, Jie; Wang, Peng; Li, Jingyi; Ying, Qi] Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX 77845 USA. [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Sherman, Seth] Emmes Corp, Rockville, MD 20850 USA. [Li, Jingyi] Princeton Univ, Atmospher & Ocean Sci Program, Princeton, NJ 08544 USA. RP Ying, Q (reprint author), Texas A&M Univ, Zachary Dept Civil Engn, College Stn, TX 77845 USA. EM qying@civil.tamu.edu FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through the Air Quality and Reproductive Health [HHSN275200800002I, HHSN27500008] FX The project was partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through the Air Quality and Reproductive Health study supported through Contract No. HHSN275200800002I, Task Order No. HHSN27500008 awarded to The EMMES Corporation. The authors have no conflicts of interests to disclose. The authors want to acknowledge the Texas A&M Supercomputing Facility (http://sc.tamu.edu) and the Texas Advanced Computing Center (http://www.tacc.utexas.edu/) for providing computing resources essential for completing the research reported in this paper. NR 53 TC 1 Z9 1 U1 17 U2 17 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 DEC PY 2016 VL 97 BP 163 EP 170 DI 10.1016/j.envint.2016.08.024 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA EE8YP UT WOS:000389912900019 PM 27613001 ER PT J AU Taylor, KW Joubert, BR Braun, JM Dilworth, C Gennings, C Hauser, R Heindel, JJ Rider, CV Webster, TF Carlin, DJ AF Taylor, Kyla W. Joubert, Bonnie R. Braun, Joe M. Dilworth, Caroline Gennings, Chris Hauser, Russ Heindel, Jerry J. Rider, Cynthia V. Webster, Thomas F. Carlin, Danielle J. TI Statistical Approaches for Assessing Health Effects of Environmental Chemical Mixtures in Epidemiology: Lessons from an Innovative Workshop SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID EXPOSURE AB Quantifying the impact of exposure to environmental chemical mixtures is important for identifying risk factors for diseases and developing more targeted public health interventions. The National Institute of Environmental Health Sciences (NIEHS) held a workshop in July 2015 to address the need to develop novel statistical approaches for multi-pollutant epidemiology studies. The primary objective of the workshop was to identify and compare different statistical approaches and methods for analyzing complex chemical mixtures data in both simulated and real-world data sets. At the workshop, participants compared approaches and results and speculated as to why they may have differed. Several themes emerged: a) no one statistical approach appeared to outperform the others, b) many methods included some form of variable reduction or summation of the data before statistical analysis, c) the statistical approach should be selected based upon a specific hypothesis or scientific question, and d) related mixtures data should be shared among researchers to more comprehensively and accurately address methodological questions and statistical approaches. Future efforts should continue to design and optimize statistical approaches to address questions about chemical mixtures in epidemiological studies. C1 [Taylor, Kyla W.; Joubert, Bonnie R.; Dilworth, Caroline; Heindel, Jerry J.; Rider, Cynthia V.; Carlin, Danielle J.] NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Braun, Joe M.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Gennings, Chris] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Webster, Thomas F.] Boston Univ, Dept Environm Hlth, Sch Publ Hlth, Boston, MA USA. RP Taylor, KW (reprint author), NIEHS, POB 12233,MD K2-04, Res Triangle Pk, NC 27709 USA. EM kyla.taylor@niehs.nih.gov RI Braun, Joseph/H-8649-2014 FU NIEHS [R00 ES020346, R01 ES024381] FX This work was supported by the following NIEHS grants: R00 ES020346 and R01 ES024381. NR 15 TC 0 Z9 0 U1 7 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2016 VL 124 IS 12 BP A227 EP A229 DI 10.1289/EHP547 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EF3FX UT WOS:000390211200004 PM 27905274 ER PT J AU Erer, B Takeuchi, M Ustek, D Tugal-Tutkun, I Seyahi, E Ozyazgan, Y Duymaz-Tozkir, J Gul, A Kastner, DL Remmers, EF Ombrello, MJ AF Erer, B. Takeuchi, M. Ustek, D. Tugal-Tutkun, I. Seyahi, E. Ozyazgan, Y. Duymaz-Tozkir, J. Gul, A. Kastner, D. L. Remmers, E. F. Ombrello, M. J. TI Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behcet's disease SO GENES AND IMMUNITY LA English DT Article ID GENOME-WIDE ASSOCIATION; MHC CLASS-I; HLA CLASS-I; ANKYLOSING-SPONDYLITIS; SUSCEPTIBILITY LOCI; KIR GENES; RECEPTOR; HLA-B-ASTERISK-51; IL23R-IL12RB2; RECOGNITION AB The Behcet's disease (BD)-associated human leukocyte antigen (HLA) allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells-KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity. We tested whether KIR-regulated mechanisms contribute to BD by testing for association of KIR3DL1/KIR3DS1 genotypes with disease in 1799 BD patients and 1710 healthy controls from Turkey, as well as in different subsets of individuals with HLA-type-defined ligands for the KIR3D receptors. HLA types were imputed from single nucleotide polymorphism genotypes determined with the Immunochip. The presence of inhibitory KIR3DL1 or activating KIR3DS1 alleles did not differ significantly between cases and controls (KIR3DL1: 92.9% vs 93.4%, P-dominant = 0.55; KIR3DS1: 42.7% vs 41.0%, Pdominant = 0.29). The KIR3DL1/KIR3DS1 alleles were also present at similar frequencies among cases and controls bearing HLA-B with a Bw4 motif; HLA-B with a Bw4 motif with isoleucine at position 80; and HLA-B*51. Our results suggest that pathogenic mechanisms associated with HLA-B*51 do not primarily involve differential interactions with KIR3DL1 and KIR3DS1 receptors. However, due to the complexity of this locus (that is, sequence variation and copy number variation), we cannot exclude a role for other types of KIR variation in the pathogenesis of BD. C1 [Erer, B.; Ombrello, M. J.] NIAMSD, Translat Genet & Genom Unit, 10 Ctr Dr,10C101,MSC 1560, Bethesda, MD 20892 USA. [Erer, B.; Tugal-Tutkun, I.; Gul, A.] Istanbul Univ, Div Rheumatol, Dept Internal Med, Istanbul Fac Med, Istanbul, Turkey. [Takeuchi, M.; Kastner, D. L.; Remmers, E. F.] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Ustek, D.] Istanbul Univ, Inst Expt Med, Dept Genet, Istanbul, Turkey. [Seyahi, E.] Istanbul Univ, Cerrahpasa Fac Med, Div Rheumatol, Dept Internal Med, Istanbul, Turkey. [Ozyazgan, Y.] Istanbul Univ, Cerrahpasa Fac Med, Dept Ophthalmol, Istanbul, Turkey. [Duymaz-Tozkir, J.] Istanbul Univ, Inst Hlth Sci, Dept Immunol, Istanbul, Turkey. RP Erer, B; Ombrello, MJ (reprint author), NIAMSD, Translat Genet & Genom Unit, 10 Ctr Dr,10C101,MSC 1560, Bethesda, MD 20892 USA. EM burakerer@yahoo.com; ombrellomj@mail.nih.gov FU National Institute of Arthritis and Muscuoskeletal and Skin Diseases of the National Institutes of Health [Z01-AR041198]; National Human Genome Research Institute of the National Institutes of Health [Z01-HG200370] FX This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Muscuoskeletal and Skin Diseases (Z01-AR041198) and the National Human Genome Research Institute (Z01-HG200370) of the National Institutes of Health. NR 34 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 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD DEC PY 2016 VL 17 IS 7 BP 396 EP 399 DI 10.1038/gene.2016.36 PG 4 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA EF6EN UT WOS:000390424000004 PM 27708262 ER PT J AU Tian, YY Yang, Y Zhang, XW Nakajima, T Tanaka, N Sugiyama, E Kamijo, Y Lu, Y Moriya, K Koike, K Gonzalez, FJ Aoyama, T AF Tian, Yangyang Yang, Yang Zhang, Xiaowei Nakajima, Takero Tanaka, Naoki Sugiyama, Eiko Kamijo, Yuji Lu, Yu Moriya, Kyoji Koike, Kazuhiko Gonzalez, Frank J. Aoyama, Toshifumi TI Age-dependent PPAR alpha activation induces hepatic sulfatide accumulation in transgenic mice carrying the hepatitis C virus core gene SO GLYCOCONJUGATE JOURNAL LA English DT Article DE Cancer; Core protein; HCV; PPAR alpha; Sphingolipid; Sulfatide ID HEPATOCELLULAR-CARCINOMA CELLS; RECEPTOR-ALPHA; SERINE PALMITOYLTRANSFERASE; CEREBROSIDE SULFOTRANSFERASE; MASS-SPECTROMETRY; CANCER-CELLS; METABOLISM; PROTEIN; EXPRESSION; SULFOGLYCOLIPIDS AB Sulfatides, a type of glycosphingolipid, are associated with carcinogenesis. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is involved in the regulation of sulfatide metabolism as well as in cancer development. We previously reported that transgenic (Tg) mice expressing hepatitis C virus core protein (HCVcp) exhibited age-dependent PPAR alpha activation and carcinogenesis in liver. However, the metabolism of sulfatides in hepatocellular carcinoma is unknown. To examine the relationship between sulfatide metabolism, carcinogenesis, HCVcp, and PPAR alpha, age-dependent changes of these factors were examined in HCVcpTg, PPAR alpha inhibitor-treated HCVcpTg, and non-Tg mice. The sulfatide content in liver, the hepatic expression of two key enzymes catalyzing the initial and last reactions in sulfatide synthesis, the hepatic expression of known sulfatide-transferring protein, oxidative stress, and hepatic PPAR alpha expression and its activation were age-dependently increased in HCVcpTg mice. The increased synthesis and accumulation of sulfatides and PPAR alpha activation were significantly enhanced in liver cancer lesions. These changes were attenuated by PPAR alpha inhibitor treatment and not observed in non-Tg mice. These results suggest that HCVcp-induced age-dependent PPAR alpha activation increases synthesis of sulfatides and the resulting sulfatide accumulation affects HCV-related liver cancer. The monitoring of hepatic sulfatide content and the modulation of sulfatide generation by intervention using a PPAR alpha inhibitor might be useful for the prediction and prevention of HCV-related hepatocarcinogenesis, respectively. C1 [Tian, Yangyang; Yang, Yang; Nakajima, Takero; Tanaka, Naoki; Lu, Yu; Aoyama, Toshifumi] Shinshu Univ, Dept Metab Regulat, Grad Sch Med, Matsumoto, Nagano 3908621, Japan. [Zhang, Xiaowei] HebeiMed Univ, Hosp 2, Dept Neurosurg, Shijiazhuang 050000, Hebei, Peoples R China. [Sugiyama, Eiko] Prefectural Coll, Dept Nutr Sci, Nagano 3808525, Japan. [Kamijo, Yuji] Shinshu Univ, Dept Nephrol, Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. [Moriya, Kyoji] Univ Tokyo, Grad Sch Med, Dept Infect Control & Prevent, Tokyo 1130033, Japan. [Koike, Kazuhiko] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1130033, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kamijo, Y (reprint author), Shinshu Univ, Dept Nephrol, Sch Med, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. EM yujibeat@shinshu-u.ac.jp NR 40 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 EI 1573-4986 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD DEC PY 2016 VL 33 IS 6 BP 927 EP 936 DI 10.1007/s10719-016-9703-1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF0GJ UT WOS:000390003600008 PM 27318478 ER PT J AU Eraso, JM Olsen, RJ Beres, SB Kachroo, P Porter, AR Nasser, W Bernard, PE DeLeo, FR Musser, JM AF Eraso, Jesus M. Olsen, Randall J. Beres, Stephen B. Kachroo, Priyanka Porter, Adeline R. Nasser, Waleed Bernard, Paul E. DeLeo, Frank R. Musser, James M. TI Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis SO INFECTION AND IMMUNITY LA English DT Article ID CROSS-REACTIVE ANTIGEN; ILLUMINA SEQUENCE DATA; TRANSCRIPTIONAL REGULATION; STAPHYLOCOCCUS-AUREUS; NECROTIZING FASCIITIS; CELL-WALL; LIPID-II; VIRULENCE; PYOGENES; BIOSYNTHESIS AB To obtain new information about Streptococcus pyogenes intrahost genetic variation during invasive infection, we sequenced the genomes of 2,954 serotype M1 strains recovered from a nonhuman primate experimental model of necrotizing fasciitis. A total of 644 strains (21.8%) acquired polymorphisms relative to the input parental strain. The fabT gene, encoding a transcriptional regulator of fatty acid biosynthesis genes, contained 54.5% of these changes. The great majority of polymorphisms were predicted to deleteriously alter FabT function. Transcriptome-sequencing (RNA-seq) analysis of a wild-type strain and an isogenic fabT deletion mutant strain found that between 3.7 and 28.5% of the S. pyogenes transcripts were differentially expressed, depending on the growth temperature (35 degrees C or 40 degrees C) and growth phase (mid-exponential or stationary phase). Genes implicated in fatty acid synthesis and lipid metabolism were significantly upregulated in the fabT deletion mutant strain. FabT also directly or indirectly regulated central carbon metabolism genes, including pyruvate hub enzymes and fermentation pathways and virulence genes. Deletion of fabT decreased virulence in a nonhuman primate model of necrotizing fasciitis. In addition, the fabT deletion strain had significantly decreased survival in human whole blood and during phagocytic interaction with polymorphonuclear leukocytes ex vivo. We conclude that FabT mutant progeny arise during infection, constitute a metabolically distinct subpopulation, and are less virulent in the experimental models used here. C1 [Eraso, Jesus M.; Olsen, Randall J.; Beres, Stephen B.; Kachroo, Priyanka; Nasser, Waleed; Bernard, Paul E.; Musser, James M.] Houston Methodist Res Inst, Dept Pathol & Genom Med, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA. [Eraso, Jesus M.; Olsen, Randall J.; Beres, Stephen B.; Kachroo, Priyanka; Nasser, Waleed; Bernard, Paul E.; Musser, James M.] Houston Methodist Hosp, Houston, TX 77030 USA. [Olsen, Randall J.; Musser, James M.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Porter, Adeline R.; DeLeo, Frank R.] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Bernard, Paul E.] Texas A&M Hlth Sci Ctr, Bryan, TX USA. RP Musser, JM (reprint author), Houston Methodist Res Inst, Dept Pathol & Genom Med, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA.; Musser, JM (reprint author), Houston Methodist Hosp, Houston, TX 77030 USA.; Musser, JM (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. EM jmmusser@houstonmethodist.org OI Kachroo, Priyanka/0000-0002-3563-7832 FU Fondren Foundation; Intramural Research Program of the NIAID, NIH FX The research was supported in part by the Fondren Foundation and the Intramural Research Program of the NIAID, NIH. The funders had no role in study design, data collection and interpretation, or decision to submit the work for publication. NR 68 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2016 VL 84 IS 12 BP 3268 EP 3281 DI 10.1128/IAI.00608-16 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EF2BG UT WOS:000390128700002 PM 27600505 ER PT J AU Break, TJ Witter, AR Indramohan, M Mummert, ME Dory, L Berg, RE AF Break, Timothy J. Witter, Alexandra R. Indramohan, Mohanalaxmi Mummert, Mark E. Dory, Ladislav Berg, Rance E. TI Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver SO INFECTION AND IMMUNITY LA English DT Article ID HEPARIN-BINDING DOMAIN; LISTERIA-MONOCYTOGENES; LUNG INJURY; MYELOPEROXIDASE DEFICIENCY; OXIDATIVE FRAGMENTATION; BACTERIAL-INFECTION; GENE POLYMORPHISM; EC-SOD; INFLAMMATION; MICE AB Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes. The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes. Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage. C1 [Break, Timothy J.; Witter, Alexandra R.; Indramohan, Mohanalaxmi; Mummert, Mark E.; Berg, Rance E.] Univ North Texas, Hlth Sci Ctr, Dept Cell Biol & Immunol, Ft Worth, TX 76107 USA. [Mummert, Mark E.] Univ North Texas, Hlth Sci Ctr, Mental Sci Inst, Ft Worth, TX USA. [Dory, Ladislav] Univ North Texas, Hlth Sci Ctr, Inst Cardiovasc & Metab Dis, Ft Worth, TX USA. [Break, Timothy J.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Indramohan, Mohanalaxmi] Northwestern Univ, Dept Med, Div Rheumatol, Chicago, IL 60611 USA. RP Berg, RE (reprint author), Univ North Texas, Hlth Sci Ctr, Dept Cell Biol & Immunol, Ft Worth, TX 76107 USA. EM Rance.Berg@unthsc.edu FU NIH/NIAID [AI109630]; BioLegend grant; UNTHSC; AAI Careers in Immunology fellowship; Sigma Xi FX This work was supported by a grant from NIH/NIAID (AI109630) to R.E.B., a BioLegend grant to R.E.B. and T.J.B., Intramural seed grants from UNTHSC to R.E.B. and T.J.B., a Sigma Xi Grant-In-Aid of Research grant to T.J.B., and an AAI Careers in Immunology fellowship to R.E.B. and A.R.W. NR 56 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2016 VL 84 IS 12 BP 3302 EP 3312 DI 10.1128/IAI.00603-16 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EF2BG UT WOS:000390128700005 PM 27600509 ER PT J AU Wrande, M Andrews-Polymenis, H Twedt, DJ Steele-Mortimer, O Porwollik, S McClelland, M Knodler, LA AF Wrande, Marie Andrews-Polymenis, Helene Twedt, Donna J. Steele-Mortimer, Olivia Porwollik, Steffen McClelland, Michael Knodler, Leigh A. TI Genetic Determinants of Salmonella enterica Serovar Typhimurium Proliferation in the Cytosol of Epithelial Cells SO INFECTION AND IMMUNITY LA English DT Article ID III SECRETION SYSTEM; HORIZONTALLY ACQUIRED GENES; FRANCISELLA-TULARENSIS; ESCHERICHIA-COLI; EXPRESSION; VIRULENCE; IDENTIFICATION; MACROPHAGES; INFECTION; AUTOPHAGY AB Intestinal epithelial cells provide an important colonization niche for Salmonella enterica serovar Typhimurium during gastrointestinal infections. In infected epithelial cells, a subpopulation of S. Typhimurium bacteria damage their internalization vacuole, leading to escape from the Salmonella-containing vacuole (SCV) and extensive proliferation in the cytosol. Little is known about the bacterial determinants of nascent SCV lysis and subsequent survival and replication of Salmonella in the cytosol. To pinpoint S. Typhimurium virulence factors responsible for these steps in the intracellular infectious cycle, we screened a S. Typhimurium multigene deletion library in Caco-2 C2Bbe1 and HeLa epithelial cells for mutants that had an altered proportion of cytosolic bacteria compared to the wild type. We used a gentamicin protection assay in combination with a chloroquine resistance assay to quantify total and cytosolic bacteria, respectively, for each strain. Mutants of three S. Typhimurium genes, STM1461 (ydgT), STM2829 (recA), and STM3952 (corA), had reduced cytosolic proliferation compared to wild-type bacteria, and one gene, STM2120 (asmA), displayed increased cytosolic replication. None of the mutants were affected for lysis of the nascent SCV or vacuolar replication in epithelial cells, indicating that these genes are specifically required for survival and proliferation of S. Typhimurium in the epithelial cell cytosol. These are the first genes identified to contribute to this step of the S. Typhimurium infectious cycle. C1 [Wrande, Marie; Twedt, Donna J.; Knodler, Leigh A.] Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. [Andrews-Polymenis, Helene] Texas A&M Univ, Dept Microbial Pathogenesis & Immunol, Coll Med, Bryan, TX USA. [Steele-Mortimer, Olivia] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Porwollik, Steffen; McClelland, Michael] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Wrande, Marie] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. RP Knodler, LA (reprint author), Washington State Univ, Coll Vet Med, Paul G Allen Sch Global Anim Hlth, Pullman, WA 99164 USA. EM lknodler@vetmed.wsu.edu FU CDMRP [W81XWH-08-1-0720]; USDA [2010-65201-20692, 2011-67017-30127, 2014-67017-21707]; Centre for Produce Safety, Binational Agricultural Research and Development Fund; North American Meat Institute; NIAID/NIH [R56 AI077645, R01 AI083646, R21 AI083964, R01 AI052237, R01 075093, R01 AI034829, 1ZIAAI000909]; Paul G. Allen School for Global Animal Health and Stanley L. Adler Research Fund; Swedish Research Council Formas; Wenner-Gren Foundation FX This work, including the efforts of Michael McClelland and Steffen Porwollik, was funded by CDMRP (W81XWH-08-1-0720), USDA (2010-65201-20692, 2011-67017-30127, and 2014-67017-21707), Centre for Produce Safety, Binational Agricultural Research and Development Fund, and North American Meat Institute. This work, including the efforts of Helene Andrews-Polymenis, was funded by NIAID/NIH (R56 AI077645, R01 AI083646, R21 AI083964, R01 AI052237, R01 075093, and R01 AI034829). This work, including the efforts of Leigh A. Knodler, was funded by Paul G. Allen School for Global Animal Health and Stanley L. Adler Research Fund. This work, including the efforts of Marie Wrande, was funded by Swedish Research Council Formas and Wenner-Gren Foundation. This work, including the efforts of Olivia Steele-Mortimer, was funded by NIAID/NIH (1ZIAAI000909). NR 52 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2016 VL 84 IS 12 BP 3517 EP 3526 DI 10.1128/IAI.00734-16 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EF2BG UT WOS:000390128700024 PM 27698022 ER PT J AU Goldstein, DS AF Goldstein, David S. TI Cardiac Dysautonomia and Survival in Hereditary Transthyretin Amyloidosis SO JACC-CARDIOVASCULAR IMAGING LA English DT Editorial Material DE amyloidosis; dysautonomia; metaiodobenzylguanidine; sympathetic nervous system ID HEART-RATE-VARIABILITY; LIVER-TRANSPLANTATION; POLYNEUROPATHY; DISEASE; NERVE; ACETYLCHOLINESTERASE; DENERVATION; TRANSPORT; VAGUS C1 [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, 10 Ctr Dr,MSC 1620,Bldg 10 Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov NR 31 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 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD DEC PY 2016 VL 9 IS 12 BP 1442 EP 1445 DI 10.1016/j.jcmg.2016.08.003 PG 4 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EF4LC UT WOS:000390295800012 PM 27838301 ER PT J AU Chawla, S Natarajan, G Shankaran, S Pappas, A Stoll, BJ Carlo, WA Saha, S Das, A Laptook, AR Higgins, RD AF Chawla, Sanjay Natarajan, Girija Shankaran, Seethe Pappas, Athina Stoll, Barbara J. Carlo, Waldemar A. Saha, Shampa Das, Abhik Laptook, Abbot R. Higgins, Rosemary D. CA Natl Inst Child Hlth Human Dev Neonatal Res Network TI Association of Neurodevelopmental Outcomes and Neonatal Morbidities of Extremely Premature Infants With Differential Exposure to Antenatal Steroids SO JAMA PEDIATRICS LA English DT Article ID CHILDREN BORN PRETERM; BIRTH-WEIGHT INFANTS; GROSS MOTOR FUNCTION; SYSTEM; CORTICOSTEROIDS; DEXAMETHASONE; MULTICENTER; HEMORRHAGE; PRESSURE; THERAPY AB IMPORTANCE Many premature infants are born without exposure to antenatal steroids (ANS) or with incomplete courses. This study evaluates the dose-dependent effect of ANS on rates of neonatal morbidities and early childhood neurodevelopmental outcomes of extremely premature infants. OBJECTIVE To compare rates of neonatal morbidities and 18-to 22-month neurodevelopmental outcomes of extremely premature infants exposed to no ANS or partial or complete courses of ANS. DESIGN, SETTING, AND PARTICIPANTS In this observational cohort study, participantswere extremely premature infants (birth weight range, 401-1000 g; gestational age, 22-27 weeks) who were born at participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 2006 and December 2011. Data were analyzed between October 2013 and May 2016. MAIN OUTCOMES AND MEASURES Rates of death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined as the presence of any of the following: moderate to severe cerebral palsy, a cognitive score less than 85 on the Bayley Scales of Infant and Toddler Development III, blindness, or deafness. RESULTS There were 848 infants in the no ANS group, 1581 in the partial ANS group, and 3692 in the complete ANS group; the mean (SD) birth weights were 725 (169), 760 (173), and 753 (170) g, respectively, and the mean (SD) gestational ages were 24.5 (1.4), 24.9 (2), and 25.1 (1.1) weeks. Of 6121 eligible infants, 4284 (70.0%) survived to 18-to 22-month follow-up, and data were available for 3892 of 4284 infants (90.8%). Among the no, partial, and complete ANS groups, there were significant differences in the rates of mortality (43.1%, 29.6%, and 25.2%, respectively), severe intracranial hemorrhage among survivors (23.3%, 19.1%, and 11.7%), death or necrotizing enterocolitis (48.1%, 37.1%, and 32.5%), and death or bronchopulmonary dysplasia (74.9%, 68.9%, and 65.5%). Additionally, death or neurodevelopmental impairment occurred in 68.1%, 54.4%, and 48.1% of patients in the no, partial, and complete ANS groups, respectively. Logistic regression analysis revealed that complete (odds ratio, 0.63; 95% CI, 0.53-0.76) and partial (odds ratio, 0.77; 95% CI, 0.63-0.95) ANS courses were associated with lower rates of death or neurodevelopmental impairment compared with the no ANS group. The reduction in the rate of death or neurodevelopmental impairment associated with exposure to a complete ANS course may be mediated through a reduction in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia in the neonatal period. CONCLUSIONS AND RELEVANCE Antenatal steroid exposurewas associated with a dose-dependent protective effect against death or neurodevelopmental impairment in extremely preterm infants. The effect was partly mediated by ANS-associated reductions in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia. These results support prompt administration of ANS, with the goal of a complete course prior to delivery. C1 [Chawla, Sanjay; Natarajan, Girija; Shankaran, Seethe; Pappas, Athina] Wayne State Univ, Dept Pediat, 3901 Beaubien, Detroit, MI 48201 USA. [Stoll, Barbara J.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Saha, Shampa; Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Laptook, Abbot R.] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Chawla, S (reprint author), Wayne State Univ, Dept Pediat, 3901 Beaubien, Detroit, MI 48201 USA. EM schawla@dmc.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; National Center for Research Resources; National Center for Advancing Translational Sciences FX This work was conducted for and supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the 17 generic database and follow-up studies of the Neonatal Research Network through cooperative agreements. NR 26 TC 1 Z9 1 U1 2 U2 2 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 DEC 1 PY 2016 VL 170 IS 12 BP 1164 EP 1172 DI 10.1001/jamapediatrics.2016.1936 PG 9 WC Pediatrics SC Pediatrics GA EF3WZ UT WOS:000390256900016 PM 27723868 ER PT J AU Rosenberg, AR Wolfe, J Wiener, L Lyon, M Feudtner, C AF Rosenberg, Abby R. Wolfe, Joanne Wiener, Lori Lyon, Maureen Feudtner, Chris TI Ethics, Emotions, and the Skills of Talking About Progressing Disease With Terminally Ill Adolescents A Review SO JAMA PEDIATRICS LA English DT Review ID OF-LIFE CARE; PEDIATRIC PALLIATIVE CARE; ADVANCED CANCER; PROGNOSTIC DISCLOSURE; YOUNG-ADULTS; BAD-NEWS; CHILDREN; PARENTS; END; COMMUNICATION AB Importance:For clinicians caring for adolescent patients living with progressive, life-threatening illness, discussions regarding prognosis, goals of care, and treatment options can be extremely challenging. While clinicians should respect and help to facilitate adolescents' emerging autonomy, they often must also work with parents' wishes to protect patients from the emotional distress of hearing bad news. Observations:We reviewed the ethical justifications for and against truth-telling, and we considered the published ethical and practice guidance, as well as the perspectives of patients, parents, and clinicians involved in these cases. We also explored particular challenges with respect to the cultural context, timing, and content of conversations at the end of adolescents' lives. In most cases, clinicians should gently but persistently engage adolescents directly in conversations about their disease prognosis and corresponding hopes, worries, and goals. These conversations need to occur multiple times, allowing significant time in each discussion for exploration of patient and family values. While truth-telling does not cause the types of harm that parents and clinicians may fear, discussing this kind of difficult news is almost always emotionally distressing. We suggest some "phrases that help" when clinicians strive to deepen understanding and facilitate difficult conversations with adolescents, parents, and other family members. Conclusions and Relevance:The pediatrician's opportunities to engage in difficult conversations about poor prognosis may be rare, but such conversations can be crucial. These discussions affect how patients live at the end of their lives, how they die, and how their families go on. Improved understanding of basic principles of communication, as well as augmented understanding of patient, family, and clinician perspectives may better enable us to navigate these important conversations. C1 [Rosenberg, Abby R.] Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. [Rosenberg, Abby R.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Rosenberg, Abby R.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Wolfe, Joanne] Harvard Med Sch, Boston, MA USA. [Wiener, Lori] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lyon, Maureen] Childrens Res Inst, Childrens Natl Hlth Syst, Ctr Translat Sci, Washington, DC USA. [Lyon, Maureen] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Pediat Adv Care Team, Philadelphia, PA 19104 USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Dept Med Eth, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Med Eth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. EM abby.rosenberg@seattlechildrens.org FU National Institutes of Health [KL2TR000421, L40 CA170049]; Intramural Research Program of the National Cancer Institute FX This work was supported in part by grants KL2TR000421 and L40 CA170049 from the National Institutes of Health (Dr Rosenberg) and the Intramural Research Program of the National Cancer Institute (Dr Wiener). NR 68 TC 0 Z9 0 U1 8 U2 8 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 DEC 1 PY 2016 VL 170 IS 12 BP 1216 EP 1223 DI 10.1001/jamapediatrics.2016.2142 PG 8 WC Pediatrics SC Pediatrics GA EF3WZ UT WOS:000390256900023 PM 27749945 ER PT J AU Dersh, D Yewdell, JW AF Dersh, Devin Yewdell, Jonathan W. TI I've got algorithm: predicting tumor and autoimmune peptide targets for CD8(+) T cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CLASS-I PATHWAY; MASS-SPECTROMETRY; MESSENGER-RNA; ANTIGEN; TRANSLATION; COMPLEX; LYMPHOCYTES; PROTEASOME; PATHOGENS AB CD8(+) T cells play a central role in eradicating intracellular pathogens, but also are important for noninfectious diseases, including cancer and autoimmunity. The ability to clinically manipulate CD8(+) T cells to target cancer and autoimmune disease is limited by our ignorance of relevant self-peptide target antigens. In this issue of the JCI, Pearson et al. describe 25,270 MHC class I-associated peptides presented by a wide range of HLA A and B allomorphs expressed by 18 different B cell lines. Via extensive bioinformatic analysis, the authors make surprising conclusions regarding the selective nature of peptide generation at the level of individual gene products and create a predictive algorithm for disease-relevant self-peptides that will be of immediate use for clinical and basic immunological research. C1 [Dersh, Devin; Yewdell, Jonathan W.] NIAID, Cellular Biol Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIH, Room 2E13-1C,Bldg 33,33 North Dr, Bethesda, MD 20892 USA. EM jyewdell@NIH.gov NR 25 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 2016 VL 126 IS 12 BP 4399 EP 4401 DI 10.1172/JCI91302 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF2CK UT WOS:000390131900004 PM 27841762 ER PT J AU Kwak, H Salvucci, O Weigert, R Martinez-Torrecuadrada, JL Henkemeyer, M Poulos, MG Butler, JM Tosato, G AF Kwak, Hyeongil Salvucci, Ombretta Weigert, Roberto Martinez-Torrecuadrada, Jorge L. Henkemeyer, Mark Poulos, Michael G. Butler, Jason M. Tosato, Giovanna TI Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PRE-METASTATIC NICHE; TYROSINE KINASE; TUMOR-GROWTH; STEM-CELLS; G-CSF; ANGIOGENESIS; MIGRATION; CYCLOPHOSPHAMIDE; MICROENVIRONMENT; INFLAMMATION AB Hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow. Stress signals from cancer and other conditions promote HSPC mobilization into circulation and subsequent homing to tissue microenvironments. HSPC infiltration into tissue microenvironments can influence disease progression; notably, in cancer, HSPCs encourage tumor growth. Here we have uncovered a mutually exclusive distribution of EPHB4 receptors in bone marrow sinusoids and ephrin B2 ligands in hematopoietic cells. We determined that signaling interactions between EPHB4 and ephrin B2 control HSPC mobilization from the bone marrow. In mice, blockade of the EPHB4/ephrin B2 signaling pathway reduced mobilization of HSPCs and other myeloid cells to the circulation. EPHB4/ephrin B2 blockade also reduced HSPC infiltration into tumors as well as tumor progression in murine models of melanoma and mammary cancer. These results identify EPHB4/ephrin B2 signaling as critical to HSPC mobilization from bone marrow and provide a potential strategy for reducing cancer progression by targeting the bone marrow. C1 [Kwak, Hyeongil; Salvucci, Ombretta; Tosato, Giovanna] NCI, Cellular Oncol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Weigert, Roberto] NIDCR, NIH, Bethesda, MD USA. [Weigert, Roberto] NCI, Cellular & Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Martinez-Torrecuadrada, Jorge L.] CNIO, Biotechnol Programme, Prote Unit, Madrid, Spain. [Henkemeyer, Mark] Univ Texas Southwestern Med Ctr, Dept Dev Biol, Dallas, TX USA. [Poulos, Michael G.; Butler, Jason M.] Weill Cornell Med Coll, Dept Genet Med, New York, NY USA. RP Tosato, G (reprint author), NIH, Cellular Oncol Lab, 37 Convent Dr,Bethesda Campus,Bldg 37,Room 4124, Bethesda, MD 20892 USA. EM Tosatog@mail.nih.gov FU intramural research program of the CCR/NCI/NIH; Regional Government of Madrid (Angiobodies Programme) [BIPEDD2 S2011/BMD-2312]; European Social Fund; Ansary Stem Cell Institute; American Society of Hematology Scholar Award; American Federation for Aging Research grant; Leukemia and Lymphoma Society Quest for Cures award FX We thank E. Pasquale for constructs; D. Soriano, R. Wong, and A. Acker-Palmer for mice; CCR animal facility personnel; D. Lowy and members of the Laboratory of Cellular Oncology for help in various aspects of this work. This work was supported by the intramural research program of the CCR/NCI/NIH. JLMT is supported by the Regional Government of Madrid (Angiobodies Programme BIPEDD2 S2011/BMD-2312) and the European Social Fund; JMB is supported by the Ansary Stem Cell Institute, an American Society of Hematology Scholar Award, an American Federation for Aging Research grant, and a Leukemia and Lymphoma Society Quest for Cures award. NR 60 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 2016 VL 126 IS 12 BP 4554 EP 4568 DI 10.1172/JCI87848 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF2CK UT WOS:000390131900017 PM 27820703 ER PT J AU Zhang, LJ Du, JH Justus, S Hsu, CW Bonet-Ponce, L Wu, WH Tsai, YT Wu, WP Jia, YD Duong, JK Mahajan, VB Lin, CS Wang, S Hurley, JB Tsang, SH AF Zhang, Lijuan Du, Jianhai Justus, Sally Hsu, Chun-Wei Bonet-Ponce, Luis Wu, Wen-Hsuan Tsai, Yi-Ting Wu, Wei-Pu Jia, Yading Duong, Jimmy K. Mahajan, Vinit B. Lin, Chyuan-Sheng Wang, Shuang Hurley, James B. Tsang, Stephen H. TI Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LEBERS CONGENITAL AMAUROSIS; RECESSIVE RETINITIS-PIGMENTOSA; ROD CGMP-PHOSPHODIESTERASE; HISTONE DEACETYLASE SIRT6; CONE VIABILITY FACTOR; GENE-THERAPY; GAMMA-SUBUNIT; OXYGEN DISTRIBUTION; PRECLINICAL MODEL; CHILDHOOD BLINDNESS AB Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders. C1 [Zhang, Lijuan; Justus, Sally; Hsu, Chun-Wei; Wu, Wen-Hsuan; Tsai, Yi-Ting; Wu, Wei-Pu; Tsang, Stephen H.] Columbia Univ, Dept Ophthalmol, Jonas Childrens Vis Care & Bernard & Shirlee Brow, New York, NY 10027 USA. [Zhang, Lijuan; Justus, Sally; Hsu, Chun-Wei; Wu, Wen-Hsuan; Tsai, Yi-Ting; Wu, Wei-Pu; Jia, Yading; Tsang, Stephen H.] New York Presbyterian Hosp, Edward S Harkness Eye Inst, New York, NY USA. [Zhang, Lijuan] Shanxi Med Univ, Shanxi Eye Hosp, Taiyuan, Peoples R China. [Du, Jianhai; Hurley, James B.] Univ Washington, Dept Biochem & Ophthalmol, Seattle, WA 98195 USA. [Bonet-Ponce, Luis] NIH, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, Bldg 10, Bethesda, MD 20892 USA. [Duong, Jimmy K.; Wang, Shuang] Columbia Univ, Med Ctr, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Mahajan, Vinit B.] Univ Iowa, Omics Lab, Iowa City, IA USA. [Lin, Chyuan-Sheng] Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Pathol & Cell Biol, New York, NY USA. [Tsang, Stephen H.] Columbia Univ, Coll Phys & Surg, Inst Human Nutr, Dept Pathol, New York, NY USA. [Tsang, Stephen H.] Columbia Univ, Coll Phys & Surg, Inst Human Nutr, Dept Cell Biol, New York, NY USA. RP Tsang, SH (reprint author), Columbia Univ, Med Ctr, 635 West 165th St,Box 112, New York, NY 10032 USA. EM sht2@columbia.edu FU NIH [5P30EY019007, R01EY018213, R01EY024698, 1R01EY026682, R21AG050437, 1R01EY02602001, 5R21AG050437]; National Cancer Institute Core [5P30CA013696]; Research to Prevent Blindness (RPB) Physician-Scientist Award; RPB; Tistou and Charlotte Kerstan Foundation; Schneeweiss Stem Cell Fund, New York State [C029572]; Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]; Gebroe Family Foundation FX The Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the NIH (5P30EY019007, R01EY018213, R01EY024698, 1R01EY026682, R21AG050437), National Cancer Institute Core (5P30CA013696), the Research to Prevent Blindness (RPB) Physician-Scientist Award, and unrestricted funds from RPB. SHT is a member of the RD-CURE Consortium and is supported by the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State (C029572), the Foundation Fighting Blindness New York Regional Research Center Grant (C-NY05-0705-0312), and the Gebroe Family Foundation. JBH is supported by NIH (1R01EY02602001). VBM is supported by NIH (1R01EY026682, 5R21AG050437). Special thanks go to Amy Caudy, Eyal Gottlieb, and Adam Rosebrock for their consultations during the metabolomics course at Cold Spring Harbor Laboratory. NR 95 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 2016 VL 126 IS 12 BP 4659 EP 4673 DI 10.1172/JCI86905 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF2CK UT WOS:000390131900025 PM 27841758 ER PT J AU Szyniszewska, AM Leppla, NC Huang, Z Tatem, AJ AF Szyniszewska, A. M. Leppla, N. C. Huang, Z. Tatem, A. J. TI Analysis of Seasonal Risk for Importation of the Mediterranean Fruit Fly, Ceratitis capitata (Diptera: Tephritidae), via Air Passenger Traffic Arriving in Florida and California SO JOURNAL OF ECONOMIC ENTOMOLOGY LA English DT Article DE Ceratitis capitata; Mediterranean fruit fly; risk analysis ID BIOLOGICAL INVASIONS; INTERNATIONAL-TRADE; NORTHERN GREECE; CARGO AIRCRAFT; UNITED-STATES; INTERCEPTIONS; PATHWAY; DISEASE; TRAVEL; PESTS AB The Mediterranean fruit fly, Ceratitis capitata ( Wiedemann), is one of the most economically damaging pests in the world and has repeatedly invaded two major agricultural states in the United States, Florida and California, each time requiring costly eradication. The Mediterranean fruit fly gains entry primarily in infested fruit carried by airline passengers and, since Florida and California each receive about 13 million international passengers annually, the risk of Mediterranean fruit fly entering the United States is potentially very high. The risk of passengers bringing the pest into Florida or California from Mediterranean fruit fly-infested countries was determined with two novel models, one estimated seasonal variation in airline passenger number and the other defined the seasonal and spatial variability in Mediterranean fruit fly abundance. These models elucidated relationships among the risk factors for Mediterranean fruit fly introduction, such as amount of passenger traffic, routes traveled, season of travel, abundance of Mediterranean fruit fly in countries where flights departed, and risk of the pest arriving at destination airports. The risk of Mediterranean fruit fly being introduced into Florida was greatest from Colombia, Brazil, Panama, Venezuela, Argentina, and Ecuador during January-August, whereas primarily the risk to California was from Brazil, Panama, Colombia, and Italy in May-August. About three times more Mediterranean fruit flies were intercepted in passenger baggage at airports in Florida than California, although the data were compromised by a lack of systematic sampling and other limitations. Nevertheless, this study achieved the goal of analyzing available data on seasonal passenger flow and Mediterranean fruit fly population levels to determine when surveillance should be intensified at key airports in Florida and California. C1 [Szyniszewska, A. M.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Szyniszewska, A. M.; Leppla, N. C.] Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. [Huang, Z.] Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, Beijing, Peoples R China. [Tatem, A. J.] Univ Southampton, WorldPop Project, Dept Geog & Environm, Southampton, Hants, England. [Tatem, A. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, A. J.] Flowminder Fdn, Stockholm, Sweden. RP Leppla, NC (reprint author), Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. EM aniasz@gmail.com; ncleppla@ufl.edu; seenhzj@gmail.com; Andy.Tatem@gmail.com FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank Daniel Borchert (USDA, APHIS) for accessing the pest interception records. Kevin Bigsby (North Carolina State University, Center for Integrated Pest Management), Barney Caton (USDA, APHIS), and Denys Yemshanov (Natural Resources Canada) provided helpful reviews of the manuscript. This research was made possible, in part, by Cooperative Agreements No. 12-8130-0158-CA and 14-8130-0158-CA from the USDA, APHIS. It may not necessarily express the views of APHIS. Funding support for A.J.T. was provided by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, 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 53 TC 0 Z9 0 U1 8 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-0493 EI 1938-291X J9 J ECON ENTOMOL JI J. Econ. Entomol. PD DEC PY 2016 VL 109 IS 6 BP 2317 EP 2328 DI 10.1093/jee/tow196 PG 12 WC Entomology SC Entomology GA EF4WU UT WOS:000390333500009 ER PT J AU Jenewein, J Erni, J Moergeli, H Grillon, C Schumacher, S Mueller-Pfeiffer, C Hassanpour, K Seiler, A Wittmann, L Schnyder, U Hasler, G AF Jenewein, Josef Erni, Jeannine Moergeli, Hanspeter Grillon, Christian Schumacher, Sonja Mueller-Pfeiffer, Christoph Hassanpour, Katayun Seiler, Annina Wittmann, Lutz Schnyder, Ulrich Hasler, Gregor TI Altered Pain Perception and Fear-Learning Deficits in Subjects With Posttraumatic Stress Disorder SO JOURNAL OF PAIN LA English DT Article DE Anxiety; fear; fear-learning; chronic pain; post-traumatic stress disorder ID ADMINISTERED PTSD SCALE; MUTUAL MAINTENANCE; ANXIETY; SYMPTOMS; INHIBITION; AWARENESS; HUMANS; MODELS; CUES AB There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD. We included 19 subjects with PTSD and 21 age-and sex-matched healthy control subjects in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs flashed upon a screen in front of each subject. The unconditioned stimulus was either a low or high temperature impulse delivered through a thermal contact thermode on the subjects' hand. A designation of 'CS-' was assigned to CS always followed by nonpainful low-temperature stimuli; a designation of 'CS+' was given to CS that were randomly followed by either a low or a more painful high temperature. Skin conductance was used as a physiological marker of fear. In healthy control subjects, CS+ induced more fear than CS, and a low-temperature stimulus induced less subjective pain after CS than after CS+. PTSD subjects failed to demonstrate such adaptive conditioning. Fear ratings after CS presentation were significantly higher in the PTSD group than in the control group. There were significant interaction effects between group and the type of CS on fear and pain ratings. Fear-learning deficits are a potentially promising, specific psychopathological factor in altered pain perception associated with PTSD. Deficits in safety learning may increase fear and, consequently, pain sensations. These findings may contribute to elucidating the pathogenesis behind the highly prevalent comorbidity that exists between PTSD and pain disorders, and to developing new treatments. Perspective: This study provides new insights into the pathogenesis of chronic pain in patients with PTSD. The findings may help to develop new treatment strategies for this highly prevalent co-morbidity in PTSD. (C) 2016 by the American Pain Society C1 [Jenewein, Josef; Erni, Jeannine; Moergeli, Hanspeter; Schumacher, Sonja; Mueller-Pfeiffer, Christoph; Hassanpour, Katayun; Seiler, Annina; Schnyder, Ulrich] Univ Zurich, Univ Zurich Hosp, Dept Psychiat & Psychotherapy, CH-8091 Zurich, Switzerland. [Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. [Wittmann, Lutz] Int Psychoanalyt Univ, Berlin, Germany. [Hasler, Gregor] Univ Bern, Univ Hosp Psychiat & Psychotherapy, Bern, Switzerland. RP Jenewein, J (reprint author), Univ Zurich Hosp, Dept Psychiat & Psychotherapy, Ramistr 100, CH-8091 Zurich, Switzerland. EM josef.jenewein@usz.ch OI Hasler, Gregor/0000-0002-8311-0138; Jenewein, Josef/0000-0003-4271-918X FU Hermann Klaus Foundation, Zurich, Switzerland; Werner Alfred Selo Foundation, Zurich, Switzerland; Kurt and Senta Herrmann Foundation, Zurich, Switzerland FX This work was supported by the Hermann Klaus Foundation, Zurich, Switzerland; Werner Alfred Selo Foundation, Zurich, Switzerland; and the Kurt and Senta Herrmann Foundation, Zurich, Switzerland. NR 36 TC 0 Z9 0 U1 7 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD DEC PY 2016 VL 17 IS 12 BP 1325 EP 1333 DI 10.1016/j.jpain.2016.09.002 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EF4KD UT WOS:000390293300007 PM 27641312 ER PT J AU Mohammad, S Wolfe, LA Stobe, P Biskup, S Wainwright, MS Melin-Aldana, H Malladi, P Muenke, M Gahl, WA Whitington, PF AF Mohammad, Saeed Wolfe, Lynne A. Stoebe, Petra Biskup, Saskia Wainwright, Mark S. Melin-Aldana, Hector Malladi, Padmini Muenke, Maximilian Gahl, William A. Whitington, Peter F. TI Infantile Cirrhosis, Growth Impairment, and Neurodevelopmental Anomalies Associated with Deficiency of PPP1R15B SO JOURNAL OF PEDIATRICS LA English DT Article ID VANISHING WHITE-MATTER; UNDIAGNOSED DISEASES; PROTEIN-SYNTHESIS; SEVERE VARIANT; SHORT STATURE; TRANSLATION; LEUKOENCEPHALOPATHY; MUTATION; GENE; APOPTOSIS AB Objective To assess the utility of whole-exome sequencing (WES) in a sibling pair with undetermined liver disease and describe the phenotype associated with mutations discovered therein. Study design Next-generation WES was performed on 2 siblings (S1 and S2) who were born to nonconsanguineous parents of European extraction. Both siblings developed cirrhosis of indeterminate etiology and required liver transplantation; S1 at 7 months and S2 at 22 months. Results Sequencing of germline DNA identified compound heterozygous mutations in PPP1R15B resulting in increased levels of phosphorylated eukaryotic translation initiation factor 2 alpha. Conclusions The first demonstration of PPP1R15B associated with liver disease expands the phenotypic spectrum of PPP1R15B related diseases. Our findings validate the application of WES in the diagnosis of children with undetermined liver disease. Understanding the genetic basis of liver disease may allow the development of targeted therapies for treatment and adequate counseling of families. C1 [Mohammad, Saeed; Malladi, Padmini; Whitington, Peter F.] Northwestren Univ, Feinberg Sch Med, Dept Pediat, Div Gastroenterol, Chicago, IL 60208 USA. [Mohammad, Saeed; Wainwright, Mark S.; Melin-Aldana, Hector] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60208 USA. [Wolfe, Lynne A.] NIH, Undiagnosed Dis Program, Common Fund, Bethesda, MD USA. [Stoebe, Petra; Biskup, Saskia] Cent Genom & Transcript, Tubingen, Germany. [Wainwright, Mark S.] Northwestren Univ, Feinberg Sch Med, Dept Pediat, Div Neurol, Chicago, IL 60208 USA. [Melin-Aldana, Hector] Northwestren Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60208 USA. [Muenke, Maximilian] NIH, Natl Human Genome Res Inst, Med Genet Branch, Bethesda, MD USA. [Gahl, William A.] NIH, Natl Human Genome Res Inst, Bethesda, MD USA. RP Mohammad, S (reprint author), Northwestren Univ, Feinberg Sch Med, Dept Pediat, Div Gastroenterol, Chicago, IL 60208 USA.; Mohammad, S (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60208 USA. NR 21 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2016 VL 179 BP 144 EP + DI 10.1016/j.jpeds.2016.08.043 PG 8 WC Pediatrics SC Pediatrics GA EF0PD UT WOS:000390027100032 PM 27640355 ER PT J AU Moore, RA Choi, YP Head, MW Ironside, JW Faris, R Ritchie, DL Zanusso, G Priola, SA AF Moore, Roger A. Choi, Young Pyo Head, Mark W. Ironside, James W. Faris, Robert Ritchie, Diane L. Zanusso, Gianluigi Priola, Suzette A. TI Relative Abundance of apoE and A beta 1-42 Associated with Abnormal Prion Protein Differs between Creutzfeldt-Jakob Disease Subtypes SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE prion protein; transmissible spongiform encephalopathies; Creutzfeld-Jakob disease; mass spectrometry; proteomics; creatine kinase; apolipoprotein E; amyloid beta ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE PRION; MASS-SPECTROMETRY; STATISTICAL-MODEL; DATABASE SEARCH; PURIFICATION; AGENT; IDENTIFICATION; PROTEOMICS; SIZE AB Aggregated and protease-resistant mammalian prion protein (PrPsc) is the primary protein component of infectious prions. Enriched PrPsc preparations are often used to study the mechanisms that underly prion disease. However, most enrichment procedures are relatively nonspecific and tend to yield significant amounts of non-PrPsc components including various proteins that could confound functional and structural studies. It is thus important to identify these proteins and assess their potential relevance to prion pathogenesis. Following proteinase K treatment and phosphotungstic acid precipitation of brain homogenate, we have used mass spectrometry to analyze the protein content of PrPsc isolated from prion-infected mice, multiple cases of sporadic Creutzfeldt-Jakob disease (sCJD), and human growth hormone associated cases of iatrogenic CJD (iCJD). Creatine kinase was the primary protein contaminant in all PrPsc samples, while many of the other proteins identified were also found in non-CJD controls, which suggests that they are not CJD specific. Interestingly, the Alzheimer's disease associated peptide amyloid beta 1-42 (A beta 1-42) was identified in the majority of the sCJD cases as well as non-CJD age-matched controls, while apoliprotein E was found in greater abundance in the sCJD cases. By contrast, while some of the iCJD cases showed evidence of higher molecular weight A beta oligomers, monomeric A beta 1-42 peptide was not detected by immunoblot, and only one case had significant levels of apolipoprotein E. Our data are consistent with the age-associated deposition of A beta 1-42 in older sporadic CJD and non-CJD patients and suggest that both apolipoprotein E and A beta 1-42 abundance can differ depending upon the type of CJD. C1 [Moore, Roger A.; Faris, Robert; Priola, Suzette A.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Choi, Young Pyo] Korea Brain Res Inst, Div Res, Lab Anim Ctr, Daegu 41068, South Korea. [Head, Mark W.; Ironside, James W.; Ritchie, Diane L.] Univ Edinburgh, Sch Clin Sci, Ctr Clin Brain Sci, Natl CJD Res & Surveillance Unit, Edinburgh EH8 9YL, Midlothian, Scotland. [Zanusso, Gianluigi] Univ Verona, Dept Neurosci Biomed & Movement Sci, I-37129 Verona, Italy. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM spriola@nih.gov FU National Institute of Allergy and Infectious Disease, National Institutes of Health [1-Z01-AI000752-12]; Fondation Alliance Biosecure "Multicenter evaluation of improved RT-QuIC diagnostic assays for Creutzfeldt-Jakob and other human prion diseases"; Medical Research Council [MRC G0900580]; KBRI Research program of the Ministry of Science, ICT, and Future Planning [2231-415] FX The authors would like to thank Dr. Andrew Timmes for generously providing purified mouse PrPsc and Drs. Byron Caughey, Karin Peterson, and Brad Groveman for critically evaluating the manuscript. The authors also thank Anita Mora and Ryan Kissinger for providing technical assistance in preparation of the figures and the table of contents illustration. This research was supported by the intramural research program of the National Institute of Allergy and Infectious Disease, National Institutes of Health (Project No. 1-Z01-AI000752-12) and by Fondation Alliance Biosecure "Multicenter evaluation of improved RT-QuIC diagnostic assays for Creutzfeldt-Jakob and other human prion diseases". Edinburgh Brain Banks is supported by the Medical Research Council (MRC G0900580) and Y.P.C. by the KBRI Research program of the Ministry of Science, ICT, and Future Planning (2231-415). NR 54 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD DEC PY 2016 VL 15 IS 12 BP 4518 EP 4531 DI 10.1021/acs.jproteome.6b00633 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EE2EM UT WOS:000389396500030 PM 27597180 ER PT J AU Oliver, B Boehm, M Rosing, DR Shapiro, LS Dempsey, DT Merkel, PA Lee, CCR Cowen, EW AF Oliver, Brittany Boehm, Manfred Rosing, Douglas R. Shapiro, Lee S. Dempsey, Daniel T. Merkel, Peter A. Lee, Chyi-Chia Richard Cowen, Edward W. TI Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE complement; Degos disease; eculizumab; interferon; malignant atrophic papulosis; treprostinil; vasculopathy ID PAPULOSIS DEGOS-DISEASE; FAMILY C1 [Oliver, Brittany] NIH, Bethesda, MD USA. [Boehm, Manfred] NHLBI, Ctr Mol Med, Bldg 10, Bethesda, MD 20892 USA. [Rosing, Douglas R.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Shapiro, Lee S.] Ctr Rheumatol, Saratoga Springs, NY USA. [Dempsey, Daniel T.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10 Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10 Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 18 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2016 VL 75 IS 6 BP 1274 EP 1277 DI 10.1016/j.jaad.2016.09.015 PG 4 WC Dermatology SC Dermatology GA EF0QX UT WOS:000390032000055 PM 27717619 ER PT J AU Ernst, ME Davis, BR Soliman, EZ Prineas, RJ Okin, PM Ghosh, A Cushman, WC Einhorn, PT Oparil, S Grimm, RH AF Ernst, Michael E. Davis, Barry R. Soliman, Elsayed Z. Prineas, Ronald J. Okin, Peter M. Ghosh, Alokananda Cushman, William C. Einhorn, Paula T. Oparil, Suzanne Grimm, Richard H., Jr. CA ALLHAT Collaborative Res Grp TI Electrocardiographic measures of left ventricular hypertrophy in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE Amlodipine; chlorthalidone; electrocardiography; lisinopril ID FACTOR INTERVENTION TRIAL; TO-VISIT VARIABILITY; SYSTOLIC BLOOD-PRESSURE; DRUG-THERAPY; FOLLOW-UP; HYPERTENSION; RISK; MORTALITY; AMLODIPINE; DISEASE AB Left ventricular hypertrophy (LVH) predicts cardiovascular risk in hypertensive patients. We analyzed baseline/follow-up electrocardiographies in 26,376 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to amlodipine (A), lisinopril (L), or chlorthalidone (C). Prevalent/incident LVH was examined using continuous and categorical classifications of Cornell voltage. At 2 and 4 years, prevalence of LVH in the C group (5.57%; 6.14%) was not statistically different from A group (2 years: 5.47%; P = .806, 4 years: 6.54%; P = 857) or L group (2 years: 5.64%; P = .857, 4 years: 6.50%; P = .430). Incident LVH followed similarly, with no difference at 2 years for C (2.99%) compared to A (2.57%; P = .173) or L (3.16%; P = .605) and at 4 years (C = 3.52%, A = 3.29%, L = 3.71%; P = .521 C vs. A, P = .618 C vs. L). Mean Cornell voltage decreased comparably across treatment groups (Delta baseline, 2 years = +3 to -27 mu V, analysis of variance P = .8612; 4 years = +10 to -17 mu V, analysis of variance P = .9692). We conclude that risk reductions associated with C treatment in secondary end points of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial cannot be attributed to differential improvements in electrocardiography LVH. (C) 2016 American Society of Hypertension. All rights reserved. C1 [Ernst, Michael E.] Univ Iowa, Coll Pharm, Dept Pharm Practice & Sci, Iowa City, IA 52242 USA. [Ernst, Michael E.] Univ Iowa, Dept Family Med, Carver Coll Med, Iowa City, IA USA. [Davis, Barry R.; Ghosh, Alokananda] Univ Texas Sch Publ Hlth, Dept Biostat, Coordinating Ctr Clin Trials, Houston, TX USA. [Soliman, Elsayed Z.; Prineas, Ronald J.] Wake Forest Univ, Epidemiol Cardiol Res Ctr EPICARE, Dept Epidemiol & Prevent, Div Publ Hlth Sci,Sch Med, Winston Salem, NC 27109 USA. [Okin, Peter M.] Weill Cornell Med Coll, Div Cardiol, New York, NY USA. [Cushman, William C.] Vet Affairs Med Ctr, Prevent Med Sect, Memphis, TN USA. [Einhorn, Paula T.] NHLBI, Div Heart & Vasc Dis, Bldg 10, Bethesda, MD 20892 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Div Cardiovasc Dis, Vasc Biol & Hypertens Program, Birmingham, AL USA. [Grimm, Richard H., Jr.] Minneapolis Med Res Fdn Inc, Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. [Grimm, Richard H., Jr.] Hennepin Cty Med Ctr, Div Clin Epidemiol, Minneapolis, MN 55415 USA. [Grimm, Richard H., Jr.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. RP Davis, BR (reprint author), Univ Texas Sch Publ Hlth, Coordinating Ctr Clin Trials, 1200 Pressler St W-916, Houston, TX 77030 USA. EM barry.r.davis@uth.tmc.edu OI Prineas, Ronald/0000-0001-7494-0634 FU National Heart, Lung, and Blood Institute [NO1-HC-35130, HHSN268201100036C] FX This study was supported by contracts NO1-HC-35130 and HHSN268201100036C with the National Heart, Lung, and Blood Institute. NR 29 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 1933-1711 EI 1878-7436 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD DEC PY 2016 VL 10 IS 12 BP 930 EP 938 DI 10.1016/j.jash.2016.10.010 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF4KA UT WOS:000390293000005 PM 27938852 ER PT J AU Iranzo, J Koonin, EV Prangishvili, D Krupovic, M AF Iranzo, Jaime Koonin, Eugene V. Prangishvili, David Krupovic, Mart TI Bipartite Network Analysis of the Archaeal Virosphere: Evolutionary Connections between Viruses and Capsidless Mobile Elements SO JOURNAL OF VIROLOGY LA English DT Article ID STRANDED DNA VIRUSES; CRISPR-CAS SYSTEMS; VIRAL GENOMES; SHAPED VIRUS; HYPERTHERMOPHILIC ARCHAEA; THERMOPHILIC BACTERIA; VIRION ARCHITECTURE; HALOPHILIC ARCHAEA; TAILED VIRUSES; HOT-SPRINGS AB Archaea and particularly hyperthermophilic crenarchaea are hosts to many unusual viruses with diverse virion shapes and distinct gene compositions. As is typical of viruses in general, there are no universal genes in the archaeal virosphere. Therefore, to obtain a comprehensive picture of the evolutionary relationships between viruses, network analysis methods are more productive than traditional phylogenetic approaches. Here we present a comprehensive comparative analysis of genomes and proteomes from all currently known taxonomically classified and unclassified, cultivated and uncultivated archaeal viruses. We constructed a bipartite network of archaeal viruses that includes two classes of nodes, the genomes and gene families that connect them. Dissection of this network using formal community detection methods reveals strong modularity, with 10 distinct modules and 3 putative supermodules. However, compared to similar previously analyzed networks of eukaryotic and bacterial viruses, the archaeal virus network is sparsely connected. With the exception of the tailed viruses related to bacteriophages of the order Caudovirales and the families Turriviridae and Sphaerolipoviridae that are linked to a distinct supermodule of eukaryotic and bacterial viruses, there are few connector genes shared by different archaeal virus modules. In contrast, most of these modules include, in addition to viruses, capsidless mobile elements, emphasizing tight evolutionary connections between the two types of entities in archaea. The relative contributions of distinct evolutionary origins, in particular from nonviral elements, and insufficient sampling to the sparsity of the archaeal virus network remain to be determined by further exploration of the archaeal virosphere. IMPORTANCE Viruses infecting archaea are among the most mysterious denizens of the virosphere. Many of these viruses display no genetic or even morphological relationship to viruses of bacteria and eukaryotes, raising questions regarding their origins and position in the global virosphere. Analysis of 5,740 protein sequences from 116 genomes allowed dissection of the archaeal virus network and showed that most groups of archaeal viruses are evolutionarily connected to capsidless mobile genetic elements, including various plasmids and transposons. This finding could reflect actual independent origins of the distinct groups of archaeal viruses from different nonviral elements, providing important insights into the emergence and evolution of the archaeal virome. C1 [Iranzo, Jaime; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Prangishvili, David; Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, Paris, France. RP Krupovic, M (reprint author), Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, Paris, France. EM krupovic@pasteur.fr OI Krupovic, Mart/0000-0001-5486-0098; Iranzo, Jaime/0000-0002-4538-7726 FU HHS \ National Institutes of Health (NIH) (intramural funds of the US Department of Health and Human Services); Agence Nationale de la Recherche (ANR) (program BLANC project EXAVIR) FX This work, including the efforts of Jaime Iranzo and Eugene V. Koonin, was funded by HHS vertical bar National Institutes of Health (NIH) (intramural funds of the US Department of Health and Human Services). This work, including the efforts of David Prangishvili, was funded by Agence Nationale de la Recherche (ANR) (program BLANC project EXAVIR). NR 82 TC 1 Z9 1 U1 2 U2 2 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 DEC PY 2016 VL 90 IS 24 BP 11043 EP 11055 DI 10.1128/JVI.01622-16 PG 13 WC Virology SC Virology GA EF2BL UT WOS:000390129300006 PM 27681128 ER PT J AU Chen, CY Shingai, M Welbourn, S Martin, MA Borrego, P Taveira, N Strebel, K AF Chen, Chia-Yen Shingai, Masashi Welbourn, Sarah Martin, Malcolm A. Borrego, Pedro Taveira, Nuno Strebel, Klaus TI Antagonism of BST-2/Tetherin Is a Conserved Function of the Env Glycoprotein of Primary HIV-2 Isolates SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-2 ENVELOPE PROTEIN; VIRAL PARTICLE RELEASE; VPU PROTEIN; CELL-SURFACE; RETROVIRUS RELEASE; TETHERIN; BST-2; RESTRICTION; NEF AB Although HIV-2 does not encode a vpu gene, the ability to antagonize bone marrow stromal antigen 2 (BST-2) is conserved in some HIV-2 isolates, where it is controlled by the Env glycoprotein. We previously reported that a single-amino-acid difference between the laboratory-adapted ROD10 and ROD14 Envs controlled the enhancement of virus release (referred to here as Vpu-like) activity. Here, we investigated how conserved the Vpu-like activity is in primary HIV-2 isolates. We found that half of the 34 tested primary HIV-2 Env isolates obtained from 7 different patients enhanced virus release. Interestingly, most HIV-2 patients harbored a mixed population of viruses containing or lacking Vpu-like activity. Vpu-like activity and Envelope functionality varied significantly among Env isolates; however, there was no direct correlation between these two functions, suggesting they evolved independently. In comparing the Env sequences from one HIV-2 patient, we found that similar to the ROD10/ROD14 Envs, a single-amino-acid change (T568I) in the ectodomain of the TM subunit was sufficient to confer Vpu-like activity to an inactive Env variant. Surprisingly, however, absence of Vpu-like activity was not correlated with absence of BST-2 interaction. Taken together, our data suggest that maintaining the ability to antagonize BST-2 is of functional relevance not only to HIV-1 but also to HIV-2 as well. Our data show that as with Vpu, binding of HIV-2 Env to BST-2 is important but not sufficient for antagonism. Finally, as observed previously, the Vpu-like activity in HIV-2 Env can be controlled by single-residue changes in the TM subunit. IMPORTANCE Lentiviruses such as HIV-1 and HIV-2 encode accessory proteins whose function is to overcome host restriction mechanisms. Vpu is a well-studied HIV-1 accessory protein that enhances virus release by antagonizing the host restriction factor BST-2. HIV-2 does not encode a vpu gene. Instead, the HIV-2 Env glycoprotein was found to antagonize BST-2 in some isolates. Here, we cloned multiple Env sequences from 7 HIV-2-infected patients and found that about half were able to antagonize BST-2. Importantly, most HIV-2 patients harbored a mixed population of viruses containing or lacking the ability to antagonize BST-2. In fact, in comparing Env sequences from one patient combined with site-directed mutagenesis, we were able to restore BST-2 antagonism to an inactive Env protein by a single-amino-acid change. Our data suggest that targeting BST-2 by HIV-2 Env is a dynamic process that can be regulated by simple changes in the Env sequence. C1 [Chen, Chia-Yen; Shingai, Masashi; Welbourn, Sarah; Martin, Malcolm A.; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Borrego, Pedro; Taveira, Nuno] Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, Lisbon, Portugal. [Taveira, Nuno] Inst Super Ciencias Saude Egas Moniz, Ctr Invest Interdisciplinar Egas Moniz, Caparica, Portugal. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kstrebel@nih.gov RI Taveira, Nuno/A-6252-2014; iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, EEPHIV /B-4222-2014; OI Taveira, Nuno/0000-0003-0176-5585; Borrego, Pedro/0000-0002-1949-9484 FU NIH [AI000669] FX This work, including the efforts of Klaus Strebel, was funded by NIH Intramural Research Program (AI000669). NR 55 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2016 VL 90 IS 24 BP 11062 EP 11074 DI 10.1128/JVI.01451-16 PG 13 WC Virology SC Virology GA EF2BL UT WOS:000390129300008 PM 27681141 ER PT J AU Wu, F Kirmaier, A White, E Ourmanov, I Whitted, S Matsuda, K Riddick, N Hall, LR Morgan, JS Plishka, RJ Buckler-White, A Johnson, WE Hirsch, VM AF Wu, Fan Kirmaier, Andrea White, Ellen Ourmanov, Ilnour Whitted, Sonya Matsuda, Kenta Riddick, Nadeene Hall, Laura R. Morgan, Jennifer S. Plishka, Ronald J. Buckler-White, Alicia Johnson, Welkin E. Hirsch, Vanessa M. TI TRIM5 alpha Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS MACAQUES; INTRARECTAL CHALLENGE; MONKEY TRIM5-ALPHA; INFECTION; TRIM5; ACQUISITION; SIV; VACCINE; NEUTRALIZATION; REPLICATION AB TRIM5 alpha polymorphism limits and complicates the use of simian immunodeficiency virus (SIV) for evaluation of human immunodeficiency virus (HIV) vaccine strategies in rhesus macaques. We previously reported that the TRIM5 alpha-sensitive SIV from sooty mangabeys (SIVsm) clone SIVsmE543-3 acquired amino acid substitutions in the capsid that overcame TRIM5 alpha restriction when it was passaged in rhesus macaques expressing restrictive TRIM5 alpha alleles. Here we generated TRIM5 alpha-resistant clones of the related SIVsmE660 strain without animal passage by introducing the same amino acid capsid substitutions. We evaluated one of the variants in rhesus macaques expressing permissive and restrictive TRIM5 alpha alleles. The SIVsmE660 variant infected and replicated in macaques with restrictive TRIM5 alpha genotypes as efficiently as in macaques with permissive TRIM5 alpha genotypes. These results demonstrated that mutations in the SIV capsid can confer SIV resistance to TRIM5 alpha restriction without animal passage, suggesting an applicable method to generate more diverse SIV strains for HIV vaccine studies. IMPORTANCE Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5 alpha alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5 alpha genotype and thus will eliminate the confounding effects of TRIM5 alpha in vaccine studies. C1 [Wu, Fan; White, Ellen; Ourmanov, Ilnour; Whitted, Sonya; Matsuda, Kenta; Riddick, Nadeene; Plishka, Ronald J.; Buckler-White, Alicia; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Kirmaier, Andrea; Hall, Laura R.; Morgan, Jennifer S.; Johnson, Welkin E.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. RP Wu, F; Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM wuf2@niaid.nih.gov; vhirsch@niaid.nih.gov FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI083118] FX This work, including the efforts of Fan Wu, Ellen White, Ilnour Ourmanov, Sonya Whitted, Kenta Matsuda, Nadeene Riddick, Ronald J. Plishka, Alicia Buckler-White, and Vanessa M. Hirsch, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (Intramural program). This work, including the efforts of Andrea Kirmaier, Laura R. Hall, Jennifer S. Morgan, and Welkin E. Johnson, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI083118). NR 35 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2016 VL 90 IS 24 BP 11087 EP 11095 DI 10.1128/JVI.01620-16 PG 9 WC Virology SC Virology GA EF2BL UT WOS:000390129300010 PM 27681142 ER PT J AU Luque, D Mata, CP Gonzalez-Camacho, F Gonzalez, JM Gomez-Blanco, J Alfonso, C Rivas, G Havens, WM Kanematsu, S Suzuki, N Ghabrial, SA Trus, BL Caston, JR AF Luque, Daniel Mata, Carlos P. Gonzalez-Camacho, Fernando Gonzalez, Jose M. Gomez-Blanco, Josue Alfonso, Carlos Rivas, German Havens, Wendy M. Kanematsu, Satoko Suzuki, Nobuhiro Ghabrial, Said A. Trus, Benes L. Caston, Jose R. TI Heterodimers as the Structural Unit of the T=1 Capsid of the Fungal Double-Stranded RNA Rosellinia necatrix Quadrivirus 1 SO JOURNAL OF VIROLOGY LA English DT Article ID PHYTOPATHOGENIC FILAMENTOUS FUNGUS; PENICILLIUM-CHRYSOGENUM-VIRUS; BURSAL DISEASE VIRUS; L-A VIRUS; DSRNA VIRUS; STRUCTURE REVEALS; CRYOELECTRON MICROSCOPY; ATOMIC-STRUCTURE; 3-DIMENSIONAL STRUCTURE; ANGSTROM RESOLUTION AB Most double-stranded RNA (dsRNA) viruses are transcribed and replicated in a specialized icosahedral capsid with a T = 1 lattice consisting of 60 asymmetric capsid protein (CP) dimers. These capsids help to organize the viral genome and replicative complex( es). They also act as molecular sieves that isolate the virus genome from host defense mechanisms and allow the passage of nucleotides and viral transcripts. Rosellinia necatrix quadrivirus 1 (RnQV1), the type species of the family Quadriviridae, is a dsRNA fungal virus with a multipartite genome consisting of four monocistronic segments (segments 1 to 4). dsRNA-2 and dsRNA-4 encode two CPs (P2 and P4, respectively), which coassemble into similar to 450-angstrom-diameter capsids. We used three-dimensional cryo-electron microscopy combined with complementary biophysical techniques to determine the structures of RnQV1 virion strains W1075 and W1118. RnQV1 has a quadripartite genome, and the capsid is based on a single-shelled T = 1 lattice built of P2-P4 dimers. Whereas the RnQV1-W1118 capsid is built of full-length CP, P2 and P4 of RnQV1-W1075 are cleaved into several polypeptides, maintaining the capsid structural organization. RnQV1 heterodimers have a quaternary organization similar to that of homodimers of reoviruses and other dsRNA mycoviruses. The RnQV1 capsid is the first T = 1 capsid with a heterodimer as an asymmetric unit reported to date and follows the architectural principle for dsRNA viruses that a 120-subunit capsid is a conserved assembly that supports dsRNA replication and organization. IMPORTANCE Given their importance to health, members of the family Reoviridae are the basis of most structural and functional studies and provide much of our knowledge of dsRNA viruses. Analysis of bacterial, protozoal, and fungal dsRNA viruses has improved our understanding of their structure, function, and evolution, as well. Here, we studied a dsRNA virus that infects the fungus Rosellinia necatrix, an ascomycete that is pathogenic to a wide range of plants. Using three-dimensional cryo-electron microscopy and analytical ultracentrifugation analysis, we determined the structure and stoichiometry of Rosellinia necatrix quadrivirus 1 (RnQV1). The RnQV1 capsid is a T = 1 capsid with 60 heterodimers as the asymmetric units. The large amount of genetic information used by RnQV1 to construct a simple T = 1 capsid is probably related to the numerous virus-host and virus-virus interactions that it must face in its life cycle, which lacks an extracellular phase. C1 [Luque, Daniel; Mata, Carlos P.; Gonzalez, Jose M.; Gomez-Blanco, Josue; Caston, Jose R.] CSIC, CNB, Dept Struct Macromol, Madrid, Spain. [Luque, Daniel; Gonzalez-Camacho, Fernando] ISCIII, Ctr Nacl Microbiol, Carretera Majadahonda Pozuelo, Madrid, Spain. [Alfonso, Carlos; Rivas, German] CSIC, Ctr Invest Biol, Madrid, Spain. [Havens, Wendy M.; Ghabrial, Said A.] Univ Kentucky, Dept Plant Pathol, Lexington, KY 40546 USA. [Kanematsu, Satoko] Natl Agr & Food Res Org NARO, Inst Fruit Tree Sci, Morioka, Iwate, Japan. [Suzuki, Nobuhiro] Inst Plant Sci & Resources, Okayama, Japan. [Trus, Benes L.] NIH, Imaging Sci Lab, CIT, Bldg 10, Bethesda, MD 20892 USA. [Gonzalez, Jose M.] Wellcome Trust Sanger Inst, Cambridge, England. RP Caston, JR (reprint author), CSIC, CNB, Dept Struct Macromol, Madrid, Spain. EM jrcaston@cnb.csic.es RI Suzuki, Nobuhiro/B-2517-2011; Alfonso, Carlos/K-1316-2014; Luque, Daniel/I-6467-2015 OI Alfonso, Carlos/0000-0001-7165-4800; Luque, Daniel/0000-0002-0151-6020 FU Spanish Ministry of Economy and Competitively [BFU2014-52070-C2-2-P]; Spanish Ministry of Economy and Competitivity [BFU2014-55475 R]; Comunidad Autonoma de Madrid [S2013/MIT-2807]; Intramural Research Program of NIH; Ministry of Education, Culture, Science, Sports and Technology (MEXT) of Japan [16H06436] FX This work, including the efforts of Carlos Alfonso and German Rivas, was funded by Spanish Ministry of Economy and Competitively (BFU2014-52070-C2-2-P). This work, including the efforts of Jose R. Caston, was funded by Spanish Ministry of Economy and Competitivity (BFU2014-55475 R). This work, including the efforts of Jose R. Caston, was funded by Comunidad Autonoma de Madrid (S2013/MIT-2807). This work, including the efforts of Benes L. Trus, was funded by Intramural Research Program of the NIH. This work, including the efforts of Nobuhiro Suzuki, was funded by Ministry of Education, Culture, Science, Sports and Technology (MEXT) of Japan (16H06436). NR 63 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2016 VL 90 IS 24 BP 11220 EP 11230 DI 10.1128/JVI.01013-16 PG 11 WC Virology SC Virology GA EF2BL UT WOS:000390129300021 PM 27707923 ER PT J AU Bas-Hoogendam, JM Blackford, JU Bruhl, AB Blair, KS van der Wee, NJA Westenberg, PM AF Bas-Hoogendam, Janna Marie Blackford, Jennifer U. Bruhl, Annette B. Blair, Karina S. van der Wee, Nic J. A. Westenberg, P. Michiel TI Neurobiological candidate endophenotypes of social anxiety disorder SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Social anxiety disorder; Genetic vulnerability; Endophenotypes; Neuroimaging; Amygdala; Medial prefrontal cortex; Connectivity; Uncinate fasciculus ID DEFAULT MODE NETWORK; VOXEL-BASED MORPHOMETRY; CEREBRAL BLOOD-FLOW; COMORBIDITY SURVEY REPLICATION; BRAIN FUNCTIONAL CONNECTIVITY; AVOIDANT PERSONALITY-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; COGNITIVE-BEHAVIORAL THERAPY; PREDICTS ANXIOUS TEMPERAMENT; WHITE-MATTER MICROSTRUCTURE AB Social anxiety disorder (SAD) is a disabling psychiatric disorder with a complex pathogenesis. Studies indicate a genetic component in the development of SAD, but the search for genetic mechanisms underlying this vulnerability is complicated. A focus on endophenotypes instead of the disorder itself may provide a fruitful path forward. Endophenotypes are measurable characteristics related to complex psychiatric disorders and reflective of genetically-based disease mechanisms, and could shed light on the ways by which genes contribute to the development of SAD. We review evidence for candidate MRI endophenotypes of SAD and discuss the extent to which they meet the criteria for an endophenotype, focussing on the amygdala, the medial prefrontal cortex, whole-brain functional connectivity and structural-anatomical changes. Strongest evidence is present for the primary endophenotype criterion of association between the candidate endophenotypes and SAD, while the other criteria, involving trait-stability, heritability and co-segregation of the endophenotype with the disorder within families, warrant further investigation. We highlight the potential of neuroimaging endophenotypes and stress the need for family studies into SAD endophenotypes. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Bas-Hoogendam, Janna Marie; Westenberg, P. Michiel] Leiden Univ, Inst Psychol, Wassenaarseweg 52, NL-2333 AK Leiden, Netherlands. [Bas-Hoogendam, Janna Marie; van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Dept Psychiat, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. [Bas-Hoogendam, Janna Marie; van der Wee, Nic J. A.; Westenberg, P. Michiel] Leiden Inst Brain & Cognit, Leiden, Netherlands. [Blackford, Jennifer U.] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Blackford, Jennifer U.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Bruhl, Annette B.] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge, England. [Bruhl, Annette B.] Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, Zurich, Switzerland. [Blair, Karina S.] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bas-Hoogendam, JM (reprint author), Leiden Univ, Inst Psychol, Dev & Educ Psychol, Wassenaarseweg 52,Pieter Court Bldg,Room 3-B43, NL-2333 AK Leiden, Netherlands. EM j.m.hoogendam@fsw.leidenuniv.nl; jenni.blackford@Vanderbilt.Edu; abb41@medschl.cam.ac.uk; blair.karina@gmail.com; N.J.A.van_der_Wee@lumc.nl; westenberg@fsw.leidenuniv.nl FU Leiden University Research Profile 'Health, Prevention and the Human Life Cycle' FX This research has been funded by the Leiden University Research Profile 'Health, Prevention and the Human Life Cycle'. The funding source had no involvement in writing this review nor in the decision to submit this review for publication. We thank the Lorentz Center (Leiden, the Netherlands) for their support in organizing the workshop 'Endophenotypes of Social Anxiety Disorder: Can We Detect Them and Are They Useful in Clinical Practice?' (14-18 December 2015). This workshop was of high value for the preparation of the present review. NR 282 TC 0 Z9 0 U1 12 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD DEC PY 2016 VL 71 BP 362 EP 378 DI 10.1016/j.neubiorev.2016.08.040 PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EF7IA UT WOS:000390502100025 PM 27593443 ER PT J AU Radin, RM Shomaker, LB Kelly, NR Pickworth, CK Thompson, KA Brady, SM Demidowich, A Galescu, O Altschul, AM Shank, LM Yanovski, SZ Tanofsky-Kraff, M Yanovski, JA AF Radin, R. M. Shomaker, L. B. Kelly, N. R. Pickworth, C. K. Thompson, K. A. Brady, S. M. Demidowich, A. Galescu, O. Altschul, A. M. Shank, L. M. Yanovski, S. Z. Tanofsky-Kraff, M. Yanovski, J. A. TI Cortisol response to an induction of negative affect among adolescents with and without loss of control eating SO PEDIATRIC OBESITY LA English DT Article DE binge eating; loss of control eating; cortisol; depressive symptoms; adolescence ID DEPRESSIVE SYMPTOMS; INSULIN-RESISTANCE; DIURNAL CORTISOL; ADULT OBESITY; MEAL INTAKE; BINGE; STRESS; GIRLS; RISK; DISORDERS AB Background: Adults with binge eating disorder may have an exaggerated or blunted cortisol response to stress. Yet, limited data exist among youth who report loss of control (LOC) eating, a developmental precursor to binge eating disorder. Methods: We studied cortisol reactivity among 178 healthy adolescents with and without LOC eating. Following a buffet lunch meal adolescents were randomly assigned to watch a neutral or sad film clip. After, they were offered snacks from a multi-item array to assess eating in the absence of hunger. Salivary cortisol was collected at -80, 0, 30 and 50 min relative to film administration, and state mood ratings were reported before and after the film. Results: Adolescents with LOC had greater increases in negative affect during the experimental paradigm in both conditions (ps>0.05). Depressive symptoms, but not LOC, related to a greater cortisol response in the sad film condition (ps>0.05). Depressive symptoms and state LOC were related to different aspects of eating behaviour, independent of film condition or cortisol response (ps>0.05). Conclusions: A film clip that induced depressed state affect increased salivary cortisol only in adolescents with more elevated depressive symptoms. Adolescents with and without LOC were differentiated by greater increases in state depressed affect during laboratory test meals but had no difference in cortisol reactivity. Future studies are required to determine if adolescents with LOC manifest alterations in stress reactivity to alternative stress-inducing situations. C1 [Radin, R. M.; Shomaker, L. B.; Kelly, N. R.; Pickworth, C. K.; Thompson, K. A.; Brady, S. M.; Demidowich, A.; Galescu, O.; Altschul, A. M.; Shank, L. M.; Yanovski, S. Z.; Tanofsky-Kraff, M.; Yanovski, J. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Radin, R. M.; Kelly, N. R.; Shank, L. M.; Tanofsky-Kraff, M.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Shomaker, L. B.; Kelly, N. R.] Colorado State Univ, Dept Human Dev & Family Studies, 303 Behav Sci Bldg,410 Pitkin St, Ft Collins, CO 80523 USA. [Yanovski, S. Z.] Natl Inst Diabet Digest & Kidney Dis, Off Obes Res, Div Digest Dis & Nutr, NIH,DHHS, Bethesda, MD 20892 USA. RP Shomaker, LB (reprint author), Colorado State Univ, Dept Human Dev & Family Studies, 303 Behav Sci Bldg,410 Pitkin St, Ft Collins, CO 80523 USA. EM Lauren.Shomaker@colostate.edu OI Shank, Lisa/0000-0002-6922-7946 FU NIH National Research Service [F32HD056762]; NICHD [K99/R00HD069516]; NIH Intramural Research Program Grant from NICHD [1ZIAHD000641]; NIH Bench to Bedside Program; Office of Behavioral and Social Sciences Research FX R.M.R., L.B.S., M.T.K. and J.A.Y. conceived the hypothesis for this article. R.M.R., L.B.S., M.T.K. and J.A.Y. wrote the first draft of the manuscript. R.M.R., M.T.K., L.B.S. and J.A.Y. conducted data analysis. All authors (R.M.R., M.T.K., L.B.S., N.R.K., C.K.P., K.A.T., S.M.B., A.D., O.G., A.A., L.M.S., S.Z.Y. and J.A.Y.) participated in data collection, reviewed and edited the manuscript and approved the final version of the manuscript. J. Yanovski is a commissioned officer in the US Public Health Service (PHS). Funding for this study was provided by the following sources: NIH National Research Service Award F32HD056762 and Pathway to Independence Award K99/R00HD069516 (L. Shomaker) from NICHD; NIH Intramural Research Program Grant 1ZIAHD000641 (J. Yanovski) from NICHD with supplemental funding from the NIH Bench to Bedside Program and the Office of Behavioral and Social Sciences Research. The aforementioned funding source (NICHD) had no role in the study design, collection, analysis or interpretation of data, writing of the manuscript or decision to submit the paper for publication. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the PHS, USUHS or the US Department of Defense. Portions of this study were presented at The Obesity Society, Boston, MA, November, 2014. NR 32 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-6310 EI 2047-6302 J9 PEDIATR OBES JI Pediatr. Obes. PD DEC PY 2016 VL 11 IS 6 BP 513 EP 520 DI 10.1111/ijpo.12095 PG 8 WC Pediatrics SC Pediatrics GA EF0RF UT WOS:000390032800015 PM 26667312 ER PT J AU Krause, AJ Cines, B Pogrebniak, E Sherafat-Kazemzadeh, R Demidowich, AP Galescu, OA Brady, SM Reynolds, JC Hubbard, VS Yanovski, JA AF Krause, A. J. Cines, B. Pogrebniak, E. Sherafat-Kazemzadeh, R. Demidowich, A. P. Galescu, O. A. Brady, S. M. Reynolds, J. C. Hubbard, V. S. Yanovski, J. A. TI Associations between adiposity and indicators of thyroid status in children and adolescents SO PEDIATRIC OBESITY LA English DT Article DE Free thyroxine; obesity; paediatric; TSH ID BODY-MASS INDEX; OBESE CHILDREN; WEIGHT-LOSS; METABOLIC PARAMETERS; HORMONE-LEVELS; HYPOTHYROIDISM; INSULIN; TSH; THYROTROPIN; EXPRESSION AB Background: In adults, obesity is associated with abnormalities of thyroid function; there are fewer studies in paediatric cohorts. Objectives: To examine associations of weight and adiposity with indices of thyroid function and thyroid-related metabolic factors in children. Design/Methods: A sample of 1203 children without obesity (body mass index [BMI] <95th percentile; N=631) and with obesity (BMI >= 95th percentile; N=572), age 5-18 years, had height and weight measured (to calculate BMI-Z score for age and sex) and had blood collected in the morning for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and leptin. A subset (N=829) also underwent measurement of fat mass by dual-energy X-ray absorptiometry. Analyses examined associations of TSH and FT4 with adiposity and obesity-related conditions accounting for sociodemographic factors. Results: Thyroid-stimulating hormone was positively related to BMIz and fat mass (both p-values <0.001). FT4 was negatively related to BMIz and fat mass (both p-values <0.001). TSH was positively correlated to leptin (p=0.001) even after accounting for fat mass. Conclusions: Paediatric obesity is associated with higher TSH and lower FT4 concentrations and with a greater prevalence of abnormally high TSH. Leptin concentrations may in part explain obesity's effects on thyroid status, perhaps through leptin's effects on TSH secretion. C1 [Krause, A. J.; Cines, B.; Pogrebniak, E.; Sherafat-Kazemzadeh, R.; Demidowich, A. P.; Galescu, O. A.; Brady, S. M.; Yanovski, J. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Krause, A. J.; Hubbard, V. S.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, NIH, Div Nutr Res Coordinat, Bethesda, MD USA. [Reynolds, J. C.] NIH, Div Nucl Med, Radiol & Imaging Sci Dept, Hatfield Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM jy15i@nih.gov FU National Institutes of Child Health and Human Development/NIH Intramural Research Program Grant from NIMHD [ZIAHD000641]; NIH Division of Nutrition Research Coordination, NIDDK, NIH FX J. A. Yanovski was supported by the National Institutes of Child Health and Human Development/NIH Intramural Research Program Grant ZIAHD000641 with supplemental funding from NIMHD. A. Krause was supported by the NIH Division of Nutrition Research Coordination, NIDDK, NIH. NR 30 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-6310 EI 2047-6302 J9 PEDIATR OBES JI Pediatr. Obes. PD DEC PY 2016 VL 11 IS 6 BP 551 EP 558 DI 10.1111/ijpo.12112 PG 8 WC Pediatrics SC Pediatrics GA EF0RF UT WOS:000390032800020 PM 26910299 ER PT J AU Schwarz, B Morabito, KM Ruckwardt, TJ Patterson, DP Avera, J Miettinen, HM Graham, BS Douglas, T AF Schwarz, Benjamin Morabito, Kaitlyn M. Ruckwardt, Tracy J. Patterson, Dustin P. Avera, John Miettinen, Heini M. Graham, Barney S. Douglas, Trevor TI Viruslike Particles Encapsidating Respiratory Syncytial Virus M and M2 Proteins Induce Robust T Cell Responses SO ACS BIOMATERIALS SCIENCE & ENGINEERING LA English DT Article DE subunit vaccine; viruslike particle; respiratory syncytial virus; CD8+T cell immunity; tissue-resident memory T cells ID RANDOMIZED CONTROLLED-TRIAL; VACCINE DEVELOPMENT; BACTERIOPHAGE P22; DENDRITIC CELLS; INFECTION; INFLUENZA; MICE; LYMPHOCYTES; PLATFORM; MODEL AB Subunit vaccines provide a safe, focused alternative to conventional vaccines. However, these vaccines often require significant adjuvants and are particularly hard to target toward cytotoxic T lymphocyte (CTL) immunity. Viruslike particles (VLPs) provide biomaterial scaffolds with pathogen-like polyvalent structures making them useful platforms for biomimetic antigen delivery to the immune system. Encapsidation of antigens within VLPs has been shown to enhance antigen availability for CD8 T cell responses. Here, we examine the potential to generate complex responses to multiple subunit antigens localized within the same VLP particle. Two proteins of respiratory syncytial virus (RSV) with well-characterized CD8 T cell responses, the matrix (M) and matrix 2 (M2) proteins, were successfully coencapsidated within the P22 VLP. Upon intranasal administration in mice, the particles stimulated CD8 T cell memory responses against both antigens. In addition, vaccination elicited tissue-resident T cell populations. Upon subsequent RSV challenge, P22-M/M2-treated mice displayed significantly reduced lung viral titers. This demonstrates the utility of the P22 VLP in directing immune responses to multiple encapsidated viral antigens, demonstrating the potential of this technology to facilitate immunity to multiple targets simultaneously. C1 [Schwarz, Benjamin; Avera, John; Douglas, Trevor] Indiana Univ, Dept Chem, 800 East Kirkwood Ave, Bloomington, IN 47405 USA. [Morabito, Kaitlyn M.; Ruckwardt, Tracy J.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Morabito, Kaitlyn M.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. [Patterson, Dustin P.] Univ Texas Tyler, Dept Chem & Biochem, 3900 Univ Blvd, Tyler, TX 75799 USA. [Miettinen, Heini M.] Montana State Univ, Dept Microbiol & Immunol, POB 173400, Bozeman, MT 59717 USA. RP Douglas, T (reprint author), Indiana Univ, Dept Chem, 800 East Kirkwood Ave, Bloomington, IN 47405 USA.; Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@mail.nih.gov; trevdoug@indiana.edu RI Douglas, Trevor/F-2748-2011 FU NIH [R01 AI104905, R01 EB012027]; Department of Defense (DoD) Air Force Office of Sponsored Research through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program; Intramural National Institute of Allergy and Infectious diseases FX Research supported by NIH grants NIH grants R01 AI104905 and R01 EB012027. B.S. was supported by the Department of Defense (DoD) Air Force Office of Sponsored Research through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program. All animal work was supported by Intramural National Institute of Allergy and Infectious diseases. NR 53 TC 0 Z9 0 U1 6 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-9878 J9 ACS BIOMATER SCI ENG JI ACS Biomater. Sci. Eng. PD DEC PY 2016 VL 2 IS 12 BP 2324 EP 2332 DI 10.1021/acsbiomaterials.6b00532 PG 9 WC Materials Science, Biomaterials SC Materials Science GA EE7IN UT WOS:000389789200022 ER PT J AU Jose, GS Jackson, ER Haymond, A Johny, C Edwards, RL Wang, X Brothers, RC Edelstein, EK Odom, AR Boshoff, HI Couch, RD Dowd, CS AF Jose, Geraldine San Jackson, Emily R. Haymond, Amanda Johny, Chinchu Edwards, Rachel L. Wang, Xu Brothers, R. Carl Edelstein, Emma K. Odom, Audrey R. Boshoff, Helena I. Couch, Robin D. Dowd, Cynthia S. TI Structure-Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis SO ACS INFECTIOUS DISEASES LA English DT Article DE MEP pathway; antibiotic; phosphonate prodrug; Mycobacterium tuberculosis; Yersinia pestis ID 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE; NON-MEVALONATE-PATHWAY; SUBSTITUTED FOSMIDOMYCIN ANALOGS; ISOPRENOID BIOSYNTHESIS; NONMEVALONATE PATHWAY; TERPENOID BIOSYNTHESIS; RESISTANCE; ANTIMALARIAL; ANTIBACTERIAL; DISCOVERY AB Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended N-acyl or O-linked alkyl/aryl group and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homologue, with the best analogs displaying nanomolar ICso values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and dipivaloyloxymethyl (POM) prodrug esters of these compounds were made. While the added lipophilicity did not enhance Yersinia activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3-12 pg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologues from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development. C1 [Jose, Geraldine San; Jackson, Emily R.; Wang, Xu; Brothers, R. Carl; Edelstein, Emma K.; Dowd, Cynthia S.] George Washington Univ, Dept Chem, 800 22nd St NW, Washington, DC 20052 USA. [Haymond, Amanda; Johny, Chinchu; Couch, Robin D.] George Mason Univ, Dept Chem & Biochem, 10900 Univ Blvd, Manassas, VA 20110 USA. [Edwards, Rachel L.; Odom, Audrey R.] Washington Univ, Sch Med, Dept Pediat, 660 S Euclid Ave, St Louis, MO 63110 USA. [Boshoff, Helena I.] NIAID, TB Res Sect, LCID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Dowd, CS (reprint author), George Washington Univ, Dept Chem, 800 22nd St NW, Washington, DC 20052 USA. EM cdowd@gwu.edu OI Edwards, Rachel/0000-0002-7928-7440 FU George Washington University's Department of Chemistry; University Facilitating Fund, NIH [AI086453, AI103280, AI123808]; George Mason University's Department of Chemistry and Biochemistry, the U.S. Army Medical Research and Materiel Command [W23RYX1291N601]; Division of Intramural Research, NIAID, NIH FX We gratefully acknowledge technical assistance from Teresa Hawley (GWU Medical Center), Joshua Wilhide (UMBC), and Phil Mortimer OHU) for assistance with HRMS analysis. Financial support was provided by George Washington University's Department of Chemistry and University Facilitating Fund, NIH (Grant AI086453 to C.S.D. and Grants AI103280 and AI123808 to A.R.O.), George Mason University's Department of Chemistry and Biochemistry, the U.S. Army Medical Research and Materiel Command (Grant W23RYX1291N601 to R.D.C.), and the Division of Intramural Research, NIAID, NIH. NR 47 TC 0 Z9 0 U1 9 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD DEC PY 2016 VL 2 IS 12 BP 35 EP 47 DI 10.1021/acsinfecdis.6b00125 PG 13 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA EE6QY UT WOS:000389738500004 ER PT J AU Evans, JC Trujillo, C Wang, Z Eoh, H Ehrt, S Schnappinger, D Boshoff, HIM Rhee, KY Barry, CE Mizrahi, V AF Evans, Joanna C. Trujillo, Carolina Wang, Zhe Eoh, Hyungjin Ehrt, Sabine Schnappinger, Dirk Boshoff, Helena I. M. Rhee, Kyu Y. Barry, Clifton E., III Mizrahi, Valerie TI Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis SO ACS INFECTIOUS DISEASES LA English DT Article DE tuberculosis; drug discovery; CoA; pantetheine; CoaBC ID ACYL CARRIER PROTEIN; MECHANISTICALLY DIVERSE INHIBITORS; MYCOLIC ACID BIOSYNTHESIS; PANTOTHENATE KINASE; ESCHERICHIA-COLI; PHOSPHOPANTETHEINE ADENYLYLTRANSFERASE; PYRAZINAMIDE RESISTANCE; ASPARTATE DECARBOXYLASE; REACTION INTERMEDIATE; GENE-EXPRESSION AB Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target. C1 [Evans, Joanna C.; Barry, Clifton E., III; Mizrahi, Valerie] Univ Cape Town, Fac Hlth Sci, MRC NHLS UCT Mol Mycobacteriol Res Unit, Anzio Rd, ZA-7925 Observatory, South Africa. [Evans, Joanna C.; Barry, Clifton E., III; Mizrahi, Valerie] Univ Cape Town, Fac Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Inst Infect Dis & Mol Med, Anzio Rd, ZA-7925 Observatory, South Africa. [Evans, Joanna C.; Barry, Clifton E., III; Mizrahi, Valerie] Univ Cape Town, Fac Hlth Sci, Dept Pathol, Anzio Rd, ZA-7925 Observatory, South Africa. [Trujillo, Carolina; Wang, Zhe; Eoh, Hyungjin; Ehrt, Sabine; Schnappinger, Dirk; Rhee, Kyu Y.] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA. [Wang, Zhe; Eoh, Hyungjin; Rhee, Kyu Y.] Weill Cornell Med Coll, Dept Med, Div Infect Dis, New York, NY 10065 USA. [Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Eoh, Hyungjin] Univ Southern Calif, Zilkha Neurogenet Inst, Keck Sch Med, Dept Mol Microbiol & Immunol, 1501 San Pablo St, Los Angeles, CA 90033 USA. RP Mizrahi, V (reprint author), Univ Cape Town, Fac Hlth Sci, MRC NHLS UCT Mol Mycobacteriol Res Unit, Anzio Rd, ZA-7925 Observatory, South Africa.; Mizrahi, V (reprint author), Univ Cape Town, Fac Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Inst Infect Dis & Mol Med, Anzio Rd, ZA-7925 Observatory, South Africa.; Mizrahi, V (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Pathol, Anzio Rd, ZA-7925 Observatory, South Africa. EM valerie.mizrahi@uct.ac.za FU TB Drug Accelerator program of the Bill and Melinda Gates Foundation; South African Medical Research Council; National Research Foundation of South Africa; International Research Scholar's grant from the HHMI; Intramural Research Program of NIAID FX This work was supported by grants from the TB Drug Accelerator program of the Bill and Melinda Gates Foundation (to C.E.B. III, K.Y.R, D.S., and V.M.); the South African Medical Research Council; the National Research Foundation of South Africa, and an International Research Scholar's grant from the HHMI (to V.M.); and, in part, by the Intramural Research Program of NIAID (H.I.M.B. and C.E.B. HI). We thank Erick Strauss for valuable discussions and for kindly providing P-PantSH, Jonathan Blackburn and Nelson Soares for advice and assistance with mass spectrometry, and Digby Warner for helpful discussions and for critically reviewing the manuscript. NR 69 TC 1 Z9 1 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD DEC PY 2016 VL 2 IS 12 BP 70 EP 80 DI 10.1021/acsinfecdis.6b00150 PG 11 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA EE6QY UT WOS:000389738500007 PM 27676316 ER PT J AU Pilotto, A Gallina, P Panza, F Copetti, M Cella, A Cruz-Jentoft, A Daragjati, J Ferrucci, L Maggi, S Mattace-Raso, F Paccalin, M Polidori, MC Topinkova, E Trifiro, G Welmer, AK Strandberg, T Marchionni, N AF Pilotto, Alberto Gallina, Pietro Panza, Francesco Copetti, Massimiliano Cella, Alberto Cruz-Jentoft, Alfonso Daragjati, Julia Ferrucci, Luigi Maggi, Stefania Mattace-Raso, Francesco Paccalin, Marc Polidori, Maria Cristina Topinkova, Eva Trifiro, Gianluca Welmer, Anna-Karin Strandberg, Timo Marchionni, Niccolo CA MPI AGE Project Investigators TI Relation of Statin Use and Mortality in Community-Dwelling Frail Older Patients With Coronary Artery Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MULTIDIMENSIONAL PROGNOSTIC INDEX; ACUTE MYOCARDIAL-INFARCTION; ADULTS; VALIDATION; GUIDELINES; THERAPY; CARE; MEN AB Clinical decision-making for statin treatment in older patients with coronary artery disease (CAD) is under debate, particularly in community-dwelling frail patients at high risk of death. In this retrospective observational study on 2,597 community-dwelling patients aged >= 65 years with a previous hospitalization for CAD, we estimated mortality risk assessed with the Multidimensional Prognostic Index (MPI), based on the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA), used to determine accessibility to homecare services/nursing home admission in 2005 to 2013 in the Padua Health District, Veneto, Italy. Participants were categorized as having mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) baseline mortality risk, and propensity score-adjusted hazard ratios (HRs) of 3-year mortality rate were calculated according to statin treatment in these subgroups. Greater MPI-SVaMA scores were associated with lower rates of statin treatment and higher 3-year mortality rate (MPI-SVaMA-1 = 23.4%; MPI-SVaMA-2 = 39.1%; MPI-SVaMA-3 = 76.2%). After adjusting for propensity score quintiles, statin treatment was associated with lower 3-year mortality risk irrespective of MPI-SVaMA group (HRs [95% confidence intervals] 0.45 [0.37 to 0.55], 0.44 [0.36 to 0.53], and 0.28 [0.21 to 0.39] in MPI-SVaMA-1,-2, and-3 groups, respectively [interaction test p = 0.202]). Subgroup analyses showed that statin treatment was also beneficial irrespective of age (HRs [95% confidence intervals] 0.38 [0.27 to 0.53], 0.45 [0.38 to 0.54], and 0.44 [0.37 to 0.54] in 65 to 74, 75 to 84, and Z85 year age groups, respectively [interaction test p = 0.597]). In conclusion, in community-dwelling frail older patients with CAD, statin treatment was significantly associated with reduced 3-year mortality rate irrespective of age and multidimensional impairment, although the frailest patients were less likely to be treated with statins. (C) 2016 Elsevier Inc. All rights reserved. C1 [Pilotto, Alberto; Cella, Alberto] Natl Relevance & High Specializat Hosp, EO Galliera Hosp, Dept Geriatr Care OrthoGeriatr & Rehabil, Frailty Area, Genoa, Italy. [Pilotto, Alberto; Daragjati, Julia] S Antonio Hosp, Azienda ULSS Padova 16, Geriatr Unit, Padua, Italy. [Gallina, Pietro] Azienda ULSS 16, Hlth Directorate, Padua, Italy. [Panza, Francesco] Univ Ban Aldo Moro, Dept Basic Med Neurosci & Sense Organs, Neurodegenerat Dis Unit, Bari, Italy. [Copetti, Massimiliano] IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Unit Biostat, Foggia, Italy. [Cruz-Jentoft, Alfonso] Hosp Univ Ramon & Cajal, Madrid, Spain. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Maggi, Stefania] CNR, Neurosci Sect, Padua, Italy. [Mattace-Raso, Francesco; Trifiro, Gianluca] Erasmus MC, Rotterdam, Netherlands. [Paccalin, Marc] Univ Hosp Poitiers, Poitiers, France. [Polidori, Maria Cristina] Univ Cologne, Dept Med 2, Unit Aging Clin Res, Cologne, Germany. [Topinkova, Eva] Univ Charles I, Prague, Czech Republic. [Trifiro, Gianluca] Univ Messina, Messina, Italy. [Welmer, Anna-Karin] Karolinska Inst, Aging Res Ctr, Stockholm, Sweden. [Strandberg, Timo] Univ Helsinki, Dept Med, Geriatr Clin, Helsinki, Finland. [Strandberg, Timo] Univ Oulu, Inst Hlth Sci Geriatr, Oulu, Finland. [Strandberg, Timo] Oulu Univ Hosp, Oulu, Finland. [Marchionni, Niccolo] Univ Florence, Div Geriatr Cardiol & Med, Florence, Italy. RP Panza, F (reprint author), Univ Ban Aldo Moro, Dept Basic Med Neurosci & Sense Organs, Neurodegenerat Dis Unit, Bari, Italy. EM geriat.dot@geriatria.uniba.it OI strandberg, timo/0000-0001-6299-925X FU MPI_AGE European project - Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) in the frame of the European Innovation Partnership on Active and Healthy Aging Second Health Program FX This work was supported from the MPI_AGE European project co-funded by the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) in the frame of the European Innovation Partnership on Active and Healthy Aging Second Health Program 2008-2013. NR 26 TC 1 Z9 1 U1 4 U2 4 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 DEC 1 PY 2016 VL 118 IS 11 BP 1624 EP 1630 DI 10.1016/j.amjcard.2016.08.042 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE5YS UT WOS:000389686100003 PM 27670793 ER PT J AU Borgogna, JL Roberts, D Rath, JM Glover, ED Ravel, J Shardell, M Yeoman, CJ Brotman, RM Nelson, TM AF Borgogna, Joanna-Lynn Roberts, Dave Rath, Jessica M. Glover, Elbert D. Ravel, Jacques Shardell, Michelle Yeoman, Carl J. Brotman, Rebecca M. Nelson, Tiffanie M. TI Cigarette smoking is associated with an altered metabolomic profile of the vaginal environment SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology (ISDOG) CY AUG 11-13, 2016 CL Annapolis, MD SP Infect Dis Soc Obstet & Gynecol C1 [Borgogna, Joanna-Lynn; Roberts, Dave; Yeoman, Carl J.; Nelson, Tiffanie M.] Montana State Univ, Bozeman, MT 59717 USA. [Rath, Jessica M.; Glover, Elbert D.; Ravel, Jacques; Brotman, Rebecca M.] Univ Maryland, Baltimore, MD 21201 USA. [Shardell, Michelle] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2016 VL 215 IS 6 MA 3 BP 815 EP 815 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RM UT WOS:000389514400055 ER PT J AU Guterman, J Pawlitz, MD Pei, B Goyert, J Puder, KS Gonik, B Chen, K AF Guterman, J. Pawlitz, M. D. Pei, B. Goyert, J. Puder, K. S. Gonik, B. Chen, K. TI Maternal immunoglobulin D induced by antepartum vaccination undergoes placental transfer to the fetus SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology (ISDOG) CY AUG 11-13, 2016 CL Annapolis, MD SP Infect Dis Soc Obstet & Gynecol C1 [Guterman, J.; Pawlitz, M. D.; Pei, B.; Goyert, J.; Puder, K. S.; Gonik, B.; Chen, K.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Pawlitz, M. D.; Pei, B.; Goyert, J.; Chen, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI 48201 USA. [Pawlitz, M. D.; Chen, K.] Wayne State Univ, Grad Program Immunol & Microbiol, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Chen, K.] Wayne State Univ, Dept Oncol, Detroit, MI 48201 USA. [Chen, K.] Barbara Ann Karmanos Canc Ctr, Tumor Biol & Microenvironm Program, Detroit, MI 48201 USA. [Chen, K.] NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2016 VL 215 IS 6 MA 24 BP 825 EP 825 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RM UT WOS:000389514400076 ER PT J AU Bressler, LH Bernardi, LA De Chavez, PJD Baird, DD Carnethon, MR Marsh, EE AF Bressler, Leah Hawkins Bernardi, Lia A. De Chavez, Peter John D. Baird, Donna D. Carnethon, Mercedes R. Marsh, Erica E. TI Alcohol, cigarette smoking, and ovarian reserve in reproductive-age African-American women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE alcohol; anti-Mullerian hormone; cigarette smoking; ovarian reserve; second-hand smoke ID ANTI-MULLERIAN HORMONE; IN-VITRO FERTILIZATION; ANTRAL FOLLICLE COUNT; ANTIMULLERIAN HORMONE; LIFE-STYLE; ENVIRONMENTAL-FACTORS; RISK-FACTORS; CONSUMPTION; MENOPAUSE; FECUNDABILITY AB BACKGROUND: Although alcohol consumption and cigarette smoking are common behaviors in reproductive-age women, little is known about the impact of consumption patterns on ovarian reserve. Even less is known about the effects of smoking and alcohol use in reproductive-age African-American women. OBJECTIVE: The objective of the study was to examine the impact of the patterns of alcohol intake and cigarette smoking on anti-Mullerian hormone levels as a marker of ovarian reserve in African-American women. STUDY DESIGN: This was a cross-sectional analysis from the baseline clinical visit and data collection of the Study of Environment, Lifestyle, and Fibroids performed by the National Institute of Environmental Health Sciences. A total of 1654 volunteers, aged 23-34 years, recruited from the Detroit, Michigan community completed questionnaires on alcohol intake and cigarette smoking and provided serum for anti-Mullerian hormone measurement. Multivariable linear and logistic regressions were used as appropriate to estimate the effect of a range of exposure patterns on anti-Mullerian hormone levels while adjusting for potential confounders including age, body mass index, and hormonal contraception. RESULTS: Most participants were alcohol drinkers (74%). Of those, the majority (74%) engaged in binge drinking at least once in the last year. Women who reported binge drinking twice weekly or more had 26% lower anti-Mullerian hormone levels compared with current drinkers who never binged (95% confidence interval, -44, -2, P < .04). Other alcohol consumption patterns (both past and current) were unrelated to anti-Mullerian hormone. The minority of participants currently (19%) or formerly (7%) smoked, and only 4% of current smokers used a pack a day or more. Neither smoking status nor second-hand smoke exposure in utero, childhood, or adulthood was associated with anti-Mullerian hormone levels. CONCLUSION: Results suggest that current, frequent binge drinking may have an adverse impact on ovarian reserve. Other drinking and smoking exposures were not associated with anti-Mullerian hormone in this cohort of healthy, young, African-American women. A longitudinal study of how these common lifestyle behaviors have an impact on the variability in age-adjusted anti-Mullerian hormone levels is merited. C1 [Bressler, Leah Hawkins; Bernardi, Lia A.; Marsh, Erica E.] Northwestern Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chicago, IL 60611 USA. [De Chavez, Peter John D.; Carnethon, Mercedes R.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Baird, Donna D.] NIEHS, Dept Epidemiol, POB 12233, Res Triangle Pk, NC 27709 USA. RP Marsh, EE (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chicago, IL 60611 USA. EM erica-marsh@northwestern.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU National Institutes of Health [R21HD077479-01, K12HD050121]; Robert Wood Johnson Foundation; Friends of Prentice; Evergreen Invitational; Woman's Board; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; American Recovery and Reinvestment Act FX This study was supported by National Institutes of Health grant R21HD077479-01; National Institutes of Health Grant K12HD050121-Northwestern University Women's Reproductive Health scholar award; Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation, Friends of Prentice, Evergreen Invitational, Woman's Board. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, and in part by funds allocated for health research by the American Recovery and Reinvestment Act. NR 49 TC 0 Z9 0 U1 15 U2 15 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 DEC PY 2016 VL 215 IS 6 AR 758.e1-9 DI 10.1016/j.ajog.2016.07.012 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RM UT WOS:000389514400018 ER PT J AU Knickelbein, JE Tucker, WR Bhatt, N Armbrust, K Valent, D Obiyor, D Nussenblatt, RB Sen, HN AF Knickelbein, Jared E. Tucker, William R. Bhatt, Nirali Armbrust, Karen Valent, David Obiyor, Dominic Nussenblatt, Robert B. Sen, H. Nida TI Gevokizumab in the Treatment of Autoimmune Non-necrotizing Anterior Scleritis: Results of a Phase I/II Clinical Trial SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID RHEUMATOID-ARTHRITIS; BEHCETS-DISEASE; RITUXIMAB; EFFICACY; THERAPY AB PURPOSE: To evaluate the safety and potential efficacy of gevokizumab, an anti-interleukin 1 beta (IL-1 beta) monoclonal antibody, in the treatment of active, noninfectious, non-necrotizing anterior scleritis. DESIGN: Phase 1/2, open label, nonrandomized, prospective, single-arm pilot trial. METHODS: Eight patients with active, noninfectious, non-necrotizing anterior scleritis with a scleral inflammatory grade of +1 to +3 in at least 1 eye were enrolled. In 1 patient both eyes were enrolled, for a total of 9 eyes (4 eyes with +1, 1 eye with +2, and 4 eyes with +3). Patients received 1 subcutaneous injection of 60 mg gevokizumab at baseline and then every 4 weeks for 12 weeks. Complete physical and ocular examinations were performed at each visit. The primary outcome was at least a 2-step reduction or reduction to grade 0 in scleral inflammation on a 0 to +4 scale according to a standardized photographic scleritis grading system by 16 weeks in the study eye compared to baseline. Secondary outcomes included changes in visual acuity, intraocular pressure, and trends in scleral grading. Participants who met the primary outcome were eligible to continue in the study for up to 52 weeks and received additional gevokizumab injections every 4 weeks until week 36, followed by 2 safety visits at weeks 40 and 52. RESULTS: Seven eyes from 7 patients met the primary outcome within a median time of 2 weeks following the first gevokizumab injection. No definitive changes in visual acuity or intraocular pressure were identified. There were no serious adverse events related to the study drug. A total of 43 adverse effects were reported, with 93% described as mild, 95% as nonocular, and only 14% deemed possibly caused by the investigational treatment. CONCLUSIONS: The results of this small study suggest that blockage of IL-1 beta using gevokizumab may be beneficial in treating active, noninfectious anterior scleritis and that gevokizumab is well tolerated. Larger randomized trials are warranted to assess the true efficacy of gevokizumab in the treatment of non-necrotizing anterior scleritis. Published by Elsevier Inc. C1 [Knickelbein, Jared E.; Tucker, William R.; Bhatt, Nirali; Armbrust, Karen; Valent, David; Obiyor, Dominic; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU INTRAMURAL RESEARCH PROGRAM OF THE NIH, NEI FX THIS RESEARCH WAS SUPPORTED BY THE INTRAMURAL RESEARCH PROGRAM OF THE NIH, NEI. THE STUDY medication was provided by XOMA Corporation (Berkeley, California, USA). NR 21 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 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2016 VL 172 BP 104 EP 110 DI 10.1016/j.ajo.2016.09.017 PG 7 WC Ophthalmology SC Ophthalmology GA EE5AF UT WOS:000389616400015 PM 27663070 ER PT J AU Jung, HJ Kwon, TH AF Jung, Hyun Jun Kwon, Tae-Hwan TI Molecular mechanisms regulating aquaporin-2 in kidney collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE arginine vasopressin; aquaporin-2; body water balance; intracellular trafficking ID NEPHROGENIC DIABETES-INSIPIDUS; RENAL PRINCIPAL CELLS; WATER CHANNEL AQUAPORIN-2; PROTEIN-KINASE-A; VASOPRESSIN-MEDIATED TRANSLOCATION; BLADDER EPITHELIAL-CELLS; THICK ASCENDING LIMB; LC-MS/MS ANALYSIS; RAT-KIDNEY; APICAL MEMBRANE AB The kidney collecting duct is an important renal tubular segment for regulation of body water homeostasis and urine concentration. Water reabsorption in the collecting duct principal cells is controlled by vasopressin, a peptide hormone that induces the osmotic water transport across the collecting duct epithelia through regulation of water channel proteins aquaporin-2 (AQP2) and aquaporin-3 (AQP3). In particular, vasopressin induces both intracellular translocation of AQP2-bearing vesicles to the apical plasma membrane and transcription of the Aqp2 gene to increase AQP2 protein abundance. The signaling pathways, including AQP2 phosphorylation, RhoA phosphorylation, intracellular calcium mobilization, and actin depolymerization, play a key role in the translocation of AQP2. This review summarizes recent data demonstrating the regulation of AQP2 as the underlying molecular mechanism for the homeostasis of water balance in the body. C1 [Jung, Hyun Jun] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kwon, Tae-Hwan] Kyungpook Natl Univ, Sch Med, Dept Biochem & Cell Biol, Dongin Dong 101, Taegu 41944, South Korea. RP Kwon, TH (reprint author), Kyungpook Natl Univ, Sch Med, Dept Biochem & Cell Biol, Dongin Dong 101, Taegu 41944, South Korea. EM thkwon@knu.ac.kr FU National Research Foundation of Korea (NRF) - Ministry of Science, ICT, and Future Planning, Korea [2014R1A5A2009242, 2016R1A2B4009365] FX This study was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning, Korea (2014R1A5A2009242 and 2016R1A2B4009365). NR 161 TC 0 Z9 0 U1 14 U2 14 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC 1 PY 2016 VL 311 IS 6 BP F1318 EP F1328 DI 10.1152/ajprenal.00485.2016 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EE5KW UT WOS:000389647100026 PM 27760771 ER PT J AU Brown, J Grudzen, C Kyriacou, DN Obermeyer, Z Quest, T Rivera, D Stone, S Wright, J Shelburne, N AF Brown, Jeremy Grudzen, Corita Kyriacou, Demetrios N. Obermeyer, Ziad Quest, Tammie Rivera, Donna Stone, Susan Wright, Jason Shelburne, Nonniekaye TI The Emergency Care of Patients With Cancer: Setting the Research Agenda SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; CLINICAL-PRACTICE GUIDELINE; RANDOMIZED CONTROLLED-TRIAL; TO-BALLOON TIME; FEBRILE NEUTROPENIA; PALLIATIVE CARE; ACUTE-LEUKEMIA; MANAGEMENT; FEVER; ONCOLOGY AB To identify research priorities and appropriate resources and to establish the infrastructure required to address the emergency care of patients with cancer, the National Institutes of Health's National Cancer Institute and the Office of Emergency Care Research sponsored a one-day workshop, "Cancer and Emergency Medicine: Setting the Research Agenda," in March 2015 in Bethesda, MD. Participants included leading researchers and clinicians in the fields of oncology, emergency medicine, and palliative care, and representatives from the National Institutes of Health. Attendees were charged with identifying research opportunities and priorities to advance the understanding of the emergency care of cancer patients. Recommendations were made in 4 areas: the collection of epidemioiogic data, care of the patient with febrile neutropenia, acute events such as dyspnea, and palliative care in the emergency department setting. C1 [Brown, Jeremy] NYU, Sch Med, Natl Inst Gen Med Sci, Off Emergency Care Res, New York, NY USA. [Grudzen, Corita] NYU, Sch Med, Dept Emergency Med, New York, NY USA. [Kyriacou, Demetrios N.] Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Chicago, IL 60611 USA. [Obermeyer, Ziad] Harvard Med Sch, Dept Emergency Med & Hlth Care Policy, Boston, MA USA. [Quest, Tammie] Emory Univ, Dept Emergency Med, Atlanta, GA 30322 USA. [Quest, Tammie] Emory Univ, Div Geriatr & Gerontol, Atlanta, GA 30322 USA. [Rivera, Donna; Shelburne, Nonniekaye] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Stone, Susan] Cedars Sinai Med Ctr, Palliat Care Serv, Los Angeles, CA 90048 USA. [Wright, Jason] Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Brown, J (reprint author), NYU, Sch Med, Natl Inst Gen Med Sci, Off Emergency Care Res, New York, NY USA. EM jeremy.brown@nih.gov OI Grudzen, Corita/0000-0003-3039-8497 NR 40 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 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2016 VL 68 IS 6 BP 706 EP 711 DI 10.1016/j.annemergmed.2016.01.021 PG 6 WC Emergency Medicine SC Emergency Medicine GA ED9BJ UT WOS:000389164800011 ER PT J AU Takeuchi, M Ombrello, MJ Kirino, Y Erer, B Tugal-Tutkun, I Seyahi, E Ozyazgan, Y Watts, NR Gul, A Kastner, DL Remmers, EF AF Takeuchi, Masaki Ombrello, Michael J. Kirino, Yohei Erer, Burak Tugal-Tutkun, Ilknur Seyahi, Emire Ozyazgan, Yilmaz Watts, Norman R. Gul, Ahmet Kastner, Daniel L. Remmers, Elaine F. TI A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behcet's disease in HLA-B(star)51 carriers SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID GENOME-WIDE ASSOCIATION; ANKYLOSING-SPONDYLITIS; SUSCEPTIBILITY LOCI; ERAP1; INDIVIDUALS; HAPLOTYPE; HLA-B27 AB Introduction Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behcet's disease. Methods Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behcet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behcet's disease risk were determined by haplotype identification and disease association analyses. Results One ERAP1 protein allotype with five nonancestral amino acids was recessively associated with disease (p=3.13x10(-6), OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B(star)51. Individuals who carry HLA-B(star)51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80x10(-20), OR 10.96, 95% CI 5.91 to 20.32). Discussion The Behcet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B(star)51, these data suggest that a hypoactive ERAP1 allotype contributes to Behcet's disease risk by altering the peptides available for binding to HLA-B(star)51. C1 [Takeuchi, Masaki; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, 10 Ctr Dr,MSC 1849,Bldg 10 CRC East,Room B2-5235, Bethesda, MD 20892 USA. [Takeuchi, Masaki] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa, Japan. [Ombrello, Michael J.] NIAMSD, Translat Genet & Genom Unit, Bethesda, MD 20892 USA. [Kirino, Yohei] Yokohama City Univ, Grad Sch Med, Dept Stem Cell & Immune Regulat, Yokohama, Kanagawa 232, Japan. [Erer, Burak; Tugal-Tutkun, Ilknur; Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey. [Seyahi, Emire; Ozyazgan, Yilmaz] Istanbul Univ, Cerrahpasa Fac Med, Istanbul, Turkey. [Watts, Norman R.] NIAMSD, Prot Express Lab, Bethesda, MD 20892 USA. RP Remmers, EF (reprint author), NHGRI, Inflammatory Dis Sect, 10 Ctr Dr,MSC 1849,Bldg 10 CRC East,Room B2-5235, Bethesda, MD 20892 USA. EM remmerse@mail.nih.gov RI 桐野, 洋平/B-3701-2009 OI 桐野, 洋平/0000-0002-9488-661X FU National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Japan Society for the Promotion of Science [26713036]; Naito Memorial Foundation; Kanae Foundation for the Promotion of Medical Science; Yokohama Foundation for Advancement of Medical Science FX This study was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Kirino is supported by grants from Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant No. 26713036), the Naito Memorial Foundation, the Kanae Foundation for the Promotion of Medical Science and Yokohama Foundation for Advancement of Medical Science. NR 17 TC 1 Z9 1 U1 1 U2 1 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 DEC PY 2016 VL 75 IS 12 BP 2208 EP 2211 DI 10.1136/annrheumdis-2015-209059 PG 4 WC Rheumatology SC Rheumatology GA EE1JZ UT WOS:000389338900032 PM 27217550 ER PT J AU Duffy, VB Rawal, S Park, J Brand, MH Sharafi, M Bolling, BW AF Duffy, Valerie B. Rawal, Shristi Park, Jeeha Brand, Mark H. Sharafi, Mastaneh Bolling, Bradley W. TI Characterizing and improving the sensory and hedonic responses to polyphenol-rich aronia berry juice SO APPETITE LA English DT Article DE Food preferences; Beverages/*analysis; Psychophysics; Fruit; Surveys and questionnaires; Polyphenols ID REPEATED EXPOSURE; FOOD-CONSUMPTION; BITTER TASTE; CARDIOVASCULAR-DISEASE; CHEMICAL-COMPOSITION; DIETARY QUALITY; LIKING; CHILDREN; ADULTS; PREFERENCE AB Interest in nutrient-rich berry juices is growing, but their high polyphenol levels render them sensorily unappealing. Fifty adults, who were assessed for sensory phenotype and dietary behaviors, provided sensory and palatability ratings of juices from 'Viking' aronia berries for each of seven harvest weeks. By peak harvest, juice preference increased two-fold, averaging neither like/dislike. This hedonic shift was associated with: increases in juice sugars paralleling increases in perceived sweetness (maximum = weak); reductions in percent acidity paralleling reductions in sourness (minimum = moderate), astringency (minimum = to just above weak) and bitterness (minimum = just below weak). About 25% of adults'liked the aronia juice, including adults who also liked an aqueous citric acid solution (average rating = moderately sour) or those who reported adventurous eating behaviors. Bitter taste phenotype, measured by propylthiouracil or quinine bitterness, failed to explain significant variation in juice sensation or preference. We also collected sensory and preference ratings from juice collected at peak harvest blended with sugar and/or sweet olfactory flavoring (10 ppm ethyl butyrate). Increasing juice sweetness by adding 5% sucrose decreased sourness and improved preference from weak dislike to weak like. Adding sweet olfactory flavoring decreased juice sourness without changing preference. Adding sweet flavoring and 3% sucrose resulted in reduction of sourness and improvements in preference ratings comparable to 5% added sucrose. Neither added sugar nor flavoring blocked juice astringency. In summary, these findings suggest that aronia juice, even from berries picked at peak harvest, appealed to only a few adults (sour likers or adventurous eaters). Although enhanced sweetness, with added sugar and sweet olfactory flavoring, improved aronia juice preference, broader sensory approaches are required to blunt astringency for greater consumer appeal. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Duffy, Valerie B.; Rawal, Shristi; Park, Jeeha; Sharafi, Mastaneh] Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd, Storrs, CT 06269 USA. [Rawal, Shristi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Brand, Mark H.] Univ Connecticut, Dept Plant Sci & Landscape Architecture, Storrs, CT USA. [Bolling, Bradley W.] Univ Wisconsin Madison, Dept Food Sci, Madison, WI USA. RP Duffy, VB (reprint author), Univ Connecticut, Dept Allied Hlth Sci, 358 Mansfield Rd, Storrs, CT 06269 USA. EM valerie.duffy@uconn.edu OI Bolling, Bradley/0000-0002-4222-2467 FU U.S. Department of Agriculture, Hatch Formula Funds [2015-31200-06009, 1001056]; USDA Northeast Sustainable Agriculture Research Education; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Food and Agriculture FX Supported by the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch Formula Funds, under award number 2015-31200-06009, accession number 1001056 and the USDA Northeast Sustainable Agriculture Research & Education. Also, Dr. S. Rawal was partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 71 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD DEC 1 PY 2016 VL 107 BP 116 EP 125 DI 10.1016/j.appet.2016.07.026 PG 10 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA EE2BP UT WOS:000389389000014 PM 27457970 ER PT J AU Jin, XT Sviridov, D Liu, Y Vaisman, B Addadi, L Remaley, AT Kruth, HS AF Jin, Xueting Sviridov, Denis Liu, Ying Vaisman, Boris Addadi, Lia Remaley, Alan T. Kruth, Howard S. TI ABCA1 (ATP-Binding Cassette Transporter A1) Mediates ApoA-I (Apolipoprotein A-I) and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE apolipoprotein A-I; atherosclerosis; cholesterol; extracellular matrix; macrophages ID HIGH-DENSITY-LIPOPROTEIN; CELLULAR LIPID EFFLUX; SMOOTH-MUSCLE-CELLS; PLASMA-MEMBRANE MICROSOLUBILIZATION; O-NEGATIVE PARTICLES; ATHEROSCLEROTIC LESIONS; ANTIBODY RECOGNITION; PHOSPHOLIPID EFFLUX; HUMAN-COMPLEMENT; MODEL MEMBRANES AB Objective-We examined the function of ABCA1 (ATP-binding cassette transporter A1) in ApoA-I (apolipoprotein A-I) mobilization of cholesterol microdomains deposited into the extracellular matrix by cholesterol-enriched macrophages. We have also determined whether an ApoA-I mimetic peptide without and with complexing to sphingomyelin can mobilize macrophage-deposited cholesterol microdomains. Approach and Results-Extracellular cholesterol microdomains deposited by cholesterol-enriched macrophages were detected with a monoclonal antibody, 58B1. ApoA-I and an ApoA-I mimetic peptide 5A mobilized cholesterol microdomains deposited by ABCA1(+/+) macrophages but not by ABCA1(-/-) macrophages. In contrast, ApoA-I mimetic peptide 5A complexed with sphingomyelin could mobilize cholesterol microdomains deposited by ABCA1(-/-) macrophages. Conclusions-Our findings show that a unique pool of extracellular cholesterol microdomains deposited by macrophages can be mobilized by both ApoA-I and an ApoA-I mimetic peptide but that mobilization depends on macrophage ABCA1. It is known that ABCA1 complexes ApoA-I and ApoA-I mimetic peptide with phospholipid, a cholesterol-solubilizing agent, explaining the requirement for ABCA1 in extracellular cholesterol microdomain mobilization. Importantly, ApoA-I mimetic peptide already complexed with phospholipid can mobilize macrophage-deposited extracellular cholesterol microdomains even in the absence of ABCA1. C1 [Jin, Xueting; Liu, Ying; Kruth, Howard S.] NHLBI, Expt Atherosclerosis Sect, NIH, Bldg 10,Room 5N-113,10 Ctr Dr MSC 1422, Bethesda, MD 20892 USA. [Sviridov, Denis; Vaisman, Boris; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Addadi, Lia] Weizmann Inst Sci, Dept Biol Struct, Rehovot, Israel. RP Kruth, HS (reprint author), NHLBI, Expt Atherosclerosis Sect, NIH, Bldg 10,Room 5N-113,10 Ctr Dr MSC 1422, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health; US-Israel Binational Science Foundation [2013045] FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, and by the US-Israel Binational Science Foundation (grant 2013045). NR 63 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 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2016 VL 36 IS 12 BP 2283 EP 2291 DI 10.1161/ATVBAHA.116.308334 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EE1KO UT WOS:000389340500005 PM 27758769 ER PT J AU Breton-Romero, R Wang, N Palmisano, J Larson, MG Vasan, RS Mitchell, GF Benjamin, EJ Vita, JA Hamburg, NM AF Breton-Romero, Rosa Wang, Na Palmisano, Joseph Larson, Martin G. Vasan, Ramachandran S. Mitchell, Gary F. Benjamin, Emelia J. Vita, Joseph A. Hamburg, Naomi M. TI Cross-Sectional Associations of Flow Reversal, Vascular Function, and Arterial Stiffness in the Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE arterial stiffness; endothelium; epidemiology; hyperemia; vascular function ID IMPAIR ENDOTHELIAL FUNCTION; LOCAL SHEAR-STRESS; BRACHIAL-ARTERY; NITRIC-OXIDE; SUPEROXIDE-PRODUCTION; CARDIOVASCULAR RISK; AORTIC STIFFNESS; RETROGRADE FLOW; IN-VIVO; ATHEROSCLEROSIS AB Objective-Experimental studies link oscillatory flow accompanied by flow reversal to impaired endothelial cell function. The relation of flow reversal with vascular function and arterial stiffness remains incompletely defined. Approach and Results-We measured brachial diastolic flow patterns along with vasodilator function in addition to tonometry-based central and peripheral arterial stiffness in 5708 participants (age 47 +/- 13 years, 53% women) in the Framingham Heart Study Offspring and Third Generation cohorts. Brachial artery diastolic flow reversal was present in 35% of the participants. In multivariable regression models, the presence of flow reversal was associated with lower flow-mediated dilation (3.9 +/- 0.2 versus 5.0 +/- 0.2%; P<0.0001) and reactive hyperemic flow velocity (50 +/- 0.99 versus 57 +/- 0.93 cm/s; P<0.0001). The presence of flow reversal (compared with absence) was associated with higher central aortic stiffness (carotid-femoral pulse wave velocity 9.3 +/- 0.1 versus 8.9 +/- 0.1 m/s), lower muscular artery stiffness (carotid-radial pulse wave velocity 9.6 +/- 0.1 versus 9.8 +/- 0.1 m/s), and higher forearm vascular resistance (5.32 +/- 0.03 versus 4.66 +/- 0.02 log dyne/s/cm(5); P<0.0001). The relations of diastolic flow velocity with flow-mediated dilation, aortic stiffness, and forearm vascular resistance were nonlinear, with a steeper decline in vascular function associated with increasing magnitude of flow reversal. Conclusions-In our large, community-based sample, brachial artery flow reversal was common and associated with impaired vasodilator function and higher aortic stiffness. Our findings are consistent with the concept that flow reversal may contribute to vascular dysfunction. C1 [Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, 88 E Newton St C818, Boston, MA 02215 USA. [Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Boston, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.; Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Cardiol, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Prevent Med Sect, Boston, MA 02215 USA. [Breton-Romero, Rosa; Vasan, Ramachandran S.; Benjamin, Emelia J.; Vita, Joseph A.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Wang, Na; Palmisano, Joseph; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Stat, Boston, MA 02215 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Hamburg, NM (reprint author), Boston Univ, 88 E Newton St C818, Boston, MA 02215 USA. EM nhamburg@bu.edu FU National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) [N01-HC25195, HHSN268201500001l]; NIH [R01HL107385, 1R01HL126136-01, 1R01HL60040, HL70100, HL076784, AG028321, HL080124, 2K24-HL4334, HL083781, HL102299]; Donald W. Reynolds Foundation; American Heart Association [16POST27260178]; Department of Medicine at Boston University School of Medicine FX The Framingham Heart Study is funded by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) contract N01-HC25195 and HHSN268201500001l. The project was supported by NIH grants R01HL107385, 1R01HL126136-01, 1R01HL60040, HL70100, HL076784, AG028321, HL080124, 2K24-HL4334, and the Donald W. Reynolds Foundation. Dr Hamburg is supported by NIH grants HL083781 and HL102299. Dr Breton-Romero is supported by an American Heart Association Postdoctoral Fellowship 16POST27260178. Dr Vasan is partly supported by the Evans Scholar award from the Department of Medicine at Boston University School of Medicine. NR 42 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 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2016 VL 36 IS 12 BP 2452 EP 2459 DI 10.1161/ATVBAHA.116.307948 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EE1KO UT WOS:000389340500023 PM 27789476 ER PT J AU Tchantchaleishvili, V Phillips, SJ AF Tchantchaleishvili, Vakhtang Phillips, Steven J. TI Update in Artificial Heart Technology: Are We There Yet? SO ARTIFICIAL ORGANS LA English DT Editorial Material C1 [Tchantchaleishvili, Vakhtang] Mayo Clin, Dept Cardiovasc Surg, Rochester, MN USA. [Phillips, Steven J.] NIH, US Dept HHS, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Phillips, SJ (reprint author), NIH, US Dept HHS, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM steven_phillips@nlm.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-564X EI 1525-1594 J9 ARTIF ORGANS JI Artif. Organs PD DEC PY 2016 VL 40 IS 12 BP 1099 EP 1100 DI 10.1111/aor.12877 PG 2 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA EE3CT UT WOS:000389465300006 PM 27911029 ER PT J AU Nelson, KB Sartwelle, TP Rouse, DJ AF Nelson, Karin B. Sartwelle, Thomas P. Rouse, Dwight J. TI Electronic fetal monitoring, cerebral palsy, and caesarean section: assumptions versus evidence SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID HEART-RATE; DELIVERY RATE; LITIGATION; MORTALITY; RISK; AUSCULTATION; HEALTH; TRENDS; TRIALS; INJURY C1 [Nelson, Karin B.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sartwelle, Thomas P.] Deans & Lyons, Houston, TX USA. [Rouse, Dwight J.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Rouse, Dwight J.] Brown Univ, Providence, RI 02912 USA. RP Nelson, KB (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM nelsonk@ninds.nih.gov NR 38 TC 1 Z9 1 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD DEC 1 PY 2016 VL 355 AR i6405 DI 10.1136/bmj.i6405 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZO UT WOS:000389309800004 PM 27908902 ER PT J AU Schindler, CW Thorndike, EB Suzuki, M Rice, KC Baumann, MH AF Schindler, Charles W. Thorndike, Eric B. Suzuki, Masaki Rice, Kenner C. Baumann, Michael H. TI Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV) SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID NEURONAL MONOAMINE UPTAKE; CONSCIOUS RATS; DESIGNER DRUG; CONCISE GUIDE; COCAINE; TRANSPORTERS; METABOLITES; MEPHEDRONE; MDMA; STIMULATION AB Background and Purpose3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. Experimental ApproachMale Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3h sessions. Key ResultsRacemic MDPV (0.3-3.0mgkg(-1)) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0mgkg(-1)) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0mgkg(-1)) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3mgkg(-1)) antagonized the increases in BP and HR produced by 1mgkg(-1) MDPV. The (1)-adrenoceptor antagonist prazosin (0.3mgkg(-1)) attenuated the increase in BP following MDPV, while the -adrenoceptor antagonists propranolol (1mgkg(-1)) and atenolol (1 and 3mgkg(-1)) attenuated the HR increases. Conclusions and ImplicationsThe S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action /-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV. C1 [Schindler, Charles W.; Thorndike, Eric B.] NIDA, Preclin Pharmacol Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Suzuki, Masaki; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, NIH, Intramural Res Program, Baltimore, MD USA. [Baumann, Michael H.] NIDA, Designer Drug Res Unit, NIH, Intramural Res Program, Baltimore, MD USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. EM cschind@helix.nih.gov FU Intramural Research Programs of the National Institute on Drug Abuse (NIDA); National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health. NR 44 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 173 IS 24 BP 3492 EP 3501 DI 10.1111/bph.13640 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED6SL UT WOS:000388986200007 PM 27714779 ER PT J AU Pinsky, PF Yu, K Black, A Huang, WY Prorok, PC AF Pinsky, P. F. Yu, K. Black, A. Huang, W. Y. Prorok, P. C. TI Active follow-up versus passive linkage with cancer registries for case ascertainment in a cohort SO CANCER EPIDEMIOLOGY LA English DT Article DE Cancer registries; Linkage; Active-follow-up; Case ascertainment AB Background: Ascertaining incident cancers is a critical component of cancer-focused epidemiologic cohorts and of cancer prevention trials. Potential methods: for cancer case ascertainment include active follow-up and passive linkage with state cancer registries. Here we compare the two approaches in a large cancer screening trial. Methods: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial enrolled 154,955 subjects at ten U.S. centers and followed them for all-cancer incidence. Cancers were ascertained by an active follow-up process involving annual questionnaires, retrieval of records and medical record abstracting to ascertain and confirm cancers. For a subset of centers, linkage with state cancer registries was also performed. We assessed the agreement of the two methods in ascertaining incident cancers from 1993 to 2009 in 80,083 subjects from six PLCO centers where cancers were ascertained both by active follow-up and through linkages with 14 state registries. Results: The ratio (times 100) of confirmed cases ascertained by registry linkage compared to active follow-up was 96.4 (95% CI: 95.1-98.2). Of cancers ascertained by either method, 86.6% and 83.5% were identified by active follow-up and by registry linkage, respectively. Of cancers missed by active follow-up, 30% were after subjects were lost to follow-up and 16% were reported but could not be confirmed. Of cancers missed by the registries, 27% were not sent to the state registry of the subject's current address at the time of linkage. Conclusion: Linkage with state registries identified a similar number of cancers as active follow-up and can be a cost-effective method to ascertain incident cancers in a large cohort. Published by Elsevier Ltd. C1 [Pinsky, P. F.; Yu, K.; Prorok, P. C.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Black, A.; Huang, W. Y.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA. EM pp4f@nih.gov FU National Cancer Institute [HHSN261201100008C]; Centers for Disease Control and Prevention, National Program for Central Registries; National Cancer Institute, Surveillance, Epidemiology, and End Results Program FX This research was supported by contract number HHSN261201100008C from the National Cancer Institute. The funding agency had no role in the research, other than the fact that the authors were employees of the funding agency.; Cancer incidence data have been provided by the following registries: Arizona, California, Colorado, D.C., Hawaii, Idaho, Maryland, Michigan, Nevada, Ohio, Pennsylvania, Texas, Utah, Virginia. All are supported in part by funds from the Centers for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results Program. The results reported here and the conclusions derived are the sole responsibility of the authors. NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2016 VL 45 BP 26 EP 31 DI 10.1016/j.canep.2016.09.003 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RV UT WOS:000389515900005 PM 27687075 ER PT J AU Jedy-Agba, EE Dareng, EO Adebamowo, SN Odutola, M Oga, EA Igbinoba, F Otu, T Ezeome, E Bray, F Hassan, R Adebamowo, CA AF Jedy-Agba, E. E. Dareng, E. O. Adebamowo, S. N. Odutola, M. Oga, E. A. Igbinoba, F. Otu, T. Ezeome, E. Bray, F. Hassan, R. Adebamowo, C. A. TI The burden of HPV associated cancers in two regions in Nigeria 2012-2014 SO CANCER EPIDEMIOLOGY LA English DT Article DE HPV; HPV associated cancers; Cancer registries; Cancer incidence; Nigeria ID SUB-SAHARAN AFRICA; HUMAN-PAPILLOMAVIRUS PREVALENCE; CERVICAL-CANCER; PENILE CANCER; VAGINAL-CANCER; GLOBAL BURDEN; ORAL-CAVITY; ANAL CANCER; METAANALYSIS; CARCINOMA AB Introduction: HPV attributable cancers are the second most common infection-related cancers worldwide, with much higher burden in less developed regions. There are currently no country-specific estimates of the burden of these cancers in Nigeria just like many other low and middle income countries. Methods: In this study, we quantified the proportion of the cancer burden in Nigeria that is attributable to HPV infection from 2012 to 2014 using HPV prevalence estimated from previous studies and data from two population based cancer registries (PBCR) in Nigeria. We considered cancer sites for which there is strong evidence of an association with HPV infection based on the International Agency for Research on Cancer (IARC) classification. We obtained age and sex-specific estimates of incident cancers and using the World Standard Population, we derived age standardized incidence (ASR) rates for each cancer type by categories of sex, and estimated the population attributable fractions (PAF). Results: The two PBCR reported 4336 new cancer cases from 2012 to 2014. Of these, 1627 (37.5%) were in males and 2709 (62.5%) in females. Some 11% (488/4336) of these cancers were HPV associated; 2% (38/1627) in men and 17% (450/2709) in women. Of the HPV associated cancers, 7.8% occurred in men and 92.2% in women. The ASRs for HPV associated cancers was 33.5 per 100,000; 2.3 and 31.2 per 100,000 in men and women respectively. The proportion of all cancers attributable to HPV infection ranged from 10.2 to 10.4% (442-453 of 4336) while the proportion of HPV associated cancers attributable to HPV infection ranged from 90.6% to 92.8% (442-453 of the 488 cases). In men, 55.3% to 68.4% of HPV associated cancers were attributable to HPV infection compared to 93.6% to 94.8% in women. The combined ASR for HPV attributable cancers ranged from 31.0 to 31.7 per 100,000. This was 1.4 to 1.7 per 100,000 in men and 29.6 to 30.0 per 100,000 in women. In women, cervical cancer (n = 392, ASR 28.3 per 100,000) was the commonest HPV attributable cancer, while anal cancer (n = 21, ASR 1.2 per 100,000) was the commonest in men. Conclusions: HPV attributable cancers constitute a substantial cancer burden in Nigerian women, much less so in men. A significant proportion of cancers in Nigerian women would be prevented if strategies such as HPV DNA based screening and HPV vaccination are implemented. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Jedy-Agba, E. E.] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Dareng, E. O.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Adebamowo, S. N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Odutola, M.; Adebamowo, C. A.] Inst Human Virol, Abuja, Nigeria. [Oga, E. A.; Adebamowo, C. A.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Igbinoba, F.] Natl Hosp Abuja, Abuja, Nigeria. [Otu, T.] Univ Abuja Teaching Hosp Gwagwalada, Abuja, Nigeria. [Ezeome, E.] Univ Nigeria Teaching Hosp Enugu, Enugu, Nigeria. [Bray, F.] Int Agcy Res Canc, Lyon, France. [Hassan, R.] Fed Minist Hlth, Abuja, Nigeria. [Adebamowo, C. A.] Univ Maryland, Sch Med, Marlene & Stewart Greenbaum Comprehens Canc Ctr, Baltimore, MD 21201 USA. [Adebamowo, C. A.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. RP Jedy-Agba, EE (reprint author), London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. EM elima.jedyagba@gmail.com FU IHV-UM Capacity Development for Research into AIDS-Associated Malignancies (CADRE) [NIH/NCI D43CA153792]; African Collaborative Center for Microbiome and Genomics Research (ACCME) [NIH/NHGRI U54HG006947] FX We acknowledge the work in data collection and data entry carried out by the cancer registrars at the Abuja and Enugu population-based cancer registries. This work was supported by IHV-UM Capacity Development for Research into AIDS-Associated Malignancies (CADRE, NIH/NCI D43CA153792) and the African Collaborative Center for Microbiome and Genomics Research (ACCME, NIH/NHGRI U54HG006947). NR 56 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 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2016 VL 45 BP 91 EP 97 DI 10.1016/j.canep.2016.10.008 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE3RV UT WOS:000389515900013 PM 27780076 ER PT J AU Meier, HCS Sandler, DP Simonsick, EM Parks, CG AF Meier, Helen C. S. Sandler, Dale P. Simonsick, Eleanor M. Parks, Christine G. TI Association between Vitamin D Deficiency and Antinuclear Antibodies in Middle-Aged and Older US Adults SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CIRCULATING 25-HYDROXYVITAMIN D; CANCER; AUTOANTIBODIES; AUTOIMMUNITY; METAANALYSIS; BIOMARKERS; DISEASE; WOMEN; SERUM AB Background: Vitamin D deficiency is associated with cancer and autoimmune diseases, but little is known about the association between vitamin D and antinuclear antibodies (ANA), a biomarker of immune dysfunction in healthy populations. The objective of this study was to determine whether vitamin D deficiency is associated with ANA in middle-aged and older U. S. adults. Methods: A cross-sectional analysis using the National Health and Nutrition Examination Survey (NHANES) 2001-2004 was conducted. Data were available for 1,012 adults aged 50 years and older. Serum 25-hydroxyvitamin D levels were measured by radioimmunoassay. ANA was measured in a 1:80 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4+). Results: Greater vitamin D deficiency was associated with higher ANA prevalence in the unadjusted (P-trend = 0.0002) logistic regression model and after adjustment for sex, age, education, race/ethnicity, season, and NHANES cycle (P-trend-0.04). After adjustment, those with severe vitamin D deficiency (< 10 ng/mL) had 2.99 (95% CI, 1.25-7.15) times the odds of ANA compared with having normal vitamin D levels (>= 30 ng/mL), while deficient and insufficient individuals had twice the odds of ANA. Conclusions: Among U. S. residents ages 50 and older, vitamin D deficiency was associated with higher prevalence of ANA. Vitamin D sufficiency may be important for preventing immune dysfunction in older populations. Impact: Our findings support the growing evidence that vitamin D is an important immune modulator. Vitamin D deficiency in older adults may increase vulnerability to cancer by contributing to immune dysfunction. Cancer Epidemiol Biomarkers Prev; 25(12); 1559-63. (C) 2016 AACR. C1 [Meier, Helen C. S.] Univ Wisconsin Milwaukee, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI USA. [Sandler, Dale P.; Parks, Christine G.] NIEHS, NIH, Epidemiol Branch, Res Triangle Pk, NC USA. [Simonsick, Eleanor M.] Natl Inst Aging, Translat Gerontol Branch, Longitudinal Studies Sect, NIH, Baltimore, MD USA. RP Sandler, DP (reprint author), NIEHS, NIH, Epidemiol Branch, Res Triangle Pk, NC USA.; Sandler, DP (reprint author), NIEHS, POB 12233 MD A3-05 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov OI Parks, Christine/0000-0002-5734-3456; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01-ES049028]; National Institute on Aging [AG000015-57] FX This work was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES049028; to DP Sandler), and the National Institute on Aging (AG000015-57; to EM Simonsick). NR 26 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1559 EP 1563 DI 10.1158/1055-9965.EPI-16-0339 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300003 PM 27543618 ER PT J AU Lin, J McGlynn, KA Carter, CA Nations, JA Anderson, WF Shriver, CD Zhu, KM AF Lin, Jie McGlynn, Katherine A. Carter, Corey A. Nations, Joel A. Anderson, William F. Shriver, Craig D. Zhu, Kangmin TI The Impact of Preexisting Mental Health Disorders on the Diagnosis, Treatment, and Survival among Lung Cancer Patients in the US Military Health System SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; ALL-CAUSE MORTALITY; AUSTRALIAN PSYCHIATRIC-PATIENTS; PROVIDER COMMUNICATION; AMERICAN SOCIETY; EXCESS MORTALITY; UNITED-STATES; BREAST-CANCER; COLON-CANCER; CARE-SYSTEM AB Background: Higher cancer-related mortality has been observed among people with mental health disorders than in the general population. Both delay in diagnosis and inadequate treatment due to health care access have been found to explain the higher mortality. The U.S. Military Health System (MHS), in which all beneficiaries have equal access to health care, provides an ideal system to study this disparity where there are no or minimal barriers to health care access. This study assessed preexisting mental health disorders and stage at diagnosis, receipt of cancer treatment, and overall survival among patients with nonsmall cell lung cancer (NSCLC) in the U.S. MHS. Methods: The study used data from the linked database from the Department of Defense's Central Cancer Registry and the MHS Data Repository (MDR). The study subjects included 5,054 patients with histologically confirmed primary NSCLC diagnosed Results: Patients with a preexisting mental disorder did not present with more advanced disease at diagnosis than those without. There were no significant differences in receiving cancer treatments between the two groups. However, patients with a mental health disorder had a higher mortality than those without [adjusted HR, 1.11; 95% confidence interval (CI), 1.03-1.20]. Conclusions: Poor survival in NSCLC in patients with a preexisting mental health disorder is not necessarily associated with delay in diagnosis and/or inadequate cancer treatment. Impact: This study contributes to the current understanding that health care access may not be sufficient to explain the poor survival among patients with NSCLC with preexisting mental health disorders. Cancer Epidemiol Biomarkers Prev; 25(12); 1564-71. (C) 2016 AACR. C1 [Lin, Jie; Carter, Corey A.; Nations, Joel A.; Shriver, Craig D.; Zhu, Kangmin] John P Murtha Canc Ctr, Walter Reed Natl Mil Med Ctr, 11300 Rockville Pike Suite 1120, Bethesda, MD 20852 USA. [McGlynn, Katherine A.; Anderson, William F.] Div Canc Epidemiol & Genet, Natl Canc Inst, Bethesda, MD USA. [Shriver, Craig D.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD USA. [Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biostatist, Bethesda, MD USA. RP Lin, J (reprint author), John P Murtha Canc Ctr, Walter Reed Natl Mil Med Ctr, 11300 Rockville Pike Suite 1120, Bethesda, MD 20852 USA. EM jlin@murthacancercenter.org FU John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine; National Cancer Institute FX This project was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the intramural research program of the National Cancer Institute. NR 57 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1564 EP 1571 DI 10.1158/1055-9965.EPI-16-0316 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300004 PM 27566418 ER PT J AU Rand, KA Song, C Dean, E Serie, DJ Curtin, K Sheng, X Hu, DL Huff, CA Bernal-Mizrachi, L Tomasson, MH Ailawadhi, S Singhal, S Pawlish, K Peters, ES Bock, CH Stram, A Van den Berg, DJ Edlund, CK Conti, DV Zimmerman, T Hwang, AE Huntsman, S Graff, J Nooka, A Kong, YF Pregja, SL Berndt, SI Blot, WJ Carpten, J Casey, G Chu, L Diver, WR Stevens, VL Lieber, MR Goodman, PJ Hennis, AJM Hsing, AW Mehta, J Kittles, RA Kolb, S Klein, EA Leske, C Murphy, AB Nemesure, B Neslund-Dudas, C Strom, SS Vij, R Rybicki, BA Stanford, JL Signorello, LB Witte, JS Ambrosone, CB Bhatti, P John, EM Bernstein, L Zheng, W Olshan, AF Hu, JJ Ziegler, RG Nyante, SJ Bandera, EV Birmann, BM Ingles, SA Press, MF Atanackovic, D Glenn, MJ Cannon-Albright, LA Jones, B Tricot, G Martin, TG Kumar, SK Wolf, JL Halverson, SLD Rothman, N Brooks-Wilson, AR Rajkumar, SV Kolonel, LN Chanock, SJ Slager, SL Severson, RK Janakiraman, N Terebelo, HR Brown, EE De Roos, AJ Mohrbacher, AF Colditz, GA Giles, GG Spinelli, JJ Chiu, BC Munshi, NC Anderson, KC Levy, J Zonder, JA Orlowski, RZ Lonial, S Camp, NJ Vachon, CM Ziv, E Stram, DO Hazelett, DJ Haiman, CA Cozen, W AF Rand, Kristin A. Song, Chi Dean, Eric Serie, Daniel J. Curtin, Karen Sheng, Xin Hu, Donglei Huff, Carol Ann Bernal-Mizrachi, Leon Tomasson, Michael H. Ailawadhi, Sikander Singhal, Seema Pawlish, Karen Peters, Edward S. Bock, Cathryn H. Stram, Alex Van den Berg, David J. Edlund, Christopher K. Conti, David V. Zimmerman, Todd Hwang, Amie E. Huntsman, Scott Graff, John Nooka, Ajay Kong, Yinfei Pregja, Silvana L. Berndt, Sonja I. Blot, William J. Carpten, John Casey, Graham Chu, Lisa Diver, W. Ryan Stevens, Victoria L. Lieber, Michael R. Goodman, Phyllis J. Hennis, Anselm J. M. Hsing, Ann W. Mehta, Jayesh Kittles, Rick A. Kolb, Suzanne Klein, Eric A. Leske, Cristina Murphy, Adam B. Nemesure, Barbara Neslund-Dudas, Christine Strom, Sara S. Vij, Ravi Rybicki, Benjamin A. Stanford, Janet L. Signorello, Lisa B. Witte, John S. Ambrosone, Christine B. Bhatti, Parveen John, Esther M. Bernstein, Leslie Zheng, Wei Olshan, Andrew F. Hu, Jennifer J. Ziegler, Regina G. Nyante, Sarah J. Bandera, Elisa V. Birmann, Brenda M. Ingles, Sue A. Press, Michael F. Atanackovic, Djordje Glenn, Martha J. Cannon-Albright, Lisa A. Jones, Brandt Tricot, Guido Martin, Thomas G. Kumar, Shaji K. Wolf, Jeffrey L. Halverson, Sandra L. Deming Rothman, Nathaniel Brooks-Wilson, Angela R. Rajkumar, S. Vincent Kolonel, Laurence N. Chanock, Stephen J. Slager, Susan L. Severson, Richard K. Janakiraman, Nalini Terebelo, Howard R. Brown, Elizabeth E. De Roos, Anneclaire J. Mohrbacher, Ann F. Colditz, Graham A. Giles, Graham G. Spinelli, John J. Chiu, Brian C. Munshi, Nikhil C. Anderson, Kenneth C. Levy, Joan Zonder, Jeffrey A. Orlowski, Robert Z. Lonial, Sagar Camp, Nicola J. Vachon, Celine M. Ziv, Elad Stram, Daniel O. Hazelett, Dennis J. Haiman, Christopher A. Cozen, Wendy TI A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; LOS-ANGELES; VARIANTS; SITES; GENOTYPES; PATTERNS; 7P15.3; TARGET AB Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 x 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. (C) 2016 AACR. C1 [Rand, Kristin A.; Song, Chi; Sheng, Xin; Van den Berg, David J.; Edlund, Christopher K.; Conti, David V.; Hwang, Amie E.; Kong, Yinfei; Casey, Graham; Lieber, Michael R.; Ingles, Sue A.; Press, Michael F.; Mohrbacher, Ann F.; Stram, Daniel O.; Haiman, Christopher A.; Cozen, Wendy] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Rand, Kristin A.; Song, Chi; Sheng, Xin; Van den Berg, David J.; Edlund, Christopher K.; Conti, David V.; Hwang, Amie E.; Kong, Yinfei; Casey, Graham; Lieber, Michael R.; Ingles, Sue A.; Press, Michael F.; Mohrbacher, Ann F.; Stram, Daniel O.; Haiman, Christopher A.; Cozen, Wendy] Univ Southern Calif, Norris Comprehens Canc Ctr, Topping Tower,1441 Eastlake Ave,Room 4451A, Los Angeles, CA 90033 USA. [Dean, Eric] Sutter Hlth, Oakland, CA USA. [Serie, Daniel J.; Ailawadhi, Sikander] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Curtin, Karen; Atanackovic, Djordje; Glenn, Martha J.; Cannon-Albright, Lisa A.; Jones, Brandt; Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Hu, Donglei; Huntsman, Scott; Martin, Thomas G.; Wolf, Jeffrey L.; Ziv, Elad] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Huff, Carol Ann] Johns Hopkins Univ, Johns Hopkins Sch Med, Baltimore, MD USA. [Bernal-Mizrachi, Leon; Nooka, Ajay; Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Tomasson, Michael H.; Vij, Ravi; Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Singhal, Seema; Mehta, Jayesh; Murphy, Adam B.] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Pawlish, Karen] New Jersey Dept Hlth, New Jersey State Canc Registry, Trenton, NJ USA. [Peters, Edward S.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Bock, Cathryn H.; Pregja, Silvana L.; Severson, Richard K.; Zonder, Jeffrey A.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Bock, Cathryn H.; Pregja, Silvana L.; Severson, Richard K.; Zonder, Jeffrey A.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Stram, Alex] Genom Hlth Inc, Redwood City, CA USA. [Zimmerman, Todd; Chiu, Brian C.] Univ Chicago, Chicago, IL 60637 USA. [Graff, John; Bandera, Elisa V.] Rutgers State Univ, Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Berndt, Sonja I.; Ziegler, Regina G.; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA. [Blot, William J.; Zheng, Wei; Halverson, Sandra L. Deming] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol, Nashville, TN 37212 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Chu, Lisa; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Chu, Lisa; Hsing, Ann W.; John, Esther M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Chu, Lisa; Hsing, Ann W.; John, Esther M.] Stanford Canc Inst, Palo Alto, CA USA. [Diver, W. Ryan; Stevens, Victoria L.] Amer Canc Soc, Atlanta, GA 30329 USA. [Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Hennis, Anselm J. M.; Leske, Cristina; Nemesure, Barbara] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Hennis, Anselm J. M.] Univ West Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ West Indies, Fac Med Sci, Bridgetown, Barbados. [Kittles, Rick A.] Univ Arizona, Dept Surg, Tucson, AZ USA. [Kolb, Suzanne; Stanford, Janet L.; Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Neslund-Dudas, Christine; Rybicki, Benjamin A.; Janakiraman, Nalini] Henry Ford Hosp, Detroit, MI 48202 USA. [Strom, Sara S.; Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Signorello, Lisa B.; Birmann, Brenda M.] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Olshan, Andrew F.; Nyante, Sarah J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Olshan, Andrew F.; Nyante, Sarah J.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Tricot, Guido] Univ Iowa, Iowa City, IA USA. [Kumar, Shaji K.; Rajkumar, S. Vincent; Slager, Susan L.; Vachon, Celine M.] Mayo Clin, Rochester, MN USA. [Brooks-Wilson, Angela R.; Spinelli, John J.] BC Canc Agcy, Vancouver, BC, Canada. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Terebelo, Howard R.] Providence Hosp, Southfield, MI 48037 USA. [Brown, Elizabeth E.] Univ Alabama Birmingham, Birmingham, AL USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Melbourne, Vic, Australia. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Munshi, Nikhil C.; Anderson, Kenneth C.] Harvard Univ, Harvard Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Levy, Joan] Multiple Myeloma Res Fdn, Norwalk, CT USA. [Hazelett, Dennis J.] Cedars Sinai Med Ctr, Ctr Bioinformat & Computat Biol, Los Angeles, CA 90048 USA. RP Cozen, W (reprint author), Univ Southern Calif, Norris Comprehens Canc Ctr, Topping Tower,1441 Eastlake Ave,Room 4451A, Los Angeles, CA 90033 USA.; Haiman, CA (reprint author), USC Norris Comprehens Canc Ctr, Harlyne Norris Res Tower,1450 Biggy St,Room 1504, Los Angeles, CA 90033 USA.; Hazelett, DJ (reprint author), Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM Dennis.Hazelett@csmc.edu; haiman@usc.edu; wcozen@usc.edu RI Brooks-Wilson, Angela/E-9399-2012 OI Brooks-Wilson, Angela/0000-0003-1009-6408 FU National Cancer Institute at the NIH [1R01CA134786, 2P50CA100707, Myeloma SPORE 2P50CA100707 Project, R01CA152336, R01CA134674, P50 CA142509, R01CA184464, R21CA155951, R25CA76023, R01CA186646, U54CA118948, P30CA13148, R21CA191896, K24CA169004]; Leukemia Lymphoma Society [LLS 6067-090]; American Cancer Society [IRG60-001-47]; Steve and Nancy Grand Multiple Myeloma Translational Initiative; National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services [N01-PC-35139]; HHSN [261201300021I, N01PC-2013 00021, HHSN261201000026C]; National Program of Cancer Registries of the Centers for Disease Control and Prevention [5U58DP003931-02, 1U58DP000807-01]; Huntsman Cancer Institute (HCI); HCI Cancer Center Support grant [P30 CA42014]; USC Norris Comprehensive Cancer Center Core grant from the National Cancer Institute [P30CA014089]; California Department of Health Services [103885]; NIH [CA63464, CA54281, CA1326792, CA148085, HG004726, CA056678, CA082664, CA092579, ES011126]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH; Cancer Research Fund [99- 00524V10258, 9712013]; University of California [98-00924V]; Department of Health Services Cancer Research Program; NCI, NIH, Department of Health and Human Services [N01-PC-35139]; Fred Hutchinson Cancer Research Center; Intramural Program of the National Human Genome Research Institute; Public Health Service from the National Cancer Institute [U10 CA37429, UM1 CA182883]; Vanderbilt-Ingram Cancer Center [CA68485]; Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-08-1-0383]; Norris Foundation [P01-CA151135, U19-CA148065]; MEC (NIH) [R01-CA63464, R37-CA54281, UM1-CA164973]; CARE (National Institute for Child Health and Development) [NO1-HD-3-3175, K05 CA136967]; WCHS [U.S. Army Medical Research and Material Command (USAMRMC)] [DAMD-17-01-0-0334]; WCHS [NIH] [R01-CA100598]; WCHS [Breast Cancer Research Foundation]; SFBCS (NIH) [R01-CA77305]; SFBCS (United States Army Medical Research Program) [DAMD17-96-6071]; NC-BCFR (NIH) [U01-CA69417]; CBCS (NIH Specialized Program of Research Excellence in Breast Cancer) [P50-CA58223]; Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH [P30-ES10126]; PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health) [R01-CA100374]; WFBC (NIH) [R01-CA73629]; National Cancer Institute, NIH [RFA-CA-06-503]; [CA68578]; [ES007784]; [DAMD W81XWH-07-1-0645]; [CA140388]; [CA88164]; [CA127298] FX This study was supported by the National Cancer Institute at the NIH (1R01CA134786 to W. Cozen and Christopher A. Haiman; 2P50CA100707 to K.C. Anderson; Myeloma SPORE 2P50CA100707 Project 6 to K.C. Anderson, W. Cozen, and D.V. Conti; R01CA152336 and R01CA134674 to N. J. Camp; P50 CA142509 and R01CA184464 to R. Z. Orlowski; R21CA155951, R25CA76023, R01CA186646, U54CA118948 Project 3 and P30CA13148 (seed grant) to E. E. Brown; and R21CA191896 and K24CA169004 to E. Ziv). The study also received support from the Leukemia Lymphoma Society (LLS 6067-090) to N. J. Camp, the American Cancer Society (IRG60-001-47) to E. E. Brown, and the Steve and Nancy Grand Multiple Myeloma Translational Initiative to E. Ziv. Data collection from the cancer registries was supported by the National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services, under contracts N01-PC-35139 (to USC for Los Angeles County), HHSN 261201300021I, N01PC-2013 00021 (to the New Jersey State Cancer Registry), and HHSN261201000026C (to the Utah Cancer Registry). Additional support for collection of incident multiple myeloma patient data was obtained from the Utah State Department of Health and the University of Utah, the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR), the National Program of Cancer Registries of the Centers for Disease Control and Prevention (5U58DP003931-02 to the New Jersey State Cancer Registry and 1U58DP000807-01 to the California Cancer Registry), the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 and by the USC Norris Comprehensive Cancer Center Core grant P30CA014089 from the National Cancer Institute. The collection of patients used in this publication was supported in part by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. AAPC studies: The MEC is supported by NIH grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99- 00524V10258 from the Cancer Research Fund, under Interagency Agreement # 9712013 (University of California contract # 98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health and Human Services, under Contract No. N01-PC-35139, and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. MDA was supported by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. CaP Genes was supported by CA88164 and CA127298. SELECT was funded in part by Public Health Service grants U10 CA37429 (C.D. Blanke) and UM1 CA182883 (I. M. Thompson/C.M. Tangen) from the National Cancer Institute. GECAP was supported by NIH grant ES011126.; SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485).; AABC studies: AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383), the Norris Foundation, P01-CA151135 and U19-CA148065. Each of the participating studies was supported by the following grants: MEC (NIH grants R01-CA63464, R37-CA54281 and UM1-CA164973); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175, K05 CA136967); WCHS [U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the NIH grant R01-CA100598, and the Breast Cancer Research Foundation]; SFBCS (NIH grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071); NC-BCFR (NIH grant U01-CA69417); CBCS (NIH Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH, grant number P30-ES10126); PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health grant R01-CA100374); WFBC (NIH grant R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. NR 38 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1609 EP 1618 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300009 PM 27587788 ER PT J AU Zhu, CS Huang, WY Pinsky, PF Berg, C Sherman, M Yu, KJ Carrick, DM Black, A Hoover, R Lenz, P Williams, C Hawkins, L Chaloux, M Yurgalevitch, S Mathew, S Miller, A Olivo, V Khan, A Pretzel, SM Multerer, D Beckmann, P Broski, KG Freedman, ND AF Zhu, Claire S. Huang, Wen-Yi Pinsky, Paulf F. Berg, Christine D. Sherman, Mark Yu, Kelly J. Carrick, Danielle M. Black, Amanda Hoover, Robert Lenz, Petra Williams, Craig Hawkins, Laura Chaloux, Matthew Yurgalevitch, Susan Mathew, Sunitha Miller, Amy Olivo, Vanessa Khan, Asia Pretzel, Shannon M. Multerer, Deborah Beckmann, Patricia Broski, Karen G. Freedman, Neal D. TI The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial Pathology Tissue Resource SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; EPIDEMIOLOGY AB Background: Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial. Methods: Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction. Results: Pathology tissue specimens were obtained for prostate cancer (n = 1,052), lung cancer (n = 434), colorectal cancer (n = 675) and adenoma (n = 658), ovarian cancer and borderline tumors (n = 212), breast cancer (n = 870), and bladder cancer (n = 204). The process of creating this resource was complex, involving multidisciplinary teams with expertise in pathology, epidemiology, information technology, project management, and specialized laboratories. Conclusions: Creating the PLCO tissue resource required a multistep process, including obtaining medical records and contacting pathology departments where pathology materials were stored after obtaining necessary patient consent and authorization. The potential to link tissue biomarkers to prospectively collected epidemiologic information, screening and clinical data, and matched blood or buccal samples offers valuable opportunities to study etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for early detection and prognosis. Impact: The methods and protocols developed for this effort, and the detailed description of this resource provided here, will be useful for those seeking to use PLCO pathology tissue specimens for their research and may also inform future tissue collection efforts in other settings. Cancer Epidemiol Biomarkers Prev; 25(12); 1635-42. (C) 2016 AACR. C1 [Zhu, Claire S.; Pinsky, Paulf F.; Sherman, Mark] NCI, Canc Prevent Div, Bethesda, MD USA. [Huang, Wen-Yi; Berg, Christine D.; Yu, Kelly J.; Black, Amanda; Hoover, Robert; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Carrick, Danielle M.] Div Canc Control & Populat Sci, NCI, Bethesda, MD USA. [Lenz, Petra] Leidos Biomedical Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus, Frederick, MD USA. [Williams, Craig; Hawkins, Laura; Chaloux, Matthew] Informat Management Serv Inc, Rockville, MD USA. [Yurgalevitch, Susan; Mathew, Sunitha; Miller, Amy; Olivo, Vanessa; Khan, Asia] Westat Corp, Rockville, MD USA. [Pretzel, Shannon M.] Univ Colorado Canc Ctr, Aurora, CO USA. [Multerer, Deborah] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Beckmann, Patricia] Univ Minnesota, Minneapolis, MN USA. [Broski, Karen G.] Henry Ford Hlth Syst, Detroit, MI USA. RP Zhu, CS (reprint author), NCI, 9606 Med Ctr Dr,Room 5E106, Rockville, MD 20850 USA. EM zhucla@mail.nih.gov FU NCI, NIH; NCI [HHSN261200800001E, N01-CN-25512, HHSN261201300008I] FX This project has been funded in whole or in part with federal funds from the NCI, NIH, to 10 PLCO screening centers, a coordinating center, a data management center, and 2 central tissue microarray construction laboratories. P. Lenz was supported by NCI contract no. HHSN261200800001E; K. Broski was supported by NCI contract no. N01-CN-25512; and M. Chaloux, L. Hawkins, and C. Williams were supported by NCI contract no. HHSN261201300008I. NR 17 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1635 EP 1642 DI 10.1158/1055-9965.EPI-16-0506 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300012 PM 27635065 ER PT J AU Moore, E Clavijo, PE Davis, R Cash, H Van Waes, C Kim, Y Allen, C AF Moore, Ellen Clavijo, Paul E. Davis, Ruth Cash, Harrison Van Waes, Carter Kim, Young Allen, Clint TI Established T Cell-Inflamed Tumors Rejected after Adaptive Resistance Was Reversed by Combination STING Activation and PD-1 Pathway Blockade SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID DENDRITIC CELLS; I INTERFERON; MICROENVIRONMENT; INNATE; CANCER; ANTITUMOR; REGRESSION; RESPONSES; IMMUNITY; RECOGNITION AB Patients with head and neck squamous cell carcinoma harbor T cell-inflamed and non-T cell-inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through pattern-recognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T cell-inflamed (MOC1), but not non-T cell-inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP, RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo. Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity. (C) 2016 AACR. C1 [Moore, Ellen; Clavijo, Paul E.; Davis, Ruth; Cash, Harrison; Van Waes, Carter; Allen, Clint] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Kim, Young; Allen, Clint] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Allen, C (reprint author), NIH, Bldg 10,Room 7N240C, Bethesda, MD 20892 USA. EM clint.allen@nih.gov OI Davis, Ruth/0000-0001-9592-932X FU Intramural NIH HHS [ZIA DC000087-01] NR 34 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD DEC PY 2016 VL 4 IS 12 BP 1061 EP 1071 DI 10.1158/2326-6066.CIR-16-0104 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA EE6FA UT WOS:000389702900008 PM 27821498 ER PT J AU Archer, TC Fertig, EJ Gosline, SJC Hafner, M Hughes, SK Joughin, BA Meyer, AS Piccolo, SR Shajahan-Haq, AN AF Archer, Tenley C. Fertig, Elana J. Gosline, Sara J. C. Hafner, Marc Hughes, Shannon K. Joughin, Brian A. Meyer, Aaron S. Piccolo, Stephen R. Shajahan-Haq, Ayesha N. TI Systems Approaches to Cancer Biology SO CANCER RESEARCH LA English DT Editorial Material ID BREAST-CANCER; REVEALS; SCIENCE AB Cancer systems biology aims to understand cancer as an integrated system of genes, proteins, networks, and interactions rather than an entity of isolated molecular and cellular components. The inaugural Systems Approaches to Cancer Biology Conference, cosponsored by the Association of Early Career Cancer Systems Biologists and the National Cancer Institute of the NIH, focused on the interdisciplinary field of cancer systems biology and the challenging cancer questions that are best addressed through the combination of experimental and computational analyses. Attendees found that elucidating the many molecular features of cancer inevitably reveals new forms of complexity and concluded that ensuring the reproducibility and impact of cancer systems biology studies will require widespread method and data sharing and, ultimately, the translation of important findings to the clinic. (C) 2016 AACR. C1 [Archer, Tenley C.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Fertig, Elana J.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Gosline, Sara J. C.] Sage Bionetworks, Seattle, WA USA. [Hafner, Marc] Harvard Med Sch, Dept Syst Biol, Boston, MA USA. [Hughes, Shannon K.] NCI, Div Canc Biol, NIH, Rockville, MD USA. [Joughin, Brian A.; Meyer, Aaron S.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Piccolo, Stephen R.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Shajahan-Haq, Ayesha N.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Meyer, AS (reprint author), MIT, 77 Massachusetts Ave,Bldg 76-361F, Cambridge, MA 02139 USA. EM ameyer@asmlab.org FU NIH HHS [DP5 OD019815] NR 19 TC 0 Z9 1 U1 8 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 DEC 1 PY 2016 VL 76 IS 23 BP 6774 EP 6777 DI 10.1158/0008-5472.CAN-16-1580 PG 4 WC Oncology SC Oncology GA EE2SX UT WOS:000389435800004 PM 27864348 ER PT J AU Skau, CT Fischer, RS Gurel, P Thiam, HR Tubbs, A Baird, MA Davidson, MW Piel, M Alushin, GM Nussenzweig, A Steeg, PS Waterman, CM AF Skau, Colleen T. Fischer, Robert S. Gurel, Pinar Thiam, Hawa Racine Tubbs, Anthony Baird, Michelle A. Davidson, Michael W. Piel, Matthieu Alushin, Gregory M. Nussenzweig, Andre Steeg, Patricia S. Waterman, Clare M. TI FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis SO CELL LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CELL-MIGRATION; DNA-DAMAGE; FOCAL ADHESIONS; INTELLECTUAL DISABILITY; FORCE TRANSMISSION; TUMOR PROGRESSION; FORMIN 2; ENVELOPE; CANCER AB Cell migration in confined 3D tissue microenvironments is critical for both normal physiological functions and dissemination of tumor cells. We discovered a cytoskeletal structure that prevents damage to the nucleus during migration in confined microenvironments. The formin-family actin filament nucleator FMN2 associates with and generates a perinuclear actin/focal adhesion (FA) system that is distinct from previously characterized actin/FA structures. This system controls nuclear shape and positioning in cells migrating on 2D surfaces. In confined 3D microenvironments, FMN2 promotes cell survival by limiting nuclear envelope damage and DNA double-strand breaks. We found that FMN2 is upregulated in human melanomas and showed that disruption of FMN2 in mouse melanoma cells inhibits their extravasation and metastasis to the lung. Our results indicate a critical role for FMN2 in generating a perinuclear actin/FA system that protects the nucleus and DNA from damage to promote cell survival during confined migration and thus promote cancer metastasis. C1 [Skau, Colleen T.; Fischer, Robert S.; Gurel, Pinar; Thiam, Hawa Racine; Baird, Michelle A.; Alushin, Gregory M.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thiam, Hawa Racine; Piel, Matthieu] CNRS UMR 144, Inst Curie, 26 Rue Ulm, F-75005 Paris, France. [Tubbs, Anthony; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Magnet Lab, Tallahassee, FL 32306 USA. [Steeg, Patricia S.] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov FU Intramural Programs of the National Heart, Lung, and Blood Institute; National Cancer Institute, NIH, Bethesda, MD; NIH Director's Early Independence Award [1DP5OD17885-1]; ANR "Netoshape"; ANR "Association pour la Recherche contre le Cancer'' [SFI20101201669] FX The authors would like to thank Dr. Mary Beckerle (Huntsman Cancer Institute), Dr. James Anderson (NHLBI), and Dr. Ken Yamada (NICDR) for reagents, Drs. Margot Quinlan and Alex M.L. Wu (NCI) for technical advice, William Shin for work on C.M.W.'s lab microscopes, and Schwanna Thacker for administrative assistance. This work is supported by the Intramural Programs of the National Heart, Lung, and Blood Institute (C.T.S., R.S.F., H.R.-T., M.A.B., G.M.A., and C.M.W.) and the National Cancer Institute (A.T., A.N., and P.S.S.), NIH, Bethesda, MD, an NIH Director's Early Independence Award (1DP5OD17885-1) (P.G. and G.M.A.), and ANR "Netoshape'' and "Association pour la Recherche contre le Cancer'' (no. SFI20101201669; M.P.). Dedicated to the memory of Michael W. Davidson. NR 63 TC 4 Z9 4 U1 18 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD DEC 1 PY 2016 VL 167 IS 6 BP 1571 EP + DI 10.1016/j.cell.2016.10.023 PG 33 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EN UT WOS:000389470500018 PM 27839864 ER PT J AU Lucas, M Gershlick, DC Vidaurrazaga, A Rojas, AL Bonifacino, JS Hierro, A AF Lucas, Maria Gershlick, David C. Vidaurrazaga, Ander Rojas, Adriana L. Bonifacino, Juan S. Hierro, Aitor TI Structural Mechanism for Cargo Recognition by the Retromer Complex SO CELL LA English DT Article ID PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; MAMMALIAN RETROMER; RETROGRADE TRANSPORT; DOMAIN; ARRESTIN; REVEALS; VPS35; YEAST; FOLD AB Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycl ing signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment. C1 [Lucas, Maria; Vidaurrazaga, Ander; Rojas, Adriana L.; Hierro, Aitor] CIC BioGUNE, Struct Biol Unit, Bizkaia Technol Pk, Derio 48160, Spain. [Gershlick, David C.; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA. [Hierro, Aitor] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. RP Hierro, A (reprint author), CIC BioGUNE, Struct Biol Unit, Bizkaia Technol Pk, Derio 48160, Spain.; Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Neurobiol Branch, NIH, Bethesda, MD 20892 USA.; Hierro, A (reprint author), Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Spain. EM bonifacinoj@helix.nih.gov; ahierro@cicbiogune.es RI Lucas, Maria/G-9788-2012; OI Lucas, Maria/0000-0002-7854-4249; Rojas, Adriana/0000-0002-7358-3505; Bonifacino, Juan S./0000-0002-5673-6370 FU Carlos III Health Institute [PI11/00121]; Basque Government [PI2011-26]; Spanish Ministry of Economy and Competitiveness [BFU2014-59759-R]; intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [ZIA HD001607]; European Community's Seventh Framework Programme (FP7) [283570]; Horizon 2020 programme iNEXT [653706] FX We thank Alberto Marina (CIC bioGUNE) for technical assistance. This work was supported by the Carlos III Health Institute grant PI11/00121, the Basque Government grant PI2011-26, the Spanish Ministry of Economy and Competitiveness grant BFU2014-59759-R (to A.H.), and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (ZIA HD001607) (to J.S.B.). This study made use of the Diamond Light Source (Oxfordshire, UK), synchrotron SOLEIL (Gif-sur Yvette, France), the European Synchrotron Radiation Facility (ESRF, Grenoble, France), and ALBA synchrotron beamline BL13-XALOC, funded in part by the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement no. 283570) and the Horizon 2020 programme iNEXT (H2020 project #653706). We thank all the staff from these facilities, and, in particular, to Andrew Thomson from SOLEIL, for assistance with X-ray data collection and processing, and Robert Rambo from Diamond for assistance with SAXS data collection. We also thank Peter Cullen, Carol R. Haft, and Mitsuaki Tabuchi for kind gifts of reagents and Philip McCoy (NHLBI, NIH) for cell sorting. NR 59 TC 2 Z9 2 U1 15 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD DEC 1 PY 2016 VL 167 IS 6 BP 1623 EP + DI 10.1016/j.cell.2016.10.056 PG 27 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3EN UT WOS:000389470500022 PM 27889239 ER PT J AU Murayi, R Chittiboina, P AF Murayi, Roger Chittiboina, Prashant TI Glucocorticoids in the management of peritumoral brain edema: a review of molecular mechanisms SO CHILDS NERVOUS SYSTEM LA English DT Review DE Peritumoral brain edema (PTBE); Glucocorticoids; Blood-brain barrier ID VASCULAR-PERMEABILITY FACTOR; CENTRAL-NERVOUS-SYSTEM; MATRIX-METALLOPROTEINASE EXPRESSION; TIGHT JUNCTION PERMEABILITY; NF-KAPPA-B; AQUAPORIN-4 EXPRESSION; ENDOTHELIAL-CELLS; DEXAMETHASONE REGULATION; CAPILLARY-PERMEABILITY; BARRIER PERMEABILITY AB Peritumoral brain edema (PTBE) is mediated by blood-brain barrier breakdown. PTBE results from interstitial vasogenic brain edema due to vascular endothelial growth factor and other inflammatory products of brain tumors. Glucocorticoids (GCs) are the mainstay for treatment of PTBE despite significant systemic side effects. GCs are thought to affect multiple cell types in the edematous brain. Here, we review preclinical studies of GC effects on edematous brain and review mechanisms underlying GC action on tumor cells, endothelial cells, and astrocytes. GCs may reduce tumor cell viability and suppress vascular endothelial growth factor (VEGF) production in tumor cells. Modulation of expression and distribution of tight junction proteins occludin, claudin-5, and ZO-1 in endothelial cells likely plays a central role in GC action on endothelial cells. GCs may also have an effect on astrocyte angiopoietin production and limited effect on astrocyte aquaporin. A better understanding of these molecular mechanisms may lead to the development of novel therapeutics for management of PTBE with a better side effect profile. C1 [Murayi, Roger; Chittiboina, Prashant] NINDS, Surg Neurol Branch, Neurosurg Unit Pituitary & Inheritable Dis, NIH, 10 Ctr Dr,Room 3D20, Bethesda, MD 20892 USA. RP Chittiboina, P (reprint author), NINDS, Surg Neurol Branch, Neurosurg Unit Pituitary & Inheritable Dis, NIH, 10 Ctr Dr,Room 3D20, Bethesda, MD 20892 USA. EM Prashant.Chittiboina@nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH); NIH FX The authors would like to thank Marsha Merrill, PhD, for discussions and historical insights. This study was funded by the intramural research program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH. The authors thank Ethan Tyler from the Medical Arts Branch of the NIH Clinical Center for the illustration. NR 108 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0256-7040 EI 1433-0350 J9 CHILD NERV SYST JI Childs Nerv. Syst. PD DEC PY 2016 VL 32 IS 12 BP 2293 EP 2302 DI 10.1007/s00381-016-3240-x PG 10 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA EE5GL UT WOS:000389633500008 PM 27613642 ER PT J AU Moxey-Mims, MM Flessner, MF Holzman, L Kaskel, F Sedor, JR Smoyer, WE Thompson, AM Yao, L AF Moxey-Mims, Marva M. Flessner, Michael F. Holzman, Lawrence Kaskel, Frederick Sedor, John R. Smoyer, William E. Thompson, Aliza M. Yao, Lynne TI Glomerular Diseases: Registries and Clinical Trials SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RANDOMIZED CONTROLLED-TRIALS; KIDNEY-DISEASE; LUPUS NEPHRITIS; MEMBRANOUS NEPHROPATHY; PATIENT-CARE; NEPHROLOGY; HEALTH AB Nephrology has conducted few high quality clinical trials, and the trials that have been conducted have not resulted in the approval of new treatments for primary or inflammatory glomerular diseases. There are over-arching process issues that affect the conduct of all clinical trials, but there are also some specialty specific issues. Within nephrology, primary glomerular diseases are rare, making adequate recruitment for meaningful trials difficult. Nephrologists need better ways, beyond histopathology, to phenotype patients with glomerular diseases and stratify the risk for progression to ESRD. Rigorous trial design is needed for the testing of new therapies, where most patients with glomerular diseases are offered the opportunity to enroll in a clinical trial if standard therapies have failed or are lacking. Training programs to develop a core group of kidney specialists with expertise in the design and implementation of clinical trials are also needed. Registries of patients with glomerular disease and observational studies can aid in the ability to determine realistic estimates of disease prevalence and inform trial design through a better understanding of the natural history of disease. Some proposed changes to the Common Rule, the federal regulations governing the ethical conduct of research involving humans, and the emerging use of electronic health records may facilitate the efficiency of initiating multicenter clinical trials. Collaborations among academia, government scientific and regulatory agencies, industry, foundations, and patient advocacy groups can accelerate therapeutic development for these complex diseases. C1 [Moxey-Mims, Marva M.] NIDDK, Div Kidney Urol & Hematol, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. RP Moxey-Mims, MM (reprint author), NIDDK, Div Kidney Urol & Hematol, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM mm726k@nih.gov FU NIDDK; Genentech (South San Francisco, CA) FX M.M.M.-M. and M.F.F. have National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; Bethesda, MD) oversight for the Cure Glomerulonephropathy (CureGN) and the Nephrotic Syndrome Study Network (NEPTUNE) studies. L.H. is funded by the NIDDK as a principal investigator for CureGN, a site principal investigator for NEPTUNE, and a consultant for GlaxoSmithKline (Brentford, United Kingdom), Pfizer (New York, NY), and Bristol-Meyers Squibb (Princeton, NJ). F.K. is a site principal investigator for CureGN and NEPTUNE studies. J.R.S. is funded by the NIDDK and serves as a site principal investigator for NEPTUNE and CureGN and a consultant for Bristol-Meyers Squibb, GlaxoSmithKline, Sanofi-Genzyme (Framingham, MA), and Thrid Rock Ventures (Boston, MA). J.R.S. is on the Scientific Advisory Board for the Phase II Treatment Resistant Nephrotic Syndrome Trial with Abatacept by Bristol-Meyers Squibb. W.E.S. is funded by the NIDDK as a principal investigator for CureGN, has received funding from Genentech (South San Francisco, CA) as a principal investigator on the Randomized Trial Comparing Rituximab Against Mycophenolate Mofetil in Children With Refractory Nephrotic Syndrome Trial, and is coprincipal investigator of the Ohio State University Clinical and Translational Science Awards. A.M.T. and L.Y. have no disclosures. NR 30 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2016 VL 11 IS 12 BP 2234 EP 2243 DI 10.2215/CJN.00540116 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EE3OF UT WOS:000389498200020 PM 27672219 ER PT J AU Cohen, SD Cukor, D Kimmel, PL AF Cohen, Scott D. Cukor, Daniel Kimmel, Paul L. TI Anxiety in Patients Treated with Hemodialysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; CHRONIC KIDNEY-DISEASE; DEPRESSION; DISORDERS; THERAPY; DIALYSIS; HEALTH; IMPAIRMENT; PREVALENCE AB Anxiety is a common yet frequently overlooked psychiatric symptom in patients with ESRD treated with hemodialysis (HD). Anxiety is characterized by disruptive feelings of uncertainty, dread, and fearfulness. A variety of common medical complaints may be manifestations of an anxiety disorder, including palpitations, tremors, indigestion, numbness/tingling, nervousness, shortness of breath, diaphoresis, and fear. It is essential for the clinician to rule out specific medical conditions, including cardiovascular, pulmonary, and neurologic diseases, before ascribing these symptoms to an anxiety disorder. In addition, there is considerable overlap between the symptoms of anxiety and those of depression and uremia. This psychiatric condition has a significant adverse impact on patients' perception of quality of life. Little is known regarding the prevalence and impact of anxiety disorders in patients with ESRD treated with HD; however, many of the seemingly irrational behaviors of patients, or behaviors which place them in conflict with staff and physicians, such as behavioral noncompliance, may be the expression of an underlying anxiety disorder. In this review, we present three clinical vignettes, highlighting the impact of anxiety disorders in patients with ESRD treated with HD. C1 [Cohen, Scott D.; Kimmel, Paul L.] George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. [Cukor, Daniel] Suny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM kimmelp@extra.niddk.nih.gov NR 33 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2016 VL 11 IS 12 BP 2250 EP 2255 DI 10.2215/CJN.02590316 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA EE3OF UT WOS:000389498200022 PM 27660303 ER PT J AU Hartz, J Yingling, L Powell-Wiley, TM AF Hartz, Jacob Yingling, Leah Powell-Wiley, Tiffany M. TI Use of Mobile Health Technology in the Prevention and Management of Diabetes Mellitus SO CURRENT CARDIOLOGY REPORTS LA English DT Review DE Mobile health technology; Diabetes mellitus; Cardiovascular disease; Racial/ethnic minorities; Children; Adolescents ID RANDOMIZED CONTROLLED-TRIAL; GLUCOSE MONITORING-SYSTEM; BEHAVIOR-CHANGE TECHNIQUES; PHYSICAL-ACTIVITY; SELF-MANAGEMENT; GLYCEMIC CONTROL; WEIGHT-LOSS; SMARTPHONE TECHNOLOGY; CHRONIC DISEASE; OLDER-ADULTS AB Cardiovascular disease is the leading cause of morbidity and mortality globally, with diabetes being an independent risk factor. Adequate diabetes management has proven to be resource-intensive, requiring frequent lab work, primary care and specialist visits, and time-consuming record-keeping by the patient and care team. New mobile health (mHealth) technologies have enhanced how diabetes is managed and care is delivered. While more recent work has investigated mHealth devices as complementary tools in behavioral interventions for diabetes prevention and management, little is still known about the effectiveness of mHealth technology as stand-alone intervention tools for reducing diabetes risk. In addition, more work is needed to identify the role of mHealth technology in treating vulnerable populations to ameliorate cardiovascular health disparities. With advances in mobile health technology development for diabetes prevention and management, these modalities will likely play an increasingly prominent role in reducing cardiometabolic risk for the US population. C1 [Hartz, Jacob] Childrens Natl Med Ctr, Dept Cardiol, 111 Michigan Ave NW, Washington, DC 20010 USA. [Yingling, Leah; Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM jhartz@childrensnational.org; leah.lingling@nih.gov; tiffany.powell-wiley@nih.gov OI Yingling, Leah/0000-0002-7851-690X FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) FX 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 U.S. Department of Health and Human Services. Funding for TP-W and LY is provided through the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). NR 91 TC 0 Z9 0 U1 29 U2 29 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD DEC PY 2016 VL 18 IS 12 AR 130 DI 10.1007/s11886-016-0796-8 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE8RM UT WOS:000389893400014 PM 27826901 ER PT J AU Hirahara, K Schwartz, D Gadina, M Kanno, Y O'Shea, JJ AF Hirahara, Kiyoshi Schwartz, Daniella Gadina, Massimo Kanno, Yuka O'Shea, John J. TI Targeting cytokine signaling in autoimmunity: back to the future and beyond SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID ACTIVE RHEUMATOID-ARTHRITIS; JANUS KINASE INHIBITOR; TO-SEVERE PSORIASIS; RANDOMIZED CONTROLLED-TRIAL; CHRONIC PLAQUE PSORIASIS; HAN CHINESE POPULATION; LONG-TERM EXTENSION; INADEQUATE RESPONSE; DOUBLE-BLIND; BACKGROUND METHOTREXATE AB Cytokines represent structurally diverse soluble factors with critical roles in normal immune function and the pathogenesis of autoimmunity. The emergence of many successful biological therapies targeting cytokines and cytokine receptors exemplifies the importance of cytokines in driving human autoimmune disease; unsurprisingly, there is no paucity of reviews on this subject. Nonetheless, many patients with autoimmune disease do not respond to biologicals, and cure remains an unmet goal. Thus, targeting the intracellular pathways employed by cytokines provides new therapeutic opportunities. A subset of cytokines utilizes the Janus kinase-signal transducer of activators of transcription (JAK-STAT) pathway as a mode of signal transduction. First generation JAK inhibitors (jakinibs) are used to treat rheumatologic disease, and second-generation jakinibs are being developed. Simultaneously, rapid advances are being made in our understanding of the genomic and epigenomic impact of cytokines. In this review, we will briefly review the role of JAKSTAT-dependent cytokines in immune-mediated disease, the current status of Jakinibs, and future possibilities for therapeutic intervention using genomic insights. C1 [Hirahara, Kiyoshi] Chiba Univ, Grad Sch Med, Dept Immunol, 1-8-1 Inohana Chuo Ku, Chiba 2608670, Japan. [Schwartz, Daniella; Kanno, Yuka; O'Shea, John J.] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Gadina, Massimo] NIAMS, Translat Immunol Sect, Off Sci Technol, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM John.Oshea@nih.gov RI Hirahara, Kiyoshi/E-2460-2017 OI Hirahara, Kiyoshi/0000-0002-9128-9449 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH FX The work of Y.K., D.S., M.G., J.O.S. is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. NR 82 TC 1 Z9 1 U1 3 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2016 VL 43 BP 89 EP 97 DI 10.1016/j.coi.2016.10.001 PG 9 WC Immunology SC Immunology GA EE6OX UT WOS:000389733200014 PM 27821272 ER PT J AU Peyre, H Hoertel, N Rivollier, F Landman, B McMahon, K Chevance, A Lemogne, C Delorme, R Blanco, C Limosin, F AF Peyre, Hugo Hoertel, Nicolas Rivollier, Fabrice Landman, Benjamin McMahon, Kibby Chevance, Astrid Lemogne, Cedric Delorme, Richard Blanco, Carlos Limosin, Frederic TI Latent class analysis of the feared situations of social anxiety disorder: A population-based study SO DEPRESSION AND ANXIETY LA English DT Article DE generalized; latent class analysis; performance only; psychiatric disorders; social anxiety disorder; social fears; social phobia; subtypes ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE-DISORDER; QUALITY-OF-LIFE; PSYCHIATRIC DIAGNOSTIC MODULES; IV AUDADIS-IV; GENERAL-POPULATION; COMORBIDITY SURVEY; PHOBIA; RELIABILITY; SUBTYPES AB BackgroundLittle is known about differences in mental health comorbidity and quality of life in individuals with social anxiety disorder (SAD) according to the number and the types of feared situations. MethodsUsing a US nationally representative sample, the National Epidemiologic Survey on Alcohol and Related Conditions, we performed latent class analysis to compare the prevalence rates of mental disorders and quality of life measures across classes defined by the number and the types of feared social situations among individuals with SAD. ResultsAmong the 2,448 participants with a lifetime diagnosis of SAD, we identified three classes of individuals who feared most social situations but differed in the number of feared social situations (generalized severe [N = 378], generalized moderate [N = 1,049] and generalized low [N = 443]) and a class of subjects who feared only performance situations [N = 578]. The magnitude of associations between each class and a wide range of mental disorders and quality of life measures were consistent with a continuum model, supporting that the deleterious effects of SAD on mental health may increase with the number of social situations feared. However, we found that individuals with the performance only specifier may constitute an exception to this model because these participants had significantly better mental health than other participants with SAD. ConclusionsOur findings give additional support to the recent changes made in the DSM-5, including the introduction of the performance only specifier and the removal of the generalized specifier to promote the dimensional approach of the number of social fears. C1 [Peyre, Hugo; Landman, Benjamin; Delorme, Richard] Robert Debre Hosp, AP HP, Dept Child & Adolescent Psychiat, Paris, France. [Peyre, Hugo] Ecole Normale Super, Cognit Sci & Psycholinguist Lab, Paris, France. [Hoertel, Nicolas; Lemogne, Cedric; Limosin, Frederic] Paris Descartes Univ, PRES Sorbonne Paris Cite, Paris, France. [Hoertel, Nicolas; Chevance, Astrid; Lemogne, Cedric; Limosin, Frederic] Corentin Celton Hosp, AP HP, Dept Psychiat, Issy Les Moulineaux, France. [Hoertel, Nicolas; Rivollier, Fabrice; Lemogne, Cedric; Limosin, Frederic] Psychiat & Neurosci Ctr, INSERM UMR 894, Paris, France. [Rivollier, Fabrice] Paris Descartes Univ, Sainte Anne Hosp, Serv Hospitalouniv, Paris, France. [McMahon, Kibby] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Blanco, Carlos] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Peyre, H (reprint author), Ecole Normale Super, Dept Etud Cognit, LSCP, 29 Rue Ulm, F-75005 Paris, France. EM peyrehugo@yahoo.fr OI Lemogne, Cedric/0000-0002-3487-4721 NR 32 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD DEC PY 2016 VL 33 IS 12 BP 1178 EP 1187 DI 10.1002/da.22547 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EE9EA UT WOS:000389927400011 PM 27575056 ER PT J AU Chen, BH Hivert, MF Peters, MJ Pilling, LC Hogan, JD Pham, LM Harries, LW Fox, CS Bandinelli, S Dehghan, A Hernandez, DG Hofman, A Hong, J Joehanes, R Johnson, AD Munson, PJ Rybin, DV Singleton, AB Uitterlinden, AG Ying, S Melzer, D Levy, D van Meurs, JBJ Ferrucci, L Florez, JC Dupuis, J Meigs, JB Kolaczyk, ED AF Chen, Brian H. Hivert, Marie-France Peters, Marjolein J. Pilling, Luke C. Hogan, John D. Pham, Lisa M. Harries, Lorna W. Fox, Caroline S. Bandinelli, Stefania Dehghan, Abbas Hernandez, Dena G. Hofman, Albert Hong, Jaeyoung Joehanes, Roby Johnson, Andrew D. Munson, Peter J. Rybin, Denis V. Singleton, Andrew B. Uitterlinden, Andre G. Ying, Saixia Melzer, David Levy, Daniel van Meurs, Joyce B. J. Ferrucci, Luigi Florez, Jose C. Dupuis, Josee Meigs, James B. Kolaczyk, Eric D. CA Magic Investigators TI Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN SKELETAL-MUSCLE; TYPE-2 DIABETES SUSCEPTIBILITY; INFLUENCING GLYCEMIC TRAITS; EAST ASIANS; LOCI; IDENTIFICATION; EXPRESSION; RESISTANCE; VARIANTS AB Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. C1 [Chen, Brian H.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Chen, Brian H.; Fox, Caroline S.; Joehanes, Roby; Johnson, Andrew D.; Levy, Daniel; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Brian H.; Fox, Caroline S.; Joehanes, Roby; Johnson, Andrew D.; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Hivert, Marie-France] Harvard Med Sch, Dept Populat Med, Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hivert, Marie-France; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus Univ, Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Rotterdam, Netherlands. [Pilling, Luke C.; Melzer, David] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Hogan, John D.; Pham, Lisa M.; Kolaczyk, Eric D.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Harries, Lorna W.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Lab Neurogenet, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Hong, Jaeyoung; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Munson, Peter J.; Ying, Saixia] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Rybin, Denis V.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Meigs, James B.] Broad Inst, Metab Program, Cambridge, MA 02142 USA. [Florez, Jose C.; Meigs, James B.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Kolaczyk, Eric D.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Kolaczyk, ED (reprint author), Boston Univ, Program Bioinformat, Boston, MA 02215 USA.; Meigs, JB (reprint author), Broad Inst, Metab Program, Cambridge, MA 02142 USA.; Meigs, JB (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Meigs, JB (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.; Kolaczyk, ED (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM jmeigs@partners.org; kolaczyk@bu.edu FU European Commission [HEALTH-F2-2008-201865, GEFOS, HEALTH-F2-2008 35627, TREAT-OA 200800]; Netherlands Organisation for Scientific Research [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing [050-060-810]; Netherlands Organisation for Scientific Research VIDI grant [917103521]; Erasmus University Medical Center Rotterdam; Erasmus University; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam FX This work was funded by the European Commission (HEALTH-F2-2008-201865, GEFOS, HEALTH-F2-2008 35627, and TREAT-OA 200800), the Netherlands Organisation for Scientific Research (175.010.2005.011 and 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015, RIDE2), the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing (050-060-810), and Netherlands Organisation for Scientific Research VIDI grant (917103521). The RS is funded by Erasmus University Medical Center Rotterdam and Erasmus University; Netherlands Organisation for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.; The FHS is funded by the National Institutes of Health (NIH) contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster (https://hpc.nih.gov/) and Helix Systems (http://helix.nih.gov) at the NIH. L.M.P., J.D., J.B.M., and E.D.K. were partially supported by NIH grant R01 DK078616. J.B.M. is partly supported by NIH grant K24 DK080140.; This research was supported in part by the Intramural Research Program, National Institute on Aging, NIH (Z01-AG000947 and Z01-AG000185). The InCHIANTI study baseline (1998-2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336). L.W.H. was funded by a grant from the U.K. Medical Research Council (MR/J006777/1). NR 42 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 65 IS 12 BP 3794 EP 3804 DI 10.2337/db16-0470 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE0RA UT WOS:000389285400029 PM 27625022 ER PT J AU Geliebter, A McOuatt, H Tetreault, CB Kordunova, D Rice, K Zammit, G Gluck, M AF Geliebter, Allan McOuatt, Haley Tetreault, Cora B. Kordunova, Dorina Rice, Kathleen Zammit, Gary Gluck, Marci TI Is night eating syndrome associated with obstructive sleep apnea, BMI, and depressed mood in patients from a sleep laboratory study? SO EATING BEHAVIORS LA English DT Article DE OSA; NES; Obesity; Eating disorders; AHI; BMI ID CLINICAL-SIGNIFICANCE; OBESE-PATIENTS; WEIGHT-LOSS; DISORDERS; EPIDEMIOLOGY; VALIDATION; STUDENTS; FEATURES; ANXIETY AB Purpose: The aim of this study was to assess night eating syndrome (NES) in patients referred for polysomnography and its association with obstructive sleep apnea (OSA). We also assessed whether participants with OSA were more likely to get up and eat at night, and whether these behaviors were associated with the apnea-hypopnea sleep index (AHI). We additionally examined whether NES and OSA were associated with BMI, and assessed depressed mood among participants with NES or OSA. Methods: The Night Eating Diagnostic Questionnaire (NEDQ), Zung Depression Scale, and demographic and medical questionnaires were used to evaluate 84 qualified participants. Polysomnography was used to assess AHI, and therefore OSA. Results: Thirty individuals met full or sub-threshold NES (NES[St]) criteria, and 54 had no night eating (Normal). Eighty-nine percent of the sample had OSA with AHI >= 5. Neither AHI nor BMI differed between NES(St) and Normal, F(1,82) - 1.67, p - 0.20 and F(1, 82) - 2.2, p - 0.14, respectively. Participants with NES(St) were, however, more likely than Normal to have depressed mood (mild, moderately, or severely depressed), x(2) = 4.47 p = 0.03. There was a positive correlation between AHI and BMI, r = 0.37, p = 0.001. Those with OSA were not more likely to eat at night, F(1,82) = 0.04, p = 0.84, or get out of bed more often, F(1,13) = 0.23, p = 0.64, and there was no correlation between AHI and eating at night (r = -0.11, p = 0.31). However, there was a positive correlation between AHI and the number of times participants got up out of bed (r = 0.81, p < 0.001). Conclusions: We found that NES was not associated with BMI or AHI severity. The findings show that NES is primarily an eating disorder, rather than a sleep disorder, and that there is an association between NES and depressed mood. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Geliebter, Allan; McOuatt, Haley; Tetreault, Cora B.; Kordunova, Dorina] Mt Sinai St Lukes Hosp, New York, NY USA. [Geliebter, Allan; Kordunova, Dorina] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Geliebter, Allan] Touro Coll & Univ Syst, Dept Psychol, New York, NY USA. [Rice, Kathleen; Zammit, Gary] Clinilabs Sleep Disorders Inst, New York, NY 10025 USA. [Gluck, Marci] NIDDK, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85099 USA. RP Geliebter, A (reprint author), Mt Sinai St Lukes Hosp, S&R, 11th Flr,Rm 1136, New York, NY 10025 USA. EM ageliebt@chpnet.org FU NIH [DK068603, DK074046] FX Funding for the study was provided in part by NIH grants DK068603 and DK074046. NIH had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 41 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD DEC PY 2016 VL 23 BP 115 EP 119 DI 10.1016/j.eatbeh.2016.08.008 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EF0EZ UT WOS:000389999800021 PM 27643566 ER PT J AU Fan, R Chiu, CY Jung, J Weeks, DE Wilson, AF Bailey-Wilson, JE Amos, CI Chen, Z Mills, JL Xiong, M AF Fan, Ruzong Chiu, Chi-yang Jung, Jeesun Weeks, Daniel E. Wilson, Alexander F. Bailey-Wilson, Joan E. Amos, Christopher I. Chen, Zhen Mills, James L. Xiong, Momiao TI A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits SO GENETIC EPIDEMIOLOGY LA English DT Article DE rare variants; common variants; association mapping; quantitative/dichotomous trait loci; complex traits; functional data analysis; multivariate linear models; logistic regressions ID FUNCTIONAL LINEAR-MODELS; QUANTITATIVE TRAITS; RARE; LOCI; METAANALYSIS; VARIANTS; DISEASES; LINKAGE AB In association studies of complex traits, fixed-effect regression models are usually used to test for association between traits and major gene loci. In recent years, variance-component tests based on mixed models were developed for region-based genetic variant association tests. In the mixed models, the association is tested by a null hypothesis of zero variance via a sequence kernel association test (SKAT), its optimal unified test (SKAT-O), and a combined sum test of rare and common variant effect (SKAT-C). Although there are some comparison studies to evaluate the performance of mixed and fixed models, there is no systematic analysis to determine when the mixed models perform better and when the fixed models perform better. Here we evaluated, based on extensive simulations, the performance of the fixed and mixed model statistics, using genetic variants located in 3, 6, 9, 12, and 15 kb simulated regions. We compared the performance of three models: (i) mixed models that lead to SKAT, SKAT-O, and SKAT-C, (ii) traditional fixed-effect additive models, and (iii) fixed-effect functional regression models. To evaluate the type I error rates of the tests of fixed models, we generated genotype data by two methods: (i) using all variants, (ii) using only rare variants. We found that the fixed-effect tests accurately control or have low false positive rates. We performed simulation analyses to compare power for two scenarios: (i) all causal variants are rare, (ii) some causal variants are rare and some are common. Either one or both of the fixed-effect models performed better than or similar to the mixed models except when (1) the region sizes are 12 and 15 kb and (2) effect sizes are small. Therefore, the assumption of mixed models could be satisfied and SKAT/SKAT-O/SKAT-C could perform better if the number of causal variants is large and each causal variant contributes a small amount to the traits (i.e., polygenes). In major gene association studies, we argue that the fixed-effect models perform better or similarly to mixed models in most cases because some variants should affect the traits relatively large. In practice, it makes sense to perform analysis by both the fixed and mixed effect models and to make a comparison, and this can be readily done using our R codes and the SKAT packages. Published 2016 Wiley Periodicals, Inc. C1 [Fan, Ruzong; Chiu, Chi-yang; Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Jung, Jeesun] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Wilson, Alexander F.; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Xiong, Momiao] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. RP Fan, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. EM fanr@mail.nih.gov OI Weeks, Daniel/0000-0001-9410-7228 NR 32 TC 1 Z9 1 U1 1 U2 1 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 DEC PY 2016 VL 40 IS 8 BP 702 EP 721 DI 10.1002/gepi.21984 PG 20 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EE5GO UT WOS:000389633800003 PM 27374056 ER PT J AU He, QC Cai, TX Liu, Y Zhao, N Harmon, QE Almli, LM Binder, EB Engel, SM Ressler, KJ Conneely, KN Lin, XH Wu, MC AF He, Qianchuan Cai, Tianxi Liu, Yang Zhao, Ni Harmon, Quaker E. Almli, Lynn M. Binder, Elisabeth B. Engel, Stephanie M. Ressler, Kerry J. Conneely, Karen N. Lin, Xihong Wu, Michael C. TI Prioritizing individual genetic variants after kernel machine testing using variable selection SO GENETIC EPIDEMIOLOGY LA English DT Article DE genetic association studies; kernel machine methods; KNIFE; set-based; variable selection ID GENOME-WIDE ASSOCIATION; REGRESSION; REGULARIZATION; EXPRESSION; OUTCOMES; STRESS; CANCER; RARE AB Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach. C1 [He, Qianchuan; Liu, Yang; Zhao, Ni; Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Cai, Tianxi; Lin, Xihong] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Harmon, Quaker E.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Almli, Lynn M.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Binder, Elisabeth B.] Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany. [Engel, Stephanie M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Ressler, Kerry J.] McLean Hosp, Div Depress & Anxiety Disorders, 115 Mill St, Belmont, MA 02178 USA. [Conneely, Karen N.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. RP He, QC; Wu, MC (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM qhe@fredhutch.org; mcwu@fredhutch.org OI Wu, Michael C./0000-0002-3357-6570 FU NCI NIH HHS [P01 CA134294]; NHGRI NIH HHS [R01 HG006292, R01 HG007508, U54 HG007963]; NICHD NIH HHS [R21 HD060207]; NIEHS NIH HHS [P30 ES000002]; NIMH NIH HHS [R01 MH071537, R01 MH096764] NR 33 TC 0 Z9 0 U1 8 U2 8 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 DEC PY 2016 VL 40 IS 8 BP 722 EP 731 DI 10.1002/gepi.21993 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EE5GO UT WOS:000389633800004 PM 27488097 ER PT J AU Loud, JT Bremer, RC Mai, PL Peters, JA Giri, N Stewart, DR Greene, MH Alter, BP Savage, SA AF Loud, Jennifer T. Bremer, Renee C. Mai, Phuong L. Peters, June A. Giri, Neelam Stewart, Douglas R. Greene, Mark H. Alter, Blanche P. Savage, Sharon A. TI Research participant interest in primary, secondary, and incidental genomic findings SO GENETICS IN MEDICINE LA English DT Article DE familial cancer syndromes; genetic testing; incidental findings; intentions to receive research genetic results; whole genome/exome sequencing ID GENETIC RESEARCH; RETURN; EXOME; ATTITUDES; PREFERENCES; CHILDREN; DISEASE; VIEWS AB Purpose: To define the frequency with which adult research participants consent to be offered clinically validated research genetic test results (RR) and incidental findings (IF). Methods: Consents were obtained from 506 adults enrolled in one of three studies within the National Cancer Institute Clinical Genetics Branch's Familial Cancer Research Program. A cross-sectional analysis was performed involving the choices indicated on study consents regarding receipt of RR and IF. Results: Ninety-seven percent opted to receive RR and IF. Participants who declined (n = 16) included two cancer survivors who were mutation-positive (1 = RR and 1 = both), eight who knew their primary mutation status (3 = RR; 4 = IF; 1 = both), three nonbloodline relatives (1 = RR; 2 = both), one untested but with the syndromic phenotype (1 = IF), and two parents of an affected child (2 = both). We speculate that these individuals either already had sufficient information, were not prepared to learn more, or felt that the information would not change their personal health-care decision making. Conclusions: Adult research participants from families at high genetic risk for cancer overwhelmingly indicated their preference to receive both RR and IF. Future research will seek to identify the reasons for declining RR and IF and to study the impact of receipt of RR and IF on personal medical decision making. C1 [Loud, Jennifer T.; Bremer, Renee C.; Mai, Phuong L.; Peters, June A.; Giri, Neelam; Stewart, Douglas R.; Greene, Mark H.; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Loud, JT (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM LoudJ@mail.nih.gov 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. We are grateful to the study participants for their valuable contributions to our research. NR 23 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2016 VL 18 IS 12 BP 1218 EP 1225 DI 10.1038/gim.2016.36 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EE4HU UT WOS:000389563700009 PM 27101135 ER PT J AU Hunter, JE Irving, SA Biesecker, LG Buchanan, A Jensen, B Lee, K Martin, CL Milko, L Muessig, K Niehaus, AD O'Daniel, J Piper, MA Ramos, EM Schully, SD Scott, AF Slavotinek, A Sobreira, N Strande, N Weaver, M Webber, EM Williams, MS Berg, JS Evans, JP Goddard, KAB AF Hunter, Jessica Ezzell Irving, Stephanie A. Biesecker, Leslie G. Buchanan, Adam Jensen, Brian Lee, Kristy Martin, Christa Lese Milko, Laura Muessig, Kristin Niehaus, Annie D. O'Daniel, Julianne Piper, Margaret A. Ramos, Erin M. Schully, Sheri D. Scott, Alan F. Slavotinek, Anne Sobreira, Nara Strande, Natasha Weaver, Meredith Webber, Elizabeth M. Williams, Marc S. Berg, Jonathan S. Evans, James P. Goddard, Katrina A. B. CA ClinGen Resource TI A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation SO GENETICS IN MEDICINE LA English DT Article DE clinical actionability; exome sequencing; genome sequencing; incidental findings; secondary findings ID INCIDENTAL FINDINGS; MANAGEMENT; EXOME; GUIDELINES; MEDICINE AB Purpose: Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research. Methods: We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semi-quantitative metric to score actionability. Results: We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders. Conclusion: The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing. C1 [Hunter, Jessica Ezzell; Irving, Stephanie A.; Muessig, Kristin; Piper, Margaret A.; Webber, Elizabeth M.; Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97232 USA. [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Buchanan, Adam; Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Jensen, Brian] Univ N Carolina, Sch Med, Div Cardiol, McAllister Heart Inst, Chapel Hill, NC USA. [Lee, Kristy; Milko, Laura; O'Daniel, Julianne; Strande, Natasha; Berg, Jonathan S.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Martin, Christa Lese] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA USA. [Niehaus, Annie D.; Ramos, Erin M.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Schully, Sheri D.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Scott, Alan F.; Sobreira, Nara] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Slavotinek, Anne] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Weaver, Meredith] Amer Coll Med Genet & Genom, Bethesda, MD USA. RP Hunter, JE (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97232 USA. EM Jessica.E.Hunter@kpchr.org OI Strande, Natasha/0000-0001-5148-9772; Hunter, Jessica/0000-0002-1117-1097 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Human Genome Research Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development [1U41HG006834-01A1, 1U01HG007437-01, 1U01HG007436-01, 1UO1HG00648701]; Intramural Research Program of the National Human Genome Research Institute FX This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The ClinGen consortium is also funded by the National Human Genome Research Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development through contracts 1U41HG006834-01A1, 1U01HG007437-01, 1U01HG007436-01, and 1UO1HG00648701. The efforts of L.G.B. were supported by the Intramural Research Program of the National Human Genome Research Institute. NR 23 TC 2 Z9 2 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2016 VL 18 IS 12 BP 1258 EP 1268 DI 10.1038/gim.2016.40 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EE4HU UT WOS:000389563700014 PM 27124788 ER PT J AU Lee, EMJ Xu, K Mosbrook, E Links, A Guzman, J Adams, DR Flynn, E Valkanas, E Toro, C Tifft, CJ Boerkoel, CF Gahl, WA Sincan, M AF Lee, Elizabeth M. J. Xu, Karen Mosbrook, Emma Links, Amanda Guzman, Jessica Adams, David R. Flynn, Elise Valkanas, Elise Toro, Camillo Tifft, Cynthia J. Boerkoel, Cornelius F. Gahl, William A. Sincan, Murat TI Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience SO GENETICS IN MEDICINE LA English DT Article DE next generation sequencing; NIH undiagnosed; diseases program; pharmacogenomics; precision medicine; secondary findings ID DNA-SEQUENCING DATA; PEDIATRIC PHARMACOGENOMICS; GENETIC-VARIANTS; DATA SETS; FRAMEWORK; MORPHINE; OPRM1; POLYMORPHISMS; ASSOCIATION; GENOTYPE AB PURPOSE: Using single-nucleotide polymorphism (SNP) chip and exome sequence data from individuals participating in the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP), we evaluated the number and therapeutic informativeness of incidental pharmacogenetic variants. METHODS: Pharmacogenomics Knowledgebase (PharmGKB) annotated sequence variants were identified in 1,101 individuals. Medication records of participants were used to identify individuals prescribed medications with a genetic variant that might alter efficacy. RESULTS: A total of 395 sequence variants, including 19 PharmGKB 1A and 1B variants, were identified in SNP chip sequence data, and 388 variants, including 21 PharmGKB 1A and 1B variants, were identified in the exome sequence data. Nine participants had incidental pharmacogenetic variants associated with altered efficacy of a prescribed medication. CONCLUSIONS: Despite the small size of the NIH UDP patient cohort, we identified pharmacogenetic incidental findings potentially useful for guiding therapy. Consequently, groups conducting clinical genomic studies might consider reporting of pharmacogenetic incidental findings C1 [Lee, Elizabeth M. J.; Xu, Karen; Mosbrook, Emma; Links, Amanda; Guzman, Jessica; Adams, David R.; Flynn, Elise; Valkanas, Elise; Toro, Camillo; Tifft, Cynthia J.; Boerkoel, Cornelius F.; Gahl, William A.; Sincan, Murat] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Lee, Elizabeth M. J.; Xu, Karen; Mosbrook, Emma; Links, Amanda; Guzman, Jessica; Adams, David R.; Flynn, Elise; Valkanas, Elise; Toro, Camillo; Tifft, Cynthia J.; Boerkoel, Cornelius F.; Gahl, William A.; Sincan, Murat] NHGRI, NIH, Bethesda, MD 20892 USA. RP Sincan, M (reprint author), NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA.; Sincan, M (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM sincanm@mail.nih.gov OI Lee, Elizabeth/0000-0003-3412-1591 FU Common Fund, Office of the Director; Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, MD, USA) FX We thank NHGRI Intramural Sequencing Center and Appistry, Inc., for their sequencing, alignment, genotyping, and annotation services. This work was supported in part by the Common Fund, Office of the Director, and the Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, MD, USA). NR 20 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2016 VL 18 IS 12 BP 1303 EP 1307 DI 10.1038/gim.2016.47 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EE4HU UT WOS:000389563700020 PM 27253732 ER PT J AU Yu, W Gwinn, M Dotson, WD Green, RF Clyne, M Wulf, A Bowen, S Kolor, K Khoury, MJ AF Yu, Wei Gwinn, Marta Dotson, W. David Green, Ridgely Fisk Clyne, Mindy Wulf, Anja Bowen, Scott Kolor, Katherine Khoury, Muin J. TI A knowledge base for tracking the impact of genomics on population health SO GENETICS IN MEDICINE LA English DT Article ID PREVENTION; MEDICINE; BEDSIDE AB Purpose: We created an online knowledge base (the Public Health Genoinics Knowledge Base (PHGKB)) to provide system, atically curated and updated informatkin that bridges population-based research on genomics with clinical and public health applications Methods: Weekly horizon scanning of a wide variety of online, resources is used to-retrieve relevant scientific publications, guide, lines, and commentaries. After curation by domain experts, links are deposited-inta Web-based databases. Results: PHGKB currently consists of nine component databases. Users can search the entire knowledge base or search one or more component databases directly and choose options. for customizing the display of their search results. Conclusion: PHGKB offers researchers, policy makers, practitioners, and the general public a way to fmd information they need to tinder- stand the complicated landscape of genomics and population health. C1 [Yu, Wei; Gwinn, Marta; Dotson, W. David; Green, Ridgely Fisk; Wulf, Anja; Bowen, Scott; Kolor, Katherine; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Gwinn, Marta] McKing Consulting Corp, Atlanta, GA USA. [Green, Ridgely Fisk] Carter Consulting Inc, Atlanta, GA USA. [Clyne, Mindy] NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. [Clyne, Mindy] Kelly Serv, Troy, NY USA. [Wulf, Anja] Cadence Grp, Atlanta, GA USA. RP Yu, W (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. EM wby0@cdc.gov OI Dotson, William David/0000-0002-9606-6594 FU Intramural CDC HHS [CC999999] NR 8 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2016 VL 18 IS 12 BP 1312 EP 1314 DI 10.1038/gim.2016.63 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA EE4HU UT WOS:000389563700022 PM 27280867 ER PT J AU Mishkin, G Minasian, LM Kohn, EC Noone, AM Temkin, SM AF Mishkin, Grace Minasian, Lori M. Kohn, Elise C. Noone, Anne-Michelle Temkin, Sarah M. TI The generalizability of NCI-sponsored clinical trials accrual among women with gynecologic malignancies SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Clinical trials; Disparities; SEER ID CANCER-TREATMENT TRIALS; UNITED-STATES; RACIAL/ETHNIC DIFFERENCES; MINORITY PARTICIPATION; AFRICAN-AMERICANS; CERVICAL-CANCER; ONCOLOGY-GROUP; DISPARITIES; ENROLLMENT; AGE AB Objectives. Enrollment of a representative population to cancer clinical trials ensures scientific reliability and generalizability of results. This study evaluated the similarity of patients enrolled in NCI-supported group gynecologic cancer trials to the incident US population. Methods. Accrual to NCI-sponsored ovarian, uterine, and cervical cancer treatment trials between 2003 and 2012 were examined. Race, ethnicity, age, and insurance status were compared to the analogous US patient population estimated using adjusted SEER incidence data. Results. There were 18,913 accruals to 156 NCI-sponsored gynecologic cancer treatment trials, ovarian (56%), uterine (32%), and cervical cancers (12%). Ovarian cancer trials included the least racial, ethnic and age diversity. Black women were notably underrepresented in ovarian trials (4% versus 11%). Hispanic patients were underrepresented in ovarian and uterine trials (4% and 5% versus 18% and 19%, respectively), but not in cervical cancer trials (14 versus 11%). Elderly patients were underrepresented in each disease area, with the greatest underrepresentation seen in ovarian cancer patients over the age of 75 (7% versus 29%). Privately insured women were overrepresented among accrued ovarian cancer patients (87% versus 76%), and the uninsured were overrepresented among women with uterine or cervical cancers. These patterns did not change over time. Conclusions. Several notable differences were observed between the patients accrued to NCI funded trials and the incident population. Improving representation of racial and ethnic minorities and elderly patients on cancer clinical trials continues to be a challenge and priority. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mishkin, Grace; Kohn, Elise C.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Minasian, Lori M.; Temkin, Sarah M.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Noone, Anne-Michelle] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Temkin, SM (reprint author), NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM temkinsm@mail.nih.gov NR 37 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2016 VL 143 IS 3 BP 611 EP 616 DI 10.1016/j.ygyno.2016.09.026 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ED9EO UT WOS:000389173200027 PM 27697287 ER PT J AU Sips, M Liu, QQ Draghi, M Ghebremichael, M Berger, CT Suscovich, TJ Sun, Y Walker, BD Carrington, M Altfeld, M Brouckaert, P De Jager, PL Alter, G AF Sips, Magdalena Liu, Qingquan Draghi, Monia Ghebremichael, Musie Berger, Christoph T. Suscovich, Todd J. Sun, Yongtao Walker, Bruce D. Carrington, Mary Altfeld, Marcus Brouckaert, Peter De Jager, Philip L. Alter, Galit TI HLA-C levels impact natural killer cell subset distribution and function SO HUMAN IMMUNOLOGY LA English DT Article DE HLA-C; KIR; Natural killer cells; HIV-1 ID HUMAN CYTOMEGALOVIRUS-INFECTION; CLASS-I MOLECULES; MHC CLASS-I; NK CELLS; INHIBITORY RECEPTORS; SURFACE EXPRESSION; SELF-TOLERANCE; B HAPLOTYPES; HIV-1; EDUCATION AB Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56(neg) NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-gamma secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NI(cell education and development. (C) 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Sips, Magdalena; Draghi, Monia; Ghebremichael, Musie; Berger, Christoph T.; Suscovich, Todd J.; Walker, Bruce D.; Carrington, Mary; Altfeld, Marcus; Alter, Galit] Ragan Inst MGH MIT & Harvard, Cambridge, MA USA. [Sips, Magdalena; Brouckaert, Peter] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium. [Liu, Qingquan] Fourth Mil Med Univ, Tangdu Hosp, Dept Endocrinol, Xian, Shaanxi, Peoples R China. [Berger, Christoph T.] Univ Basel Hosp, Basel, Switzerland. [Sun, Yongtao] Fourth Mil Med Univ, Tangdu Hosp, Dept Infect Dis, Xian, Shaanxi, Peoples R China. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Altfeld, Marcus] Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. [De Jager, Philip L.] Brigham & Womens Hosp, Div Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Med Sch, Cambridge, MA USA. [De Jager, Philip L.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP Alter, G (reprint author), Ragan Inst MGH MIT & Harvard, Cambridge, MA USA. EM galter@mgh.harvard.edu FU PhenoGenetic Project at Brigham & Women's Hospital [RC2 GM093080]; Ragon Institute; National Institute of Health [R01 AI080289]; NIH Harvard Center for AIDS Research [P30 AI060354-02]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research FX We thank the subjects of the PhenoGenetic Project at Brigham & Women's Hospital for the samples that they have provided (RC2 GM093080). This work was supported by the Ragon Institute, the National Institute of Health (R01 AI080289) and NIH Harvard Center for AIDS Research (P30 AI060354-02). This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 42 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 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD DEC PY 2016 VL 77 IS 12 BP 1147 EP 1153 DI 10.1016/j.humimm.2016.08.004 PG 7 WC Immunology SC Immunology GA EE9RY UT WOS:000389965100008 PM 27521484 ER PT J AU Lippens, C Duraes, FV Dubrot, J Brighouse, D Lacroix, M Irla, M Aubry-Lachainaye, JP Reith, W Mandl, JN Hugues, S AF Lippens, Carla Duraes, Fernanda V. Dubrot, Juan Brighouse, Dale lacroix, MathilDe Irla, Magali Aubry-Lachainaye, Jean-Pierre Reith, Walter Mandl, Judith N. Hugues, Stephanie TI IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Regulatory T cells; Plasmacytoid dendritic cells; Indoleamine 2,3-dyoxygenase; Antigen presentation; Tolerance; Experimental autoimmune; encephalomyelitis ID PLASMACYTOID DENDRITIC CELLS; REGULATORY T-CELLS; INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION; RESTRICTED ANTIGEN PRESENTATION; TRYPTOPHAN CATABOLISM; TRANSGENIC MICE; IN-VIVO; VIRAL-INFECTION; TOLERANCE; INDUCTION AB Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity. (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Lippens, Carla; Duraes, Fernanda V.; Dubrot, Juan; Brighouse, Dale; lacroix, MathilDe; Irla, Magali; Reith, Walter; Hugues, Stephanie] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. [Aubry-Lachainaye, Jean-Pierre] Univ Geneva, Flow Cytometry Core Facil, CH-1211 Geneva 4, Switzerland. [Mandl, Judith N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Duraes, Fernanda V.] Novartis Inst BioMed Res, Basel, Switzerland. [Irla, Magali] Aix Marseille Univ, Ctr Immunol Marseille Luminy, INSERM, CNRS UMR7280,U1104, Marseille, France. [Mandl, Judith N.] McGill Univ, Dept Physiol, Life Sci Complex, Montreal, PQ, Canada. [Mandl, Judith N.] McGill Univ, Complex Traits Grp, Life Sci Complex, Montreal, PQ, Canada. RP Hugues, S (reprint author), Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. EM stephanie.hugues@unige.ch OI Irla, Magali/0000-0001-8803-9708 FU Swiss National Science Foundation [PP00P3_152951]; European Research Council [281365]; Swiss Multiple Sclerosis Society; Intramural Research Program of NIAID, NIH FX The authors thank C. Gameiro for excellent assistance in flow cytometry, the E. Shevach lab for providing us with Scurfy mice and T. Sparwasser for providing us with DEREG mice. We also thank R. Germain, Leslie Guery and I. Dunand-Sauthier for valuable discussions, D. Merkler and M. Gannage for reviewing the manuscript, and C. Orabona, M. Benkhoucha and G. Schneiter for technical help. This work was supported by the Swiss National Science Foundation (PP00P3_152951 to S.H.), the European Research Council (281365 to S.H.) and the Swiss Multiple Sclerosis Society (to S.H), and by the Intramural Research Program of NIAID, NIH (to J.N.M.). NR 61 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2016 VL 75 BP 39 EP 49 DI 10.1016/j.jaut.2016.07.004 PG 11 WC Immunology SC Immunology GA EE6OD UT WOS:000389731200005 PM 27470005 ER PT J AU Yau, MS Demissie, S Zhou, YH Anderson, DE Lorbergs, AL Kiel, DP Allaire, BT Yang, LJ Cupples, LA Travison, TG Bouxsein, ML Karasik, D Samelson, EJ AF Yau, Michelle S. Demissie, Serkalem Zhou, Yanhua Anderson, Dennis E. Lorbergs, Amanda L. Kiel, Douglas P. Allaire, Brett T. Yang, Laiji Cupples, L. Adrienne Travison, Thomas G. Bouxsein, Mary L. Karasik, David Samelson, Elizabeth J. TI Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE AGING; QCT; DISEASES AND DISORDERS RELATED TO BONE; GENETIC RESEARCH; EPIDEMIOLOGY ID FACET JOINT OSTEOARTHRITIS; LOW-BACK-PAIN; ABDOMINAL AORTIC CALCIFICATION; LOWER-EXTREMITY PERFORMANCE; COMMUNITY-BASED POPULATION; MUSCLE FAT INFILTRATION; BONE-MINERAL DENSITY; OLDER MEN; COMPUTED-TOMOGRAPHY; DISC DEGENERATION AB Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T-4-T-12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (G), 0.05; 95% CI, -0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. (c) 2016 American Society for Bone and Mineral Research. C1 [Yau, Michelle S.; Lorbergs, Amanda L.; Kiel, Douglas P.; Yang, Laiji; Travison, Thomas G.; Karasik, David; Samelson, Elizabeth J.] Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. [Yau, Michelle S.; Lorbergs, Amanda L.; Kiel, Douglas P.; Travison, Thomas G.; Samelson, Elizabeth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Yau, Michelle S.; Lorbergs, Amanda L.; Kiel, Douglas P.; Travison, Thomas G.; Samelson, Elizabeth J.] Harvard Med Sch, Boston, MA USA. [Demissie, Serkalem; Zhou, Yanhua; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Anderson, Dennis E.; Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. [Anderson, Dennis E.; Allaire, Brett T.; Bouxsein, Mary L.] Harvard Med Sch, Dept Orthoped Surg, Boston, MA USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Karasik, David] Bar Ilan Univ, Fac Med Galilee, Safed, Israel. RP Yau, MS (reprint author), Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM michelleyau@hsl.harvard.edu OI Karasik, David/0000-0002-8826-0530 FU NIH (National Institute on Aging [NIA]) [R01AG041658]; NIH (National Heart Lung and Blood Institute [NHLBI] Framingham Heart Study) [HHSN268201500001I]; NIH [NIA T32AG023480]; Friends of Hebrew SeniorLife; ISF [1283/14] FX This study was supported by the NIH (National Institute on Aging [NIA], R01AG041658; National Heart Lung and Blood Institute [NHLBI] Framingham Heart Study, Contract No. HHSN268201500001I); MSY is supported by NIH (NIA T32AG023480) and Friends of Hebrew SeniorLife; DK is supported by ISF Grant No. 1283/14. NR 62 TC 1 Z9 1 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2016 VL 31 IS 12 BP 2077 EP 2084 DI 10.1002/jbmr.2925 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE2WF UT WOS:000389445100004 PM 27455046 ER PT J AU Nielson, CM Liu, CT Smith, AV Ackert-Bicknell, CL Reppe, S Jakobsdottir, J Wassel, C Register, TC Oei, L Alonso, N Oei, EH Parimi, N Samelson, EJ Nalls, MA Zmuda, J Lang, T Bouxsein, M Latourelle, J Claussnitzer, M Siggeirsdottir, K Srikanth, P Lorentzen, E Vandenput, L Langefeld, C Raffield, L Terry, G Cox, AJ Allison, MA Criqui, MH Bowden, D Ikram, MA Mellstrom, D Karlsson, MK Carr, J Budoff, M Phillips, C Cupples, LA Chou, WC Myers, RH Ralston, SH Gautvik, KM Cawthon, PM Cummings, S Karasik, D Rivadeneira, F Gudnason, V Orwoll, ES Harris, TB Ohlsson, C Kiel, DP Hsu, YH AF Nielson, Carrie M. Liu, Ching-Ti Smith, Albert V. Ackert-Bicknell, Cheryl L. Reppe, Sjur Jakobsdottir, Johanna Wassel, Christina Register, Thomas C. Oei, Ling Alonso, Nerea Oei, Edwin H. Parimi, Neeta Samelson, Elizabeth J. Nalls, Mike A. Zmuda, Joseph Lang, Thomas Bouxsein, Mary Latourelle, Jeanne Claussnitzer, Melina Siggeirsdottir, Kristin Srikanth, Priya Lorentzen, Erik Vandenput, Liesbeth Langefeld, Carl Raffield, Laura Terry, Greg Cox, Amanda J. Allison, Matthew A. Criqui, Michael H. Bowden, Don Ikram, M. Arfan Mellstrom, Dan Karlsson, Magnus K. Carr, John Budoff, Matthew Phillips, Caroline Cupples, L. Adrienne Chou, Wen-Chi Myers, Richard H. Ralston, Stuart H. Gautvik, Kaare M. Cawthon, Peggy M. Cummings, Steven Karasik, David Rivadeneira, Fernando Gudnason, Vilmundur Orwoll, Eric S. Harris, Tamara B. Ohlsson, Claes Kiel, Douglas P. Hsu, Yi-Hsiang TI Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2 SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE BONE QCT; CT; ANALYSIS; QUANTITATION OF BONE; OSTEOPOROSIS; DISEASES AND DISORDERS OF; RELATED TO BONE; GENERAL POPULATION STUDIES; EPIDEMIOLOGY; HUMAN ASSOCIATION STUDIES; GENETIC RESEARCH; FRACTURE RISK ASSESSMENT ID BONE-MINERAL DENSITY; GENOME-WIDE ASSOCIATION; OSTEOPOROTIC FRACTURES; QUANTITATIVE CT; LUMBAR SPINE; OLDER MEN; HERITABILITY; LOCI; DIFFERENTIATION; HOMEOSTASIS AB Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (=0.22, p=1.9x10(-8)) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (=0.09, p=1.2x10(-10)) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4x10(-4)). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (=0.12, FDR p=1.7x10(-3), functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. (c) 2016 American Society for Bone and Mineral Research. C1 [Nielson, Carrie M.; Srikanth, Priya] Oregon Hlth & Sci Univ, Sch Publ Hlth, 3181 SW Sam Jackson Pk Rd,CR113, Portland, OR 97239 USA. [Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Smith, Albert V.; Jakobsdottir, Johanna; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Ackert-Bicknell, Cheryl L.] Univ Rochester, Dept Orthopaed & Rehabil, Rochester, NY USA. [Reppe, Sjur] Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway. [Reppe, Sjur; Gautvik, Kaare M.] Lovisenberg Diakonale Hosp, Oslo, Norway. [Reppe, Sjur; Gautvik, Kaare M.] Univ Oslo, Inst Basic Med Sci, Oslo, Norway. [Wassel, Christina] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT USA. [Register, Thomas C.] Wake Forest Sch Med, Dept Pathol, Winston Salem, NC USA. [Oei, Ling] Erasmus MC, Internal Med, Rotterdam, Netherlands. [Oei, Ling] NCHA, Leiden, Netherlands. [Alonso, Nerea] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Oei, Edwin H.] Erasmus MC, Radiol & Nucl Med, Rotterdam, Netherlands. [Parimi, Neeta; Cawthon, Peggy M.; Cummings, Steven] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Samelson, Elizabeth J.; Karasik, David; Kiel, Douglas P.; Hsu, Yi-Hsiang] Harvard Med Sch, Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. [Nalls, Mike A.; Phillips, Caroline; Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Zmuda, Joseph] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Lang, Thomas] Univ Calif San Francisco, Sch Med, Dept Radiol, San Francisco, CA 94143 USA. [Bouxsein, Mary] Harvard Univ Med Sch, Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA USA. [Latourelle, Jeanne; Myers, Richard H.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Claussnitzer, Melina; Kiel, Douglas P.] Harvard Univ Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Claussnitzer, Melina; Chou, Wen-Chi; Hsu, Yi-Hsiang] Broad Inst MIT & Harvard, Cambridge, MA USA. [Claussnitzer, Melina] Tech Univ Munich, Munich, Germany. [Siggeirsdottir, Kristin] Iceland Heart Assoc, Imaging, Kopavogur, Iceland. [Lorentzen, Erik] Gothenburg Univ, Dept Bioinformat, Gothenburg, Sweden. [Vandenput, Liesbeth; Mellstrom, Dan; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden. [Langefeld, Carl] Wake Forest Sch Med, Publ Hlth Sci, Winston Salem, NC USA. [Raffield, Laura] Wake Forest Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Raffield, Laura] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA. [Terry, Greg; Carr, John] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Cox, Amanda J.; Bowden, Don] Wake Forest Sch Med, Dept Biochem, Ctr Diabet Res, Winston Salem, NC USA. [Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Bowden, Don] Wake Forest Sch Med, Internal Med Endocrinol, Winston Salem, NC USA. [Bowden, Don] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Ikram, M. Arfan; Rivadeneira, Fernando] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Karlsson, Magnus K.] Lund Univ, Malmo Univ Hosp, Dept Orthopaed & Clin Sci, Malmo, Sweden. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrance, CA USA. [Ralston, Stuart H.] Univ Edinburgh, Rheumat Dis Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Cawthon, Peggy M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Karasik, David] Bar Ilan Univ, Fac Med Galilee, Safed, Israel. [Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Orwoll, Eric S.] Oregon Hlth & Sci Univ, Div Endocrinol, Portland, OR 97201 USA. [Hsu, Yi-Hsiang] Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci, Boston, MA USA. RP Nielson, CM (reprint author), Oregon Hlth & Sci Univ, Sch Publ Hlth, 3181 SW Sam Jackson Pk Rd,CR113, Portland, OR 97239 USA.; Kiel, DP; Hsu, YH (reprint author), Harvard Med Sch, Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM nielsoca@ohsu.edu; kiel@hsl.harvard.edu; YiHsiangHsu@hsl.harvard.edu OI Karasik, David/0000-0002-8826-0530; Vandenput, Liesbeth/0000-0002-1712-6131; Allison, Matthew/0000-0003-0777-8272; Carr, John/0000-0002-4398-8237 FU NIH [N01-AG-12100]; National Institutes of Health [R01 HL67348, R01 HL092301, R01 AR48797, F31 AG044879, HHSN268200782096C]; National Heart, Lung, and Blood Institute [U01 HL067893, U01 HL067894, U01 HL067896, U01 HL067897, U01 HL056567, U01 HL056568, U01 HL067901]; US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging [R01 AR 41398, R01 AR061162, R01 AR 050066]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Intramural Research Program of the NIH, National Institute on Aging; U.S. National Institute of Aging (NIA) [N01AG62101, N01AG62103, N01AG62106]; NIA grant [1R01AG032098]; National Heart, Lung, and Blood Institute (NHLBI); MESA [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, DK063491]; NHLBI [N02-HL-64278]; Bone Mineral Density [HL072403]; National Institutes of Health; National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; MrOS ancillary study 'GWAS in MrOS and SOF' [RC2 AR058973]; NIAMS [K01 AR062655]; Swedish Research Council; Swedish Foundation for Strategic Research; ALF/LUA research grant from the Sahlgrenska University Hospital; Lundberg Foundation; Torsten and Ragnar Soderberg's Foundation; Novo Nordisk Foundation; Erasmus Medical Centre 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; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; NIH/NIAMS [AR060234, AR060981]; EU [LSHM-CT-2003-502941]; South-Eastern Norway Regional Health Authority; Oslo University Hospital, Ullevaal FX Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik): The Age, Gene/Environment Susceptibility Reykjavik Study was funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Fracture Registry is funded by the Icelandic Heart Association. Diabetes Heart Study: The authors thank the other investigators, the staff, and the participants of the DHS study for their valuable contributions. This study was supported by the National Institutes of Health through R01 HL67348 and R01 HL092301 (to DWB), R01 AR48797 (to JJC), and F31 AG044879 (to LMR). Family Heart Study: This study was supported by grants from the National Heart, Lung, and Blood Institute (U01 HL067893, U01 HL067894, U01 HL067896, U01 HL067897, U01 HL056567, U01 HL056568, and U01 HL067901). Framingham: The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162 to DPK; R01 AR 050066 to DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating 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. Health, Aging, and Body Composition (Health ABC): This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. This research was supported by the U.S. National Institute of Aging (NIA) contracts N01AG62101, N01AG62103, and N01AG62106. The genomewide association study was funded by NIA grant 1R01AG032098 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. We thank the participants of the Health, Aging, and Body Composition Study. Multi-Ethnic Study of Atherosclerosis (MESA): MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA, USA) and the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Support for the Bone Mineral Density dataset was provided by grant HL072403. Osteoporotic Fractures in Men (MrOS)-USA: The Osteoporotic Fractures in The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding.; The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2 AR058973. CMN is supported by NIAMS K01 AR062655. Osteoporotic Fractures in Men (MrOS)-Sweden: The MrOS Sweden study is supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant from the Sahlgrenska University Hospital, the Lundberg Foundation, the Torsten and Ragnar Soderberg's Foundation and the Novo Nordisk Foundation. Rotterdam Studies: The Rotterdam Study is funded by Erasmus Medical Centre 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. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, MSc, for the creation and analysis of imputed data. Study of Osteoporotic Fractures: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. Expression studies (C. L. Ackert-Bicknell): NIH/NIAMS AR060234 and AR060981. Expression studies (S. Reppe and K. Gautvik): This work was supported by the 6th EU framework program to "OSTEOGENE" [LSHM-CT-2003-502941]; the South-Eastern Norway Regional Health Authority; and Oslo University Hospital, Ullevaal. NR 58 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2016 VL 31 IS 12 BP 2085 EP 2097 DI 10.1002/jbmr.2913 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE2WF UT WOS:000389445100005 PM 27476799 ER PT J AU Blaine, KP Press, C Lau, K Sliwa, J Rao, VK Hill, C AF Blaine, Kevin P. Press, Christopher Lau, Ken Sliwa, Jan Rao, Vidya K. Hill, Charles TI Comparative effectiveness of epsilon-aminocaproic acid and tranexamic acid on postoperative bleeding following cardiac surgery during a national medication shortage SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE epsilon-aminocaproic acid; Tranexamic acid; Blood conservation; Perioperative bleeding; Cardiac surgery ID CARDIOPULMONARY BYPASS; APROTININ; TRANSFUSION; IMPACT AB Study objective: The aim of this study was to compare the effectiveness of epsilon-aminocaproic acid (epsilon ACA) and tranexamic acid (TXA) in contemporary clinical practice during a national medication shortage. Design: A retrospective cohort study. Setting: The study was performed in all consecutive cardiac surgery patients (n = 128) admitted to the cardiac-surgical intensive care unit after surgery at a single academic center immediately before and during a national medication shortage. Measurements: Demographic, clinical, and outcomes data were compared by descriptive statistics using X-2 and t test. Surgical drainage and transfusions were compared by multivariate linear regression for patients receiving epsilon ACA before the shortage and TXA during the shortage. Main results: In multivariate analysis, no statistical difference was found for surgical drain output (OR 1.10, CI 0.97-1.26, P = .460) or red blood cell transfusion requirement (OR 1.79, CI 0.79-2.73, P = .176). Patients receiving epsilon ACA were more likely to receive rescue hemostatic medications (OR 1.62, CI 1.02-2.55, P = .041). Conclusions: Substitution of sACA with TXA during a national medication shortage produced equivalent postoperative bleeding and red cell transfusions, although patients receiving sACA were more likely to require supplemental hemostatic agents. Published by Elsevier Inc. C1 [Blaine, Kevin P.; Press, Christopher; Lau, Ken; Sliwa, Jan; Rao, Vidya K.; Hill, Charles] Stanford Univ, Med Ctr, Dept Anesthesia Pain & Perioperat Med, 300 Pasteur Dr,H3580, Stanford, CA 94305 USA. [Lau, Ken] Anesthesia Serv Med Grp, 3626 Ruffin Rd, San Diego, CA 92123 USA. [Sliwa, Jan] Brigham & Womens Hosp, Dept Anesthesiol, 75 Francis St, Boston, MA 02115 USA. RP Blaine, KP (reprint author), NIH, Ctr Clin, Dept Crit Care Med, 9000 Rockville Pike 2C145, Bethesda, MD 20892 USA. EM kevin.blaine@nih.gov FU Stanford University School of Medicine Department of Anesthesiology, Pain, and Perioperative Medicine FX The authors would like to acknowledge the technical assistance of Fred Hurt, DPharm, and the operating room pharmacy staff at Stanford University Medical Center. This project was supported solely by departmental funds from the Stanford University School of Medicine Department of Anesthesiology, Pain, and Perioperative Medicine. NR 20 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 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD DEC PY 2016 VL 35 BP 516 EP 523 DI 10.1016/j.jclinane.2016.08.037 PG 8 WC Anesthesiology SC Anesthesiology GA EE7HD UT WOS:000389785600092 PM 27871586 ER PT J AU Deandres-Galiana, EJ Fernandez-Martinez, JL Saligan, LN Sonis, ST AF Deandres-Galiana, Enrique J. Luis Fernandez-Martinez, Juan Saligan, Leorey N. Sonis, Stephen T. TI Impact of Microarray Preprocessing Techniques in Unraveling Biological Pathways SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE cancer genomics; DNA arrays; gene expression; gene networks ID TIKHONOVS REGULARIZATION; CLONING; NOISE AB To better understand the impact of microarray preprocessing normalization techniques on the analysis of biological pathways in the prediction of chronic fatigue (CF) following radiation therapy, this study has compared the list of predictive genes found using the Robust Multiarray Averaging (RMA) and the Affymetrix MAS5 method, with the list that is obtained working with raw data (without any preprocessing). First, we modeled the spiked-in data set where differentially expressed genes were known and spiked-in at different known concentrations, showing that the precisions established by different gene ranking methods were higher than working with raw data. The results obtained from the spiked-in experiment were extrapolated to the CF data set to run learning and blind validation. RMA and MAS5 provided different sets of discriminatory genes that have a higher predictive accuracy in the learning phase, but lower predictive accuracy during the blind validation phase, suggesting that the genetic signatures generated using both preprocessing techniques cannot be generalizable. The pathways found using the raw data set better described what is a priori known for the CF disease. Besides, RMA produced more reliable pathways than MAS5. Understanding the strengths of these two preprocessing techniques in phenotype prediction is critical for precision medicine. Particularly, this article concludes that biological pathways might be better unraveled working with raw expression data. Moreover, the interpretation of the predictive gene profiles generated by RMA and MAS5 should be done with caution. This is an important conclusion with a high translational impact that should be confirmed in other disease data sets. C1 [Deandres-Galiana, Enrique J.; Luis Fernandez-Martinez, Juan] Univ Oviedo, Dept Math, E-33006 Oviedo, Asturias, Spain. [Saligan, Leorey N.] NINR, NIH, Bethesda, MD 20892 USA. [Sonis, Stephen T.] ST Sonis Biomodels LLC, Watertown, MA USA. RP Fernandez-Martinez, JL (reprint author), Univ Oviedo, Dept Math, E-33006 Oviedo, Asturias, Spain. EM jlfm@uniovi.es OI deAndres-Galiana, Enrique J/0000-0001-8555-3832 FU Ministerio de Economia y Competitividad [TIN2011-23558] FX Enrique J. de Andres was supported by the Ministerio de Economia y Competitividad (grant TIN2011-23558). NR 28 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 EI 1557-8666 J9 J COMPUT BIOL JI J. Comput. Biol. PD DEC PY 2016 VL 23 IS 12 BP 957 EP 968 DI 10.1089/cmb.2016.0042 PG 12 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 EE2NE UT WOS:000389420500004 PM 27494192 ER PT J AU Sheeler, RD Mundell, T Hurst, SA Goold, SD Thorsteinsdottir, B Tilburt, JC Danis, M AF Sheeler, Robert D. Mundell, Tim Hurst, Samia A. Goold, Susan Dorr Thorsteinsdottir, Bjorg Tilburt, Jon C. Danis, Marion TI Self-Reported Rationing Behavior Among US Physicians: A National Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cost; physician attitudes; physician behavior; rationing ID RESPONSE RATES; CARE AB Rationing is a controversial topic among US physicians. Understanding their attitudes and behaviors around rationing may be essential to a more open and sensible professional discourse on this important but controversial topic. To describe rationing behavior and associated factors among US physicians. Survey mailed to US physicians in 2012 to evaluate self-reported rationing behavior and variables related to this behavior. US physicians across a full spectrum of practice settings. A total of 2541 respondents, representing 65.6 % of the original mailing list of 3872 US addresses. The study was a cross-sectional analysis of physician attitudes and self-reported behaviors, with neutral language representations of the behaviors as well as an embedded experiment to test the influence of the word "ration" on perceived responsibility. Overall percentage of respondents reporting rationing behavior in various contexts and assessment of attitudes toward rationing. In total, 1348 respondents (53.1 %) reported having personally refrained within the past 6 months from using specific clinical services that would have provided the best patient care, because of health system cost. Prescription drugs (n = 1073 [48.3 %]) and magnetic resonance imaging (n = 922 [44.5 %]) were most frequently rationed. Surgical and procedural specialists were less likely to report rationing behavior (adjusted odds ratio [OR] [95 % CI], 0.8 [0.9-0.9] and 0.5 [0.4-0.6], respectively) compared to primary care. Compared with small or solo practices, those in medical school settings reported less rationing (adjusted OR [95 % CI], 0.4 [0.2-0.7]). Physicians who self-identified as very or somewhat liberal were significantly less likely to report rationing (adjusted OR [95 % CI], 0.7 [0.6-0.9]) than those self-reporting being very or somewhat conservative. A more positive opinion about rationing tended to align with greater odds of rationing. More than one-half of respondents engaged in behavior consistent with rationing. Practicing physicians in specific subgroups were more likely to report rationing behavior. C1 [Sheeler, Robert D.] Mayo Clin, Dept Family Med, Rochester, MN 55905 USA. [Mundell, Tim] Univ Iowa, Iowa City, IA USA. [Hurst, Samia A.] Univ Geneva, Inst Eth Hist & Human, Geneva, Switzerland. [Goold, Susan Dorr] Univ Michigan, Med Ctr, Ctr Bioeth & Social Sci Med, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Thorsteinsdottir, Bjorg; Tilburt, Jon C.] Mayo Clin, Biomed Eth Program, Rochester, MN USA. [Thorsteinsdottir, Bjorg] Mayo Clin, Div Primary Care Internal Med, Rochester, MN USA. [Tilburt, Jon C.] Mayo Clin, Div Gen Internal Med, Rochester, MN USA. [Tilburt, Jon C.] Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN USA. [Tilburt, Jon C.] Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, Rochester, MN USA. [Danis, Marion] Natl Inst Hlth, Dept Bioeth, Bethesda, MD USA. RP Sheeler, RD (reprint author), Mayo Clin, Dept Family Med, Rochester, MN 55905 USA. EM sheeler.robert@mayo.edu RI Hurst, Samia/A-9661-2008 OI Hurst, Samia/0000-0002-1980-5226 FU Greenwall Foundation; Mayo Clinic Program in Professionalism and Ethics; Research Early Career Development Award from the Mayo Foundation FX This research was funded by a grant from The Greenwall Foundation, the Mayo Clinic Program in Professionalism and Ethics, and a Research Early Career Development Award from the Mayo Foundation. The authors would like to thank Katherine Humeniuk for her support in fielding of the survey and for providing preliminary analysis of the data. Joel Pacyna contributed importantly to the preparation and formatting of revised manuscripts. NR 11 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1444 EP 1451 DI 10.1007/s11606-016-3756-5 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600009 PM 27435251 ER PT J AU Takahashi, S Fukami, T Masuo, Y Brocker, CN Xie, C Krausz, KW Wolf, CR Henderson, CJ Gonzalez, FJ AF Takahashi, Shogo Fukami, Tatsuki Masuo, Yusuke Brocker, Chad N. Xie, Cen Krausz, Kristopher W. Wolf, C. Roland Henderson, Colin J. Gonzalez, Frank J. TI Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans SO JOURNAL OF LIPID RESEARCH LA English DT Article DE chenodeoxycholic acid; cytochrome P450; Cyp2c70; enzyme kinetics; liver; muricholic acid; ursodeoxycholic acid ID DRUG-DRUG INTERACTION; BETA-MURICHOLIC ACID; X RECEPTOR; CHENODEOXYCHOLIC ACID; MOUSE LINES; ENTEROHEPATIC CIRCULATION; URSODEOXYCHOLIC ACID; RAT-LIVER; CYTOCHROME-P450; OBESITY AB Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYPs) and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6-position to form -muricholic acid (MCA) and ursodeoxycholic acid (UDCA) to form -MCA. However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that -MCA and -MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acid analysis further revealed the absence of MCAs and their conjugated derivatives, and high concentrations of CDCA and UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that -MCA and -MCA were produced by oxidation of CDCA and UDCA by Cyp2c70, respectively. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA, thus explaining the species differences in production of MCA. Because humans do not produce MCA, they lack tauro--MCA, a farnesoid X receptor antagonist in mouse that modulates obesity, insulin resistance, and hepatosteatosis. C1 [Takahashi, Shogo; Fukami, Tatsuki; Masuo, Yusuke; Brocker, Chad N.; Xie, Cen; Krausz, Kristopher W.; Gonzalez, Frank J.] Natl Canc Inst, Lab Metab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wolf, C. Roland; Henderson, Colin J.] Univ Dundee, Ninewells Hosp, Jacqui Wood Canc Ctr, Sch Med,Div Canc, Dundee DD1 9SY, Scotland. RP Gonzalez, FJ (reprint author), Natl Canc Inst, Lab Metab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov OI Wolf, Charles Roland/0000-0002-6969-0113 FU National Cancer Institute Intramural Research Program, Center for Cancer Research; National Institutes of Health [U54 ES16015]; Cancer Research UK [C4639/A10822]; Japanese Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (KAITOKU-NIH); program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from the Japanese Society for the Promotion of Sciences [S2601] FX This work was supported by the National Cancer Institute Intramural Research Program, Center for Cancer Research, and National Institutes of Health Grant U54 ES16015 (F.J.G), and a Programme Grant support from Cancer Research UK, C4639/A10822 to C.R.W. S.T. was supported by a Japanese Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (KAITOKU-NIH). T.F. and Y.M. were supported by a program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2601) from the Japanese Society for the Promotion of Sciences. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 37 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD DEC PY 2016 VL 57 IS 12 BP 2130 EP 2137 DI 10.1194/jlr.M071183 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EE3FK UT WOS:000389473000004 PM 27638959 ER PT J AU Muessgens, D Thirugnanasambandam, N Shitara, H Popa, T Hallett, M AF Muessgens, Diana Thirugnanasambandam, Nivethida Shitara, Hitoshi Popa, Traian Hallett, Mark TI Dissociable roles of preSMA in motor sequence chunking and hand switching-a TMS study SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE presupplementary motor area; transcranial magnetic stimulation; chunking; hand switching; motor sequence learning ID MEDIAL FRONTAL-CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; SIMPLE REACTION-TIME; OCCIPITAL FACE AREA; CEREBRAL-BLOOD-FLOW; HUMAN BRAIN; MOVEMENT; SUPPLEMENTARY; INHIBITION; ACTIVATION AB Motor chunking, the grouping of individual movements into larger units, is crucial for sequential motor performance. The presupplementary motor area (preSMA) is involved in chunking and other related processes such as task switching, response selection, and response inhibition that are crucial for organizing sequential movements. However, previous studies have not systematically differentiated the role of preSMA in motor chunking and hand switching, thus leaving its relative contribution to each of these processes unclear. The aim of this study is to demonstrate the differential role of preSMA in motor chunking and hand switching. We designed motor sequences in which different kinds of hand switches (switching toward the right or left hand or continuing with the right hand) were counterbalanced across between- and within-chunk sequence points. Eighteen healthy, right-handed participants practiced four short subsequences (chunks) of key presses. In a subsequent task, these chunks had to be concatenated into one long sequence. We applied double-pulse transcranial magnetic stimulation (TMS) over left preSMA or left M1 areas at sequence initiation, between chunks, or within chunks. TMS over the left preSMA significantly slowed the next response when stimulation was given between chunks, but only if a hand switch toward the contralateral (right) hand was required. PreSMA stimulation within chunks did not interfere with responses. TMS over the left M1 area delayed responses with the contralateral hand, both within and between chunks. Both preSMA and M1 stimulation decreased response times at sequence initiation. These results suggest that left preSMA is not necessary for chunking per se, but rather for organizing complex movements that require chunking and hand switching simultaneously. C1 [Muessgens, Diana; Thirugnanasambandam, Nivethida; Shitara, Hitoshi; Popa, Traian; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Muessgens, D (reprint author), Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden. EM diana.muessgens@nih.gov OI Popa, Traian/0000-0003-1160-4830 FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX Support for this study was provided by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 43 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2016 VL 116 IS 6 BP 2637 EP 2646 DI 10.1152/jn.00565.2016 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA EE5LF UT WOS:000389648300015 PM 27655967 ER PT J AU Canavier, CC Evans, RC Oster, AM Pissadaki, EK Drion, G Kuznetsov, AS Gutkin, BS AF Canavier, Carmen C. Evans, Rebekah C. Oster, Andrew M. Pissadaki, Eleftheria K. Drion, Guillaume Kuznetsov, Alexey S. Gutkin, Boris S. TI Implications of cellular models of dopamine neurons for disease SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review DE nonlinear dynamics; dopaminergic signaling ID SUBSTANTIA-NIGRA NEURONS; COUPLED-OSCILLATOR MODEL; GENE POTASSIUM CHANNELS; VENTRAL TEGMENTAL AREA; DEPOLARIZATION BLOCK; PARKINSONS-DISEASE; FIRING PATTERN; PYRAMIDAL NEURONS; ACTION-POTENTIALS; IN-VITRO AB This review addresses the present state of single-cell models of the firing pattern of midbrain dopamine neurons and the insights that can be gained from these models into the underlying mechanisms for diseases such as Parkinson's, addiction, and schizophrenia. We will explain the analytical technique of separation of time scales and show how it can produce insights into mechanisms using simplified single-compartment models. We also use morphologically realistic multicompartmental models to address spatially heterogeneous aspects of neural signaling and neural metabolism. Separation of time scale analyses are applied to pacemaking, bursting, and depolarization block in dopamine neurons. Differences in subpopulations with respect to metabolic load are addressed using multicompartmental models. C1 [Canavier, Carmen C.] Louisiana State Univ, Hlth Sci Ctr, Dept Cell Biol & Anat, New Orleans, LA USA. [Evans, Rebekah C.] NINDS, Cellular Neurophysiol Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Oster, Andrew M.] Eastern Washington Univ, Dept Math, Cheney, WA 99004 USA. [Pissadaki, Eleftheria K.] IBM TJ Watson Res Ctr, Yorktown Hts, NY USA. [Drion, Guillaume] Univ Liege, Dept Elect Engn & Comp Sci, Liege, Belgium. [Kuznetsov, Alexey S.] Indiana Univ Purdue Univ, Dept Math Sci, Indianapolis, IN 46202 USA. [Kuznetsov, Alexey S.] Indiana Univ Purdue Univ, Ctr Math Biosci, Indianapolis, IN 46202 USA. [Gutkin, Boris S.] Ecole Normale Super PSL Res Univ, Grp Neural Theory, LNC INSERM U960, Dept Etud Cognit, Paris, France. [Gutkin, Boris S.] NRU Higher Sch Econ, Ctr Cognit & Decis Making, Moscow, Russia. [Pissadaki, Eleftheria K.] Univ Sheffield, Dept Comp Sci, Sheffield, S Yorkshire, England. RP Canavier, CC (reprint author), Louisiana State Univ Hlth, 1901 Perdido St, New Orleans, LA 70112 USA. EM ccanav@lsuhsc.edu FU National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) [R01-NS-061097]; Russian Academic Excellence Project [5-100]; L'Agence Nationale de la Recherche NEUCOMP [ANR-10-LABX-0087 IEC, ANR-10-IDEX-0001-02 PSL]; NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01-AA-022821]; Eastern Washington University Faculty Grant for Research and Creative Works; NIH NINDS Intramural Research Program [NS-003135] FX This work was supported by National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Grant R01-NS-061097 to C. C. Canavier, Russian Academic Excellence Project "5-100" and L'Agence Nationale de la Recherche NEUCOMP, ANR-10-LABX-0087 IEC, and ANR-10-IDEX-0001-02 PSL to B. S. Gutkin, NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA) Grant R01-AA-022821 to A. S. Kuznetsov, and Eastern Washington University Faculty Grant for Research and Creative Works to A. M. Oster. R. C. Evans was supported by NIH NINDS Intramural Research Program Grant NS-003135 to Zayd M. Khaliq. NR 124 TC 0 Z9 0 U1 5 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2016 VL 116 IS 6 BP 2815 EP 2830 DI 10.1152/jn.00530.2016 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA EE5LF UT WOS:000389648300031 PM 27582295 ER PT J AU Di Giovanni, V Bourdon, C Wang, DX Seshadri, S Senga, E Versloot, CJ Voskuijl, W Semba, RD Trehan, I Moaddel, R Ordiz, MI Zhang, L Parkinson, J Manary, MJ Bandsma, RHJ AF Di Giovanni, Valeria Bourdon, Celine Wang, Dominic X. Seshadri, Swapna Senga, Edward Versloot, Christian J. Voskuijl, Wieger Semba, Richard D. Trehan, Indi Moaddel, Ruin Ordiz, M. Isabel Zhang, Ling Parkinson, John Manary, Mark J. Bandsma, Robert H. J. TI Metabolomic Changes in Serum of Children with Different Clinical Diagnoses of Malnutrition SO JOURNAL OF NUTRITION LA English DT Article DE marasmus; kwashiorkor; children; severe acute malnutrition; targeted metabolomics; metabolites; p180 kit ID MIDDLE-INCOME COUNTRIES; KWASHIORKOR; CARNITINE; UNDERNUTRITION; DYSFUNCTION; MORTALITY; MARASMUS AB Background: Mortality in children with severe acute malnutrition (SAM) remains high despite standardized rehabilitation protocols. Two forms of SAM are classically distinguished: kwashiorkor and marasmus. Children with kwashiorkor have nutritional edema and metabolic disturbances, including hypoalbuminemia and hepatic steatosis, whereas marasmus is characterized by severe wasting. The metabolic changes underlying these phenotypes have been poorly characterized, and whether homeostasis is achieved during hospital stay is unclear. Objectives: We aimed to characterize metabolic differences between children with marasmus and kwashiorkor at hospital admission and after clinical stabilization and to compare them with stunted and nonstunted community controls. Methods: We studied children aged 9-59 mo frorh Malawi who were hospitalized with SAM (n = 40; 21 with kwashiorkor and 19 with marasmus) or living in the community (n = 157; 78 stunted and 79 nonstunted). Serum from patients with SAM was obtained at hospital admission and 3 d after nutritional stabilization and from community controls. With the use of targeted metabolomics, 141 metabolites, including amino acids, biogenic amines, acylcarnitines, sphingomyelins, and phosphatidylcholines, were measured. Results: At admission, most metabolites (128 of 141; 91%) were lower in children with kwashiorkor than in those with marasmus, with significant differences in several amino acids and biogenic amines, including those of the kynureninetryptophan pathway. Several phosphatidylcholines and some acylcarnitines also differed. Patients with SAM had profiles that were profoundly different from those of stunted and nonstunted controls, even after clinical stabilization. Amino acids and biogenic amines generally improved with nutritional rehabilitation, but most sphingomyelins and phosphatidylcholines did not. Conclusions: Children with kwashiorkor were metabolically distinct from those with marasmus, and were more prone to severe metabolic disruptions. Children with SAM showed metabolic profiles that were Profoundly different from stunted and nonstunted controls, even after clinical stabilization. Therefore, metabolic recovery in children with SAM likely extends beyond discharge, which may explain the poor long-term outcomes in these children. This trial was registered at isrctn.org as ISRCTN13916953. C1 [Di Giovanni, Valeria; Bourdon, Celine; Wang, Dominic X.; Versloot, Christian J.; Zhang, Ling; Bandsma, Robert H. J.] Hosp Sick Children, Dept Physiol & Expt Med, Toronto, ON, Canada. [Seshadri, Swapna; Parkinson, John] Hosp Sick Children, Program Mol Struct & Funct, Toronto, ON, Canada. [Bandsma, Robert H. J.] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada. [Bandsma, Robert H. J.] Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON, Canada. [Senga, Edward; Bandsma, Robert H. J.] Univ Malawi, Coll Med, Dept Biomed Sci, Blantyre, Malawi. [Voskuijl, Wieger; Trehan, Indi] Univ Malawi, Coll Med, Dept Pediat & Child Hlth, Blantyre, Malawi. [Manary, Mark J.] Univ Malawi, Coll Med, Sch Publ Hlth & Family Med, Blantyre, Malawi. [Voskuijl, Wieger] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Global Child Hlth Grp, Amsterdam, Netherlands. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Trehan, Indi; Moaddel, Ruin] NIA, NIH, Baltimore, MD 21224 USA. [Ordiz, M. Isabel; Manary, Mark J.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Parkinson, John] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Parkinson, John] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. RP Bandsma, RHJ (reprint author), Hosp Sick Children, Dept Physiol & Expt Med, Toronto, ON, Canada.; Bandsma, RHJ (reprint author), Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada.; Bandsma, RHJ (reprint author), Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON, Canada.; Bandsma, RHJ (reprint author), Univ Malawi, Coll Med, Dept Biomed Sci, Blantyre, Malawi. FU Hospital for Sick Children, Toronto, Canada; Intramural Research Program of the National Institute on Aging, NIH; Children's Discovery Institute of Washington University; St. Louis Children's Hospital FX This study was supported by an internal grant to RHJB from the Hospital for Sick Children, Toronto, Canada. It was also supported in part by the Intramural Research Program of the National Institute on Aging, NIH (RM) and the Children's Discovery Institute of Washington University and St. Louis Children's Hospital (IT, MJM). This is a free access article, distributed under terms (http.//www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 41 TC 0 Z9 0 U1 6 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 DEC PY 2016 VL 146 IS 12 BP 2436 EP 2444 DI 10.3945/jn.116.239145 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600003 PM 27807038 ER PT J AU Nielsen, SJ Trak-Fellermeier, MA Joshipura, K Dye, BA AF Nielsen, Samara Joy Trak-Fellermeier, Maria Angelica Joshipura, Kaumudi Dye, Bruce A. TI Dietary Fiber Intake Is Inversely Associated with Periodontal Disease among US Adults SO JOURNAL OF NUTRITION LA English DT Article DE periodontal disease; dietary fiber; whole grains; NHANES; nutrition; epidemiology ID BLOOD-PRESSURE; VASCULAR-DISEASE; HYPERTENSION; PREVALENCE; NHANES; OLDER AB Background: Approximately 47% of adults in the United States have periodontal disease. Dietary guidelines recommend a diet providing adequate fiber. Healthier dietary habits, particularly an increased fiber intake, may contribute to periodontal disease prevention. Objective: Our objective was to evaluate the relation of dietary fiber intake and its sources with periodontal disease in the US adult population (>= 30 y of age). Methods: Data from 6052 adults participating in NHANES 2009-2012 were used. Periodontal disease was defined (according to the CDC/American Academy of Periodontology) as severe, moderate, mild, and none. Intake was assessed by 24-h dietary recalls. The relation between periodontal disease and dietary fiber, whole-grain, and fruit and vegetable intakes were evaluated by using multivariate models, adjusting for sociodemographic characteristics and dentition status. Results: In the multivariate logistic model, the lowest quartile of dietary fiber was associated with moderate-severe periodontitis (compared with mild-none) compared with the highest dietary fiber intake quartile (OR: 1.30; 95% CI: 1.00, 1.69). In the multivariate multinomial logistic model, intake in the lowest quartile of dietary fiber was associated with higher severity of periodontitis than dietary fiber intake in the highest quartile (OR: 1.27; 95% CI: 1.00, 1.62). In the adjusted logistic model, whole-grain intake was not associated with moderate-severe periodontitis. However, in the adjusted multinomial logistic model, adults consuming whole grains in the lowest quartile were more likely to have more severe periodontal disease than were adults consuming whole grains in the highest quartile (OR: 1.32; 95% CI: 1.08, 1.62). In fully adjusted logistic and multinomial logistic models, fruit and vegetable intake was not significantly associated with periodontitis. Conclusions: We found an inverse relation between dietary fiber intake and periodontal disease among US adults >= 30 y old. Periodontal disease was associated with low whole-grain intake but not with low fruit and vegetable intake. C1 [Nielsen, Samara Joy] Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Sports Med & Nutr, Pittsburgh, PA 15260 USA. [Trak-Fellermeier, Maria Angelica; Joshipura, Kaumudi] Univ Puerto Rico, Sch Dent Med, Ctr Clin Res & Hlth Promot, Med Sci Campus, San Juan, PR 00936 USA. [Dye, Bruce A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Nielsen, SJ (reprint author), Univ Pittsburgh, Sch Hlth & Rehabil Sci, Dept Sports Med & Nutr, Pittsburgh, PA 15260 USA. EM snielsen@pitt.edu NR 26 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 146 IS 12 BP 2530 EP 2536 DI 10.3945/jn.116.237065 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600013 PM 27798338 ER PT J AU Khan, RJ Gebreab, SY Riestra, P Sims, M Gaye, A Xu, RH Davis, SK AF Khan, Rumana J. Gebreab, Samson Y. Riestra, Pia Sims, Mario Gaye, Amadou Xu, Ruihua Davis, Sharon K. TI Associations between Vitamin D and Cardiovascular Disease Risk Factors in African Americans Are Partly Explained by Circulating Adipokines and C-Reactive Protein: The Jackson Heart Study SO JOURNAL OF NUTRITION LA English DT Article DE 25-hydroxyvitamin D; African Americans; cardiovascular disease risk factors; path analysis; adipokine ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; RENIN-ANGIOTENSIN SYSTEM; BODY-FAT DISTRIBUTION; 25-HYDROXYVITAMIN D; SERUM 25-HYDROXYVITAMIN-D; LEPTIN CONCENTRATIONS; INSULIN SENSITIVITY; METABOLIC SYNDROME; D DEFICIENCY AB Background: Although it is recognized that vitamin D deficiency is associated with cardiovascular disease (CVD) risk factors, and is more common in African Americans (AAs), the pathologic mechanisms by which vitamin D may influence these risk factors are poorly understood. Objectives: We explored the association between vitamin D status, as reflected by serum 25-hydroxyvitamin D [25(OH)D] concentrations, and CVD risk factors including mean arterial pressure (MAP), fasting plasma glucose (FPG), plasma HDL cholesterol, and waist circumference (WC) in adult AAs. We also tested whether plasma C-reactive protein (CRP), adipokines (adiponectin and leptin), and aldosterone mediated the associations between 25(OH)D and these risk factors. Methods: Data on 4010 (63.8% women; mean age: 54.0 y) individuals from the Jackson Heart Study were analyzed. Multivariable linear regression models were used to examine the associations of 25(OH)D with CVD risk factors. We used path analysis and bootstrapping methods to quantify and test the share of these associations that was statistically explained by each of the mediators by decomposing the associations into direct and indirect effects. Results: Serum 25(OH)D concentrations were inversely associated with WC, FPG, and MAP and were positively associated with HDL cholesterol in multivariable analysis. A nearly 20% effect of 25(OH)D on MAP was masked by aldosterone (total indirect effect: beta = 0.01, P < 0.05). Approximately 23% of the effect of 25(OH)D on WC (beta = 0.03, P < 0.05) and similar to 9% of the effect of 25(OH)D on FPG (beta = -0.02, P < 0.05) were mediated through CRP, adiponectin, and leptin together. A 23% share of the association between 25(OH)D and HDL cholesterol was mediated by adiponectin alone (beta = 0.03, P < 0.05). Conclusions: Our findings suggest that the associations between vitamin D status and CVD risk factors in AAs are partially mediated through circulating adipokines and CRP. More evidence, however, is required from longitudinal and randomized controlled studies to validate our findings. C1 [Khan, Rumana J.; Gebreab, Samson Y.; Riestra, Pia; Gaye, Amadou; Xu, Ruihua; Davis, Sharon K.] NHGRI, Metab Cardiovasc & Inflammatory Dis Genom Branch, Cardiovasc Sect, Social Epidemiol Unit,NIH, Bethesda, MD 20892 USA. [Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson Heart Study, Jackson, MS 39216 USA. RP Khan, RJ (reprint author), NHGRI, Metab Cardiovasc & Inflammatory Dis Genom Branch, Cardiovasc Sect, Social Epidemiol Unit,NIH, Bethesda, MD 20892 USA. OI Gaye, Amadou/0000-0002-1180-2792 FU Intramural Research Program of the NIH; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities FX Supported by the Intramural Research Program of the NIH. The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. NR 39 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 146 IS 12 BP 2537 EP 2543 DI 10.3945/jn.116.239509 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600014 PM 27798347 ER PT J AU Ma, JT Jacques, PF Meigs, JB Fox, CS Rogers, GT Smith, CE Hruby, A Saltzman, E McKeown, NM AF Ma, Jiantao Jacques, Paul F. Meigs, James B. Fox, Caroline S. Rogers, Gail T. Smith, Caren E. Hruby, Adela Saltzman, Edward McKeown, Nicola M. TI Sugar-Sweetened Beverage but Not Diet Soda Consumption Is Positively Associated with Progression of Insulin Resistance and Prediabetes SO JOURNAL OF NUTRITION LA English DT Article DE sugar-sweetened beverages; diet soda; insulin resistance; HOMA-IR; prediabetes ID CARDIOMETABOLIC RISK-FACTORS; RANDOMIZED CONTROLLED-TRIAL; SOFT DRINK CONSUMPTION; CORONARY-HEART-DISEASE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; GLYCEMIC INDEX; AGED ADULTS; FRUIT JUICE; MEN AB Background: Previous studies have shown an inconsistent relation between habitual beverage consumption and insulin resistance and prediabetes. Objective: The objective of the present study was to test the hypothesis that the consumption of sugar-sweetened beverages (SSBs), rather than diet soda, is associated with long-term progression of insulin resistance and the development of prediabetes. Methods: We analyzed the prospective association between cumulative mean consumption of SSBs or diet soda and incident prediabetes (n = 1685) identified across a median of 14 y of follow-up in participants [mean +/- SD age: 51.9 +/- 9.2 y; 59.6% women; mean +/- SD body mass index (BMI; kg/m(2)): 26.3 +/- 4.4] of the Framingham Offspring cohort. The prospective association between beverage consumption and change in homeostasis model assessment of insulin resistance (HOMA-IR; n = 2076) over 7 y was also analyzed. The cumulative mean consumption of SSBs and diet soda was estimated by using food-frequency questionnaires. Multivariable Cox proportional hazards models and linear regression models were implemented to estimate the HRs of incident prediabetes and change in HOMA-IR, respectively. Results: After adjustment for multiple potential confounders, including baseline BMI, we observed that SSB intake was positively associated with incident prediabetes (P-trend < 0.001); the highest SSB consumers (>3 servings/wk; median: 6 servings/wk) had a 46% higher risk of developing prediabetes than did the SSB nonconsumers (HR: 1.46; 95% CI: 1.16, 1.83). Higher SSB intake was also associated with a greater increase in HOMA-IR (P-trend = 0.006). No prospective associations were observed between diet soda intake and risk of prediabetes (P-trend = 0.24) or changes in HOMA-IR (P-trend = 0.25). These associations were similar after additional adjustment for change in BMI. Conclusion: Regular SSB intake, but not diet soda intake, is associated with a greater increase in insulin resistance and a higher risk of developing prediabetes in a group of middle-aged adults. C1 [Ma, Jiantao; Jacques, Paul F.; Rogers, Gail T.; Hruby, Adela; McKeown, Nicola M.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr Epidemiol Lab, Boston, MA 02111 USA. [Smith, Caren E.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Saltzman, Edward] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Energy Metab Lab, Boston, MA 02111 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Div Gen Internal Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Populat Sci Branch, Framingham, MA USA. RP McKeown, NM (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr Epidemiol Lab, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU NIH/National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Boston University School of Medicine; USDA (USDA) [58-1950-0-014] FX Supported by the NIH/National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195), the Boston University School of Medicine, and the USDA (USDA agreement 58-1950-0-014). NR 38 TC 0 Z9 0 U1 6 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 DEC PY 2016 VL 146 IS 12 BP 2544 EP 2550 DI 10.3945/jn.116.234047 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600015 PM 27934644 ER PT J AU Kirkpatrick, SI Potischman, N Dodd, KW Douglass, D Zimmerman, TP Kahle, LL Thompson, FE George, SM Subar, AF AF Kirkpatrick, Sharon I. Potischman, Nancy Dodd, Kevin W. Douglass, Deirdre Zimmerman, Thea P. Kahle, Lisa L. Thompson, Frances E. George, Stephanie M. Subar, Amy F. TI The Use of Digital Images in 24-Hour Recalls May Lead to Less Misestimation of Portion Size Compared with Traditional Interviewer Administered Recalls SO JOURNAL OF NUTRITION LA English DT Article DE 24-hour recall; dietary intake; portion size; Automated Self-Administered 24-hour dietary assessment tool; Automated Multiple-Pass Method ID MULTIPLE-PASS METHOD; DIETARY ASSESSMENT; FOOD PHOTOGRAPHS; ACCURACY; NUTRIENT; RESOURCE; VALIDITY; AIDS AB Background: The Automated Self-Administered 24-hour (ASA24) dietary recall system enhances the feasibility of collecting high-quality intake data in population-based studies. Objective: The aim of this study was to assess the accuracy of portion size reporting in the ASA24 compared with interviewer-administered recalls. Methods: True intake for 3 meals was ascertained in 81 adults aged 20-70 y from the Washington, DC area. Participants were randomly assigned to complete an unannounced ASA24 or an interviewer-administered Automated Multiple-Pass Method (AM PM) recall the following day. An adapted Bland-Altman approach was used to assess agreement between true and reported portion sizes. Linear regression was used to assess log-scale differences between true and reported portion sizes by recall mode. The proportions of reported portion sizes within 10% and 25% of truth were estimated. Analyses were conducted for all foods and drinks and predetermined categories. Results: Mean differences between true and reported portion sizes were 3.7 g for the ASA24 and 11.8 g for the AMPM. According to the Bland-Altman-type plots, between 92% and 100% (depending on food or drink category and recall mode) of observations fell within the limits of agreement. After adjustment for multiple testing, the mean ratio of reported to true portion sizes was significantly >1 for the categories of all foods and drinks, all foods excluding liquids, amorphous or soft foods, and small pieces among AM PM respondents. Misestimation in the AM PM was significantly different from that in the ASA24 for all foods and drinks and for all foods excluding liquids. Small proportions of reported portions fell within 10% (16.2% for the ASA24 and 14.9% for the AMPM) and 25% (37.5% for the ASA24 and 33.2% for the AMPM) of truth. Conclusions: The results raise the possibility that digital images tailored to different types and formats of foods may facilitate improved estimation of amounts eaten but highlight the need for continued work in this aspect of dietary assessment. This trial was registered at clinicaltrials.gov as NCT00978406. C1 [Kirkpatrick, Sharon I.] Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON, Canada. [Potischman, Nancy] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [George, Stephanie M.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Thompson, Frances E.; Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Douglass, Deirdre; Zimmerman, Thea P.] Westat Corp, Rockville, MD USA. [Kahle, Lisa L.] Informat Management Serv Inc, Rockville, MD USA. RP Kirkpatrick, SI (reprint author), Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON, Canada. EM sharon.kirkpatrick@uwaterloo.ca FU Canadian Cancer Society Research Institute Capacity Development Award [702855]; US government via Westat [NO2-PC-64406, HHSN261200644006C] FX At the time that data collection and the initial analyses were conducted, Sharon I Kirkpatrick, Nancy Potischman, and Stephanie M George were with the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute. Sharon I Kirkpatrick is currently funded by a Canadian Cancer Society Research Institute Capacity Development Award (grant no. 702855). The data for this study were collected by the US government via a contract with Westat (NO2-PC-64406, HHSN261200644006C). NR 27 TC 2 Z9 2 U1 1 U2 1 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 DEC PY 2016 VL 146 IS 12 BP 2567 EP 2573 DI 10.3945/jn.116.237271 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600018 PM 27807039 ER PT J AU McCorvy, JD Olsen, RHJ Roth, BL AF McCorvy, John D. Olsen, Reid H. J. Roth, Bryan L. TI Psilocybin for depression and anxiety associated with life-threatening illnesses SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Editorial Material ID SEROTONIN 5-HT2A RECEPTORS; SUICIDE C1 [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. EM bryan_roth@med.unc.edu NR 20 TC 0 Z9 0 U1 23 U2 23 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD DEC PY 2016 VL 30 IS 12 BP 1209 EP 1210 DI 10.1177/0269881116675771 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EE9AC UT WOS:000389917000009 PM 27909171 ER PT J AU Tempero, M AF Tempero, Margaret TI An Oncologist's Letter to Santa SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF, Pancreas Ctr, Med, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF, Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] ASCO Board, San Francisco, CA USA. [Tempero, Margaret] ASCO, San Francisco, CA USA. [Tempero, Margaret] ASCO, Conquer Canc Fdn Board, San Francisco, CA USA. [Tempero, Margaret] ASCO Methods Clin Canc Res, AACR, San Francisco, CA USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] NCI, Board Sci Counselors Subcomm A, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX USA. [Tempero, Margaret] Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY USA. [Tempero, Margaret] V Fdn, Pancreat Canc Act Network, Bethpage, NY USA. [Tempero, Margaret] Alberta Canada Canc Board, Edmonton, AB, Canada. [Tempero, Margaret] EORTC, Copenhagen, Denmark. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC, Eppley Canc Ctr, Omaha, NE 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 94143 USA.; Tempero, M (reprint author), UCSF, Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), ASCO, Conquer Canc Fdn Board, San Francisco, CA USA.; Tempero, M (reprint author), ASCO Methods Clin Canc Res, AACR, San Francisco, CA USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX USA.; Tempero, M (reprint author), Lustgarten Fdn, Sci Advisory Boards, Bethpage, NY USA.; Tempero, M (reprint author), V Fdn, Pancreat Canc Act Network, Bethpage, NY USA.; Tempero, M (reprint author), Alberta Canada Canc Board, Edmonton, AB, Canada.; Tempero, M (reprint author), EORTC, Copenhagen, Denmark.; 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 1 Z9 1 U1 0 U2 0 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 DEC PY 2016 VL 14 IS 12 BP 1491 EP 1491 PG 1 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100001 PM 27956532 ER PT J AU Redmond, SM Yao, TJ Russell, JS Rice, ML Hoffman, HJ Siberry, GK Frederick, T Purswani, M Williams, PL AF Redmond, Sean M. Yao, Tzy-Jyun Russell, Jonathan S. Rice, Mabel L. Hoffman, Howard J. Siberry, George K. Frederick, Toni Purswani, Murli Williams, Paige L. CA Pediat HIV AIDS Cohort Study TI Longitudinal Evaluation of Language Impairment in Youth With Perinatally Acquired Human Immunodeficiency Virus (HIV) and Youth With Perinatal HIV Exposure SO JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY LA English DT Article DE antiretroviral therapy; language development; language impairment; perinatal HIV; youth ID FOLLOW-UP; CHILDREN; INFECTION; OUTCOMES AB Background. Language impairment (LI) risk is increased for perinatally acquired human immunodeficiency virus-infected (PHIV) and perinatally exposed to HIV but uninfected (PHEU) youth. This study evaluates the persistence of LI in these groups. Methods. The Clinical Evaluation of Language Fundamentals was repeated on participants of the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol 18 months postbaseline. Regression models identified factors associated with change in standardized score (SC) and the resolution or development of LI. Results. Of 319 participants, 112 had LI at baseline. Upon re-evaluation, SCs were highly stable and changes were similar in PHIV (n = 212) and PHEU (n = 107) participants. Those with family history of language delays had a 2.39 point lower mean increase in SCs than those without, after controlling for demographic and socioeconomic factors and baseline LI status. Among PHIV participants, CD4 count,350 cells/mm(3) was associated with lower mean SC change (4.32 points), and exposure to combination antiretroviral therapy (cART) or protease inhibitors (PIs) was associated with a higher mean SC change (5.93 and 4.19 points, respectively). Initial LI was persistent in most cases (78%); 20 new cases occurred (10%). Female sex was associated with higher odds of LI resolution. Among PHIV, duration and baseline cART and history of PI use were associated with LI resolution; higher percentage of detectable viral loads before baseline was associated with lower odds of resolution. Conclusions. The PHIV and PHEU youth are at risk for persistent LI, and family history of language delays was a risk factor for persistence of problems. Measures of successful HIV treatment predicted more favorable outcomes among PHIV youth. C1 [Redmond, Sean M.] Univ Utah, Commun Sci & Disorders, Salt Lake City, UT 84112 USA. [Yao, Tzy-Jyun; Russell, Jonathan S.; Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Rice, Mabel L.] Univ Kansas, Child Language Program, Lawrence, KS 66045 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Frederick, Toni] Univ Southern Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, Los Angeles, CA 90033 USA. [Purswani, Murli] Bronx Lebanon Hosp Ctr, Div Pediat Infect Dis, Dept Pediat, New York, NY USA. RP Redmond, SM (reprint author), 390 S 1530 E,BEHS 1201, Salt Lake City, UT 84112 USA. EM sean.redmond@health.utah.edu FU NICHD NIH HHS [U01 HD052102, U01 HD052104] NR 9 TC 1 Z9 1 U1 1 U2 1 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 DEC PY 2016 VL 5 SU 1 BP S33 EP S40 DI 10.1093/jpids/piw045 PG 8 WC Infectious Diseases SC Infectious Diseases GA EE8DQ UT WOS:000389855700005 PM 27856674 ER PT J AU Pinzone, MR Graf, E Lynch, L McLaughlin, B Hecht, FM Connors, M Migueles, SA Hwang, WT Nunnari, G O'Doherty, U AF Pinzone, Marilia Rita Graf, Erin Lynch, Lindsay McLaughlin, Brigit Hecht, Frederick M. Connors, Mark Migueles, Stephen A. Hwang, Wei-Ting Nunnari, Giuseppe O'Doherty, Una TI Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size SO JOURNAL OF VIROLOGY LA English DT Article ID PRIMARY HIV-1 INFECTION; ANTIRETROVIRAL THERAPY; ELITE CONTROLLERS; LATENT RESERVOIR; CELL-ACTIVATION; IMMUNE CONTROL; PLASMA VIRUS; IN-VIVO; DNA; QUANTIFICATION AB The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n = 8) and noncontrollers (NCs; n = 6) before ART, whereas integration remained stable in patients on ART (n = 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n = 7) but not chronically infected (n = 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs. IMPORTANCE The establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection. C1 [Pinzone, Marilia Rita] Univ Catania, Dept Clin & Expt Med, Infect Dis Unit, Catania, Italy. [Pinzone, Marilia Rita; Graf, Erin; Lynch, Lindsay; McLaughlin, Brigit; O'Doherty, Una] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hecht, Frederick M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Hecht, Frederick M.] San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA 94110 USA. [Connors, Mark; Migueles, Stephen A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hwang, Wei-Ting] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Nunnari, Giuseppe] Univ Messina, Dept Clin & Expt Med, Infect Dis Unit, Messina, Italy. RP O'Doherty, U (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM unao@mail.med.upenn.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R21AI096993, R21AI106557, R21AI116216, T32AI007632]; amfAR, The Foundation for AIDS Research (amfAR) FX This work, including the efforts of Una O'Doherty, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R21AI096993, R21AI106557, R21AI116216, and T32AI007632). This work, including the efforts of Una O'Doherty, was funded by amfAR, The Foundation for AIDS Research (amfAR). NR 54 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2016 VL 90 IS 23 BP 10436 EP 10445 DI 10.1128/JVI.00242-16 PG 10 WC Virology SC Virology GA EE8VL UT WOS:000389904500001 PM 27630237 ER PT J AU Deng, J Mitsuki, Y Shen, GM Ray, JC Cicala, C Arthos, J Dustin, ML Hioe, CE AF Deng, Jing Mitsuki, Yu-ya Shen, Guomiao Ray, Jocelyn C. Cicala, Claudia Arthos, James Dustin, Michael L. Hioe, Catarina E. TI HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIROLOGICAL SYNAPSES; MONOCLONAL-ANTIBODIES; TYPE-1 INFECTION; DENDRITIC CELLS; STOP SIGNAL; MICROCLUSTERS; BINDING; ENV; SUBSETS AB HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells. IMPORTANCE There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells. C1 [Deng, Jing; Dustin, Michael L.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA. [Deng, Jing; Shen, Guomiao; Dustin, Michael L.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Mitsuki, Yu-ya; Hioe, Catarina E.] Icahn Sch Med Mt Sinai, Div Infect Dis, New York, NY 10029 USA. [Ray, Jocelyn C.; Cicala, Claudia; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Dustin, Michael L.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Kennedy Inst Rheumatol, Headington, England. [Hioe, Catarina E.] James J Peters Vet Affairs Med Ctr, Res Serv, Bronx, NY 10468 USA. RP Hioe, CE (reprint author), Icahn Sch Med Mt Sinai, Div Infect Dis, New York, NY 10029 USA.; Hioe, CE (reprint author), James J Peters Vet Affairs Med Ctr, Res Serv, Bronx, NY 10468 USA. EM catarina.hioe@mssm.edu FU U.S. Department of Veterans Affairs (VA); HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI093210, AI100151, AI102740, AI043542] FX This work, including the efforts of Catarina E. Hioe, was funded by U.S. Department of Veterans Affairs (VA) (Research Career Scientist Award). This work, including the efforts of Catarina E. Hioe, was funded by U.S. Department of Veterans Affairs (VA) (Merit Review Award). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI093210). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI100151). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI102740). This work, including the efforts of Michael L. Dustin, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI043542). NR 65 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 DEC PY 2016 VL 90 IS 23 BP 10513 EP 10526 DI 10.1128/JVI.01532-16 PG 14 WC Virology SC Virology GA EE8VL UT WOS:000389904500007 PM 27630246 ER PT J AU Longo, NS Sutton, MS Shiakolas, AR Guenaga, J Jarosinski, MC Georgiev, IS Mckee, K Bailer, RT Louder, MK O'Dell, S Connors, M Wyatt, RT Mascola, JR Doria-Rose, NA AF Longo, Nancy S. Sutton, Matthew S. Shiakolas, Andrea R. Guenaga, Javier Jarosinski, Marissa C. Georgiev, Ivelin S. Mckee, Krisha Bailer, Robert T. Louder, Mark K. O'Dell, Sijy Connors, Mark Wyatt, Richard T. Mascola, John R. Doria-Rose, Nicole A. TI Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding SO JOURNAL OF VIROLOGY LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; HUMAN MONOCLONAL-ANTIBODIES; B-CELL POPULATIONS; GP41-GP120 INTERFACE; PERIPHERAL-BLOOD; GENE USAGE; POTENT; RECOGNITION; IG; MEMORY AB One of the goals of HIV-1 vaccine development is the elicitation of neutralizing antibodies against vulnerable regions on the envelope glycoprotein (Env) viral spike. Broadly neutralizing antibodies targeting the Env glycan-V3 region (also called the N332 glycan supersite) have been described previously, with several single lineages each derived from different individual donors. We used a high-throughput B-cell culture method to isolate neutralizing antibodies from an HIV-1-infected donor with high serum neutralization breadth. Clonal relatives from three distinct antibody lineages were isolated. Each of these antibody lineages displayed modest breadth and potency but shared several characteristics with the well-characterized glycan-V3 antibodies, including dependence on glycans N332 and N301, VH4 family gene utilization, a heavy chain complementarity-determining region 2 (CDRH2) insertion, and a longer-than-average CDRH3. In contrast to previously described glycan-V3 antibodies, these antibodies preferentially recognized the native Env trimer compared to monomeric gp120. These data indicate the diversity of antibody specificities that target the glycan-V3 site. The quaternary binding preference of these antibodies suggests that that their elicitation likely requires the presentation of a native-like trimeric Env immunogen. IMPORTANCE Broadly neutralizing antibodies targeting the HIV-1 glycan-V3 region with single lineages from individual donors have been described previously. Here we describe three lineages from a single donor, each of which targets glycan-V3. Unlike previously described glycan-V3 antibodies, these mature antibodies bind preferentially to the native Env trimer and weakly to the gp120 monomer. These data extend our knowledge of the immune response recognition of the N332 supersite region and suggest that the mode of epitope recognition is more complex than previously anticipated. C1 [Longo, Nancy S.; Sutton, Matthew S.; Shiakolas, Andrea R.; Jarosinski, Marissa C.; Georgiev, Ivelin S.; Mckee, Krisha; Bailer, Robert T.; Louder, Mark K.; O'Dell, Sijy; Mascola, John R.; Doria-Rose, Nicole A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Guenaga, Javier; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Georgiev, Ivelin S.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN USA. [Louder, Mark K.] NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Longo, Nancy S.] 9610 Barroll Lane, Kensington, MD USA. [Sutton, Matthew S.] Univ Wisconsin, Madison, WI USA. [Jarosinski, Marissa C.] Univ Med & Dent New Jersey, New Brunswick, NJ USA. RP Doria-Rose, NA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nicole.doriarose@nih.gov FU Vaccine Research Center, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA; International AIDS Vaccine Initiative (IAVI); Bill & Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); United Kingdom Department for International Development (DFID); United States Agency for International Development (USAID) FX This work, including the efforts of Nancy S. Longo, Matthew S. Sutton, Marissa C. Jarosinski, Andrea R. Shiakolas, Ivelin S. Georgiev, Krisha McKee, Robert T. Bailer, Mark K. Louder, Sijy O'Dell, Mark Connors, John R. Mascola, and Nicole A. Doria-Rose, was funded by intramural research programs of the Vaccine Research Center, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. This work, including the efforts of Javier Guenaga and Richard T. Wyatt, was funded by the International AIDS Vaccine Initiative (IAVI), made possible by generous support from many donors, including the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. NR 53 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 90 IS 23 BP 10574 EP 10586 DI 10.1128/JVI.01012-16 PG 13 WC Virology SC Virology GA EE8VL UT WOS:000389904500012 PM 27654288 ER PT J AU Nelson, MI Stucker, KM Schobel, SA Trovao, NS Das, SR Dugan, VG Nelson, SW Sreevatsan, S Killian, ML Nolting, JM Wentworth, DE Bowman, AS AF Nelson, Martha I. Stucker, Karla M. Schobel, Seth A. Trovao, Nidia S. Das, Suman R. Dugan, Vivien G. Nelson, Sarah W. Sreevatsan, Srinand Killian, Mary L. Nolting, Jacqueline M. Wentworth, David E. Bowman, Andrew S. TI Introduction, Evolution, and Dissemination of Influenza A Viruses in Exhibition Swine in the United States during 2009 to 2013 SO JOURNAL OF VIROLOGY LA English DT Article ID DYNAMICS; HUMANS AB The swine-human interface created at agricultural fairs, along with the generation of and maintenance of influenza A virus diversity in exhibition swine, presents an ongoing threat to public health. Nucleotide sequences of influenza A virus isolates collected from exhibition swine in Ohio (n = 262) and Indiana (n = 103) during 2009 to 2013 were used to investigate viral evolution and movement within this niche sector of the swine industry. Phylogenetic and Bayesian analyses were employed to identify introductions of influenza A virus to exhibition swine and study viral population dynamics. In 2013 alone, we identified 10 independent introductions of influenza A virus into Ohio and/or Indiana exhibition swine. Frequently, viruses from the same introduction were identified at multiple fairs within the region, providing evidence of rapid and widespread viral movement within the exhibition swine populations of the two states. While pigs moving from fair to fair to fair is possible in some locations, the concurrent detection of nearly identical strains at several fairs indicates that a common viral source was more likely. Importantly, we detected an association between the high number of human variant H3N2 (H3N2v) virus infections in 2012 and the widespread circulation of influenza A viruses of the same genotype in exhibition swine in Ohio fairs sampled that year. The extent of viral diversity observed in exhibition swine and the rapidity with which it disseminated across long distances indicate that novel strains of influenza A virus will continue to emerge and spread within exhibition swine populations, presenting an ongoing threat to humans. IMPORTANCE Understanding the underlying population dynamics of influenza A viruses in commercial and exhibition swine is central to assessing the risk for human infections with variant viruses, including H3N2v. We used viral genomic sequences from isolates collected from exhibition swine during 2009 to 2013 to understand how the peak of H3N2v cases in 2012 relates to long-term trends in the population dynamics of pandemic viruses recently introduced into commercial and exhibition swine in the United States. The results of our spatial analysis underscore the key role of rapid viral dispersal in spreading multiple genetic lineages throughout a multistate network of agricultural fairs, providing opportunities for divergent lineages to coinfect, reassort, and generate new viral genotypes. The higher genetic diversity of genotypes cocirculating in exhibition swine since 2013 could facilitate the evolution of new reassortants, potentially with even greater ability to cause severe infections in humans or cause human-to-human transmission, highlighting the need for continued vigilance. C1 [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Stucker, Karla M.; Schobel, Seth A.; Das, Suman R.; Dugan, Vivien G.; Wentworth, David E.] J Craig Venter Inst, Rockville, MD USA. [Trovao, Nidia S.] Katholieke Univ Leuven, Leuven, Belgium. [Nelson, Sarah W.; Nolting, Jacqueline M.; Bowman, Andrew S.] Ohio State Univ, Columbus, OH 43210 USA. [Sreevatsan, Srinand] Univ Minnesota, St Paul, MN 55108 USA. [Killian, Mary L.] USDA, Natl Vet Serv Labs, Ames, IA 50010 USA. [Stucker, Karla M.] George Sch, Newtown, PA USA. [Schobel, Seth A.] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Das, Suman R.] Vanderbilt Univ, Med Ctr, Dept Med, Ctr Translat Immunol & Infect Dis, Nashville, TN USA. [Dugan, Vivien G.] NIAID, Off Genom & Adv Technol, NIH, Rockville, MD USA. [Wentworth, David E.] Ctr Dis Control & Prevent, Virol Surveillance & Diag Branch, Influenza Div, Atlanta, GA USA. RP Bowman, AS (reprint author), Ohio State Univ, Columbus, OH 43210 USA. EM bowman.214@osu.edu OI Sreevatsan, Srinand/0000-0002-5162-2403; Sequeira Trovao, Nidia/0000-0002-2106-1166 FU HHS \ National Institutes of Health (NIH) [HHSN272201400006C, HHSN272201400008C, HHSN266200700007C, HHSN272200900007C, U19-AI-110819] FX This work, including the efforts of Sarah W. Nelson, Jacqueline M. Nolting, and Andrew S. Bowman, was funded by HHS vertical bar National Institutes of Health (NIH) (HHSN272201400006C). This work, including the efforts of Martha I. Nelson, was funded by HHS vertical bar National Institutes of Health (NIH) (HHSN272201400008C). This work, including the efforts of Sarah W. Nelson, Srinand Sreevatsan, Jacqueline M. Nolting, and Andrew S. Bowman, was funded by HHS vertical bar National Institutes of Health (NIH) (HHSN266200700007C). This work, including the efforts of Karla M. Stucker, Seth A. Schobel, Suman R. Das, Vivien G. Dugan, and David E. Wentworth, was funded by HHS vertical bar National Institutes of Health (NIH) (HHSN272200900007C). This work, including the efforts of Suman R. Das and David E. Wentworth, was funded by HHS vertical bar National Institutes of Health (NIH) (U19-AI-110819). NR 17 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2016 VL 90 IS 23 BP 10963 EP 10971 DI 10.1128/JVI.01457-16 PG 9 WC Virology SC Virology GA EE8VL UT WOS:000389904500044 PM 27681134 ER PT J AU Bansal, N McCulloch, CE Lin, F Robinson-Cohen, C Rahman, M Kusek, JW Andersons, AH Xie, DW Townsend, RR Lora, CM Wright, J Go, AS Ojo, A Alper, A Lustigova, E Cuevas, M Kallem, R Hsu, CY AF Bansal, Nisha McCulloch, Charles E. Lin, Feng Robinson-Cohen, Cassianne Rahman, Mahboob Kusek, John W. Andersons, Amanda H. Xie, Dawei Townsend, Raymond R. Lora, Claudia M. Wright, Jackson Go, Alan S. Ojo, Akinlolu Alper, Arnold Lustigova, Eva Cuevas, Magda Kallem, Radhakrishna Hsu, Chi-yuan CA CRIC Study Investigatorsis TI Different components of blood pressure are associated with increased risk of atherosclerotic cardiovascular disease versus heart failure in advanced chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE blood pressure; cardiovascular disease; chronic kidney disease ID RENAL-INSUFFICIENCY COHORT; BASE-LINE CHARACTERISTICS; HEMODIALYSIS-PATIENTS; PULSE PRESSURE; MAINTENANCE HEMODIALYSIS; MORTALITY RISK; OLDER-ADULTS; CKD; DEATH; DIALYSIS AB Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate <30 ml/min per 1.73 m(2) and not on dialysis. The association of systolic (SBP), diastolic (DBP), and pulse pressure with the risk of physician-adjudicated atherosclerotic CVD (stroke, myocardial infarction, or peripheral arterial disease) and heart failure was tested using Cox regression adjusted for demographics, comorbidity and medications. There was a significant association with higher SBP (adjusted hazard ratio 2.04 [95% confidence interval: 1.46-2.84]) for SBP over 140 vs under 120 mmHg, higher DBP (2.52 [1.54-4.11]) for DBP >90 mm Hg versus <80 mm Hg and higher pulse pressure (2.67 [1.82-3.92]) for pulse pressure >68 mm Hg versus <51 mm Hg with atherosclerotic CVD. For heart failure, there was a significant association with higher pulse pressure only (1.42 [1.05-1.92]) for pulse pressure >68 mm Hg versus <51 mmHg, but not for SBP or DBP. Thus, among participants with stage 4 and 5 chronic kidney disease, there was an independent association between higher SBP, DBP, and pulse pressure with the risk of atherosclerotic CVD, whereas only higher pulse pressure was independently associated with a greater risk of heart failure. Further trials are needed to determine whether aggressive reduction of blood pressure decreases the risk of CVD events in patients with stage 4 and 5 chronic kidney disease. C1 [Bansal, Nisha; Robinson-Cohen, Cassianne] Univ Washington, Dept Med, Seattle, WA USA. [McCulloch, Charles E.; Lin, Feng] Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA 94143 USA. [Rahman, Mahboob; Wright, Jackson] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Andersons, Amanda H.; Xie, Dawei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Lora, Claudia M.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA USA. [Ojo, Akinlolu] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Alper, Arnold] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [Lustigova, Eva] Tulane Univ, Sch Publ Hlth, New Orleans, LA 70118 USA. [Cuevas, Magda] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Hsu, Chi-yuan] Kaiser Permanente, Div Res, Dept Med, Oakland, CA USA. RP Bansal, N (reprint author), Univ Washington, Kidney Res Inst, 908 Jefferson St,3rd Floor, Seattle, WA 98104 USA. EM nbansal@nephrology.washington.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU 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/National Center for Advancing Translational Sciences [UL1TR000003, K01 DK092353]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences component of the NIH [UL1TR000439]; NIH road map for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago National Center for Advancing Translational Sciences [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente [NIH/NCRR UCSF-CTSI UL1 RR-024131]; [K23 DK088865]; [R01 DK70939]; [K24 DK92291] FX This work was supported by the following grants: K23 DK088865 (NB), R01 DK70939 (Hsu and CH), K24 DK92291 (CH). Funding for the CRIC study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). This work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (UL1TR000003 and K01 DK092353) (A.H.A.), 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 component of the NIH and NIH road map for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) (UL1TR000433), University of Illinois at Chicago National Center for Advancing Translational Sciences (UL1RR029879), Tulane University Translational Research in Hypertension and Renal Biology (P30GM103337), and Kaiser Permanente (NIH/NCRR UCSF-CTSI UL1 RR-024131). NR 42 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2016 VL 90 IS 6 BP 1348 EP 1356 DI 10.1016/j.kint.2016.08.009 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EE4EZ UT WOS:000389556400028 PM 27717485 ER PT J AU Schmid, D Behrens, G Matthews, CE Leitzmann, MF AF Schmid, Daniela Behrens, Gundula Matthews, Charles E. Leitzmann, Michael F. TI Physical Activity and Risk of Colon Cancer in Diabetic and Nondiabetic US Adults SO MAYO CLINIC PROCEEDINGS LA English DT Article ID SERUM 25-HYDROXYVITAMIN D; NIH-AARP DIET; COLORECTAL-CANCER; INSULIN SENSITIVITY; RECTAL-CANCER; LIFE-STYLE; INFLAMMATORY MARKERS; SEDENTARY BEHAVIOR; GLUCOSE-TOLERANCE; NATIONAL-HEALTH AB Objective: To determine whether moderate to vigorous physical activity is associated with a decreased risk of colon cancer in diabetic patients. Patients and Methods: We evaluated the association between physical activity and colon cancer in 25,753 patients with a self-reported history of diabetes and in 274,965 nondiabetic individuals from the National Institutes of Health-AARP Diet and Health Study who were aged 50 to 71 years in 1995-1996. Moderate to vigorous physical activity was assessed at baseline using a self-administered questionnaire. Follow-up for colon cancer incidence extended to December 31, 2011. Results: During 13.0 years of follow-up, 480 diabetic patients and 4151 nondiabetic individuals had development of colon cancer. Among diabetic patients, compared with never/rarely engaging in physical activity, more than 7 h/wk of physical activity exhibited a reduced risk of colon cancer in the age-and sex-adjusted model (hazard ratio [HR], 0.74; 95% CI, 0.56-0.996; P =.16 for trend). This association was attenuated and no longer statistically significant after additional control for other covariates (HR, 0.78; 95% CI, 0.58-1.05; P =.29 for trend). By comparison, physical activity was inversely related to colon cancer risk in nondiabetic individuals (multivariate-adjusted HR, 0.81; 95% CI, 0.73-0.89; P<. 001 for trend). Conclusion: In this investigation of the relationship between physical activity and colon cancer in diabetic patients, we found a statistically significant inverse relationship in the age-and sex-adjusted model, which was no longer statistically significant in the multivariate-adjusted model. A reduced risk was noted among nondiabetic individuals, irrespective of other covariates. Future studies with a larger number of participants are required to explore whether physical activity beneficially affects colon cancer risk among diabetic patients. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Schmid, Daniela; Behrens, Gundula; Leitzmann, Michael F.] Univ Regensburg, Dept Epidemiol & Prevent Med, Franz Josef Str Allee 11, D-93053 Regensburg, Germany. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Metab Epidemiol Branch, Bethesda, MD 20814 USA. RP Schmid, D (reprint author), Univ Regensburg, Dept Epidemiol & Prevent Med, Franz Josef Str Allee 11, D-93053 Regensburg, Germany. EM daniela.schmid@klinik.uni-regensburg.de OI Behrens, Gundula/0000-0002-9355-6491 NR 84 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 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD DEC PY 2016 VL 91 IS 12 BP 1693 EP 1705 DI 10.1016/j.mayocp.2016.08.017 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA EE3YW UT WOS:000389539500008 PM 27916155 ER PT J AU Mueller, GA Thompson, PM DeRose, EF O'Connell, TM London, RE AF Mueller, Geoffrey A. Thompson, Peter M. DeRose, Eugene F. O'Connell, Thomas M. London, Robert E. TI A metabolomic, geographic, and seasonal analysis of the contribution of pollen-derived adenosine to allergic sensitization SO METABOLOMICS LA English DT Article DE NMR; Metabolomics; Pollen; Adenosine; Allergy ID EICOSANOID-LIKE SUBSTANCES; UNITED-STATES; AIRWAY EPITHELIA; EXPOSURE; CHALLENGE; MEDIATORS; PROTEINS; DISEASE; GRAINS AB Background Studies on ragweed and birch pollen extracts suggested that the adenosine content is an important factor in allergic sensitization. However, exposure levels from other pollens and considerations of geographic and seasonal factors have not been evaluated. Objective This study compared the metabolite profile of pollen species important for allergic disease, specifically measured the adenosine content, and evaluated exposure to pollen-derived adenosine. Methods An NMR metabolomics approach was used to measure metabolite concentrations in 26 pollen extracts. Pollen count data was analyzed from five cities to model exposure. Results A principal component analysis of the various metabolites identified by NMR showed that pollen extracts could be differentiated primarily by sugar content: glucose, fructose, sucrose, and myo-inositol. In extracts of 10 mg of pollen/ml, the adenosine was highest for grasses (45 mu M) followed by trees (23 mu M) and weeds (19 mu M). Pollen count data showed that tree pollen was typically 5-10 times the amount of other pollens. At the daily peaks of tree, grass, and weed season the pollen-derived adenosine exposure per day is likely to be only 1.1, 0.11, and 0.12 mu g, respectively. Seasonal models of pollen exposure and respiration suggest that it would be a rare event limited to tree pollen season for concentrations of pollen-derived adenosine to approach physiological levels. Conclusion Sugar content and other metabolites may be useful in classifying pollens. Unless other factors create localized exposures that are very different from these models, pollen-derived adenosine is unlikely to be a major factor in allergic sensitization. C1 [Mueller, Geoffrey A.; Thompson, Peter M.; DeRose, Eugene F.; London, Robert E.] NIEHS, Lab Genome Integr & Struct Biol, 111 TW Alexander Dr MD-MR01, Res Triangle Pk, NC 27709 USA. [O'Connell, Thomas M.] Indiana Univ Sch Med, Dept Otolaryngol Head & Neck Surg, Indianapolis, IN 46202 USA. RP Mueller, GA (reprint author), NIEHS, Lab Genome Integr & Struct Biol, 111 TW Alexander Dr MD-MR01, Res Triangle Pk, NC 27709 USA. EM mueller3@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES102885-01] FX This research was supported by Research Project Number Z01-ES102885-01 to REL in the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 34 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 EI 1573-3890 J9 METABOLOMICS JI Metabolomics PD DEC PY 2016 VL 12 IS 12 AR 187 DI 10.1007/s11306-016-1130-6 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE4VS UT WOS:000389604300012 ER PT J AU VanBlargan, LA Goo, L Pierson, TC AF VanBlargan, Laura A. Goo, Leslie Pierson, Theodore C. TI Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID WEST-NILE-VIRUS; BORNE ENCEPHALITIS-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; HIV-1 ENVELOPE TRIMER; PROTEIN DOMAIN-III; CRYO-EM STRUCTURE; RECOMBINANT SUBVIRAL PARTICLES; FLAVIVIRUS MEMBRANE-FUSION; CROSS-REACTIVE ANTIBODIES AB The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies. C1 [VanBlargan, Laura A.; Goo, Leslie; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Goo, L; Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM leslie.goo@nih.gov; piersontc@mail.nih.gov FU Division of Intramural Research, National Institute for Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research, National Institute for Allergy and Infectious Diseases. NR 298 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 EI 1098-5557 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD DEC PY 2016 VL 80 IS 4 DI 10.1128/MMBR.00024-15 PG 22 WC Microbiology SC Microbiology GA ED2NK UT WOS:000388683500005 PM 27784796 ER PT J AU Dersh, D Iwamoto, Y Argon, Y AF Dersh, Devin Iwamoto, Yuichiro Argon, Yair TI Tay-Sachs disease mutations in HEXA target the alpha chain of hexosaminidase A to endoplasmic reticulum-associated degradation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HUMAN BETA-HEXOSAMINIDASE; LYSOSOMAL STORAGE DISORDERS; SITE-DIRECTED MUTAGENESIS; PROTEIN-FOLDING DISEASES; GM2 GANGLIOSIDOSIS; SANDHOFF-DISEASE; ADULT FORM; CRYSTAL-STRUCTURE; PRO-ALPHA; FIBROBLASTS AB Loss of function of the enzyme beta-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay-Sachs disease (TSD). It has been proposed that mutations in the alpha chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA alpha mutants, seeking to identify relevant cellular quality control mechanisms. The alpha mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type alpha. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA beta chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant alpha degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant alpha folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD. C1 [Dersh, Devin; Iwamoto, Yuichiro; Argon, Yair] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Dersh, Devin] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Argon, Y (reprint author), Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM yargon@mail.med.upenn.edu FU NIH [GM-077480, AG-18001]; [F31-NS084666-01] FX We thank Oscar Burrone (ICGEB, Trieste) for advice on the retrotranslocation assay and Davide Eletto for advice with molecular biology techniques. The following colleagues generously supplied plasmids and antibodies: Oscar Burrone (ICGEB, Trieste), Richard Proia (National Institutes of Health [NIH]), Elizabeth Neufeld (University of California, Los Angels), Ron Kopito (Stanford), Marek Michalak (University of Alberta, Canada), Linda Hendershot (St. Jude Children's Hospital), and John Christianson (University of Oxford, United Kingdom). This work was supported by training grant F31-NS084666-01 (to D.D.) and NIH grants GM-077480 and AG-18001 (to Y.A.). NR 56 TC 0 Z9 0 U1 15 U2 15 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2016 VL 27 IS 24 BP 3813 EP 3827 DI 10.1091/mbc.E16-01-0012 PG 15 WC Cell Biology SC Cell Biology GA EE4UX UT WOS:000389602000003 PM 27682588 ER PT J AU Sher, A AF Sher, Alan TI Journal club A THIRD SIGNAL FROM CONDITIONED DCS DICTATES MICROBIAL EFFECTOR CHOICE SO NATURE REVIEWS IMMUNOLOGY LA English DT News Item C1 [Sher, Alan] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD DEC PY 2016 VL 16 IS 12 BP 722 EP 722 DI 10.1038/nri.2016.126 PG 1 WC Immunology SC Immunology GA ED8PX UT WOS:000389134500007 PM 27841281 ER PT J AU Chen, WJ ten Dijke, P AF Chen, WanJun ten Dijke, Peter TI Immunoregulation by members of the TGF beta superfamily SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; BONE MORPHOGENETIC PROTEIN-6; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ALLERGIC AIRWAY INFLAMMATION; EPIDERMAL LANGERHANS CELLS; HUMAN DENDRITIC CELLS; FC FUSION PROTEIN; ACTIVIN-A; RHEUMATOID-ARTHRITIS AB The transforming growth factor-beta (TGF beta) superfamily is encoded by 33 genes and includes TGF beta, bone morphogenetic proteins (BMPs) and activins. Although TGF beta is well recognized as a crucial regulator of immune responses, the immunoregulatory functions of other TGF beta family members are less clear. However, recent evidence suggests that BMPs and activins have important roles in regulating immune responses. In this Review, we briefly outline the signalling pathways of the TGF beta superfamily and discuss new insights into the immunoregulatory functions of BMPs and activins in the context of infection, inflammation and cancer. C1 [Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA. [ten Dijke, Peter] Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, Leiden, Netherlands. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD 20892 USA.; ten Dijke, P (reprint author), Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, Leiden, Netherlands. EM wchen@dir.nidcr.nih.gov; P.ten_Dijke@lumc.nl FU Intramural Research Program of the US National Institutes of Health FX The authors thank all of the members in the Mucosal Immunology Section, National Institute for Dental and Craniofacial Research, for their help preparing the tables and figures. We also thank Y. Wu and V. Chen for critically reading the manuscript. This research was supported by The Intramural Research Program of the US National Institutes of Health (W.J.C.). NR 205 TC 0 Z9 0 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD DEC PY 2016 VL 16 IS 12 BP 723 EP 740 DI 10.1038/nri.2016.112 PG 18 WC Immunology SC Immunology GA ED8PX UT WOS:000389134500008 PM 27885276 ER PT J AU Sati, P Oh, J Constable, RT Evangelou, N Guttmann, CRG Henry, RG Klawiter, EC Mainero, C Massacesi, L McFarland, H Nelson, F Ontaneda, D Rauscher, A Rooney, WD Samaraweera, APR Shinohara, RT Sobel, RA Solomon, AJ Treaba, CA Wuerfel, J Zivadinov, R Sicotte, NL Pelletier, D Reich, DS AF Sati, Pascal Oh, Jiwon Constable, R. Todd Evangelou, Nikos Guttmann, Charles R. G. Henry, Roland G. Klawiter, Eric C. Mainero, Caterina Massacesi, Luca McFarland, Henry Nelson, Flavia Ontaneda, Daniel Rauscher, Alexander Rooney, William D. Samaraweera, Amal P. R. Shinohara, Russell T. Sobel, Raymond A. Solomon, Andrew J. Treaba, Constantina A. Wuerfel, Jens Zivadinov, Robert Sicotte, Nancy L. Pelletier, Daniel Reich, Daniel S. CA NIAMS Cooperative TI The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative SO NATURE REVIEWS NEUROLOGY LA English DT Review ID WHITE-MATTER LESIONS; CERVICAL-SPINAL CORD; MS LESIONS; 7 TESLA; BRAIN-LESIONS; PREDICT CONVERSION; PARENCHYMAL VEINS; MCDONALD CRITERIA; HIGH-RESOLUTION; FLAIR-ASTERISK AB Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS. C1 [Sati, Pascal; McFarland, Henry; Reich, Daniel S.] NINDS, Translat Neuroradiol Sect, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. [Oh, Jiwon] Univ Toronto, St Michaels Hosp, Toronto, ON, Canada. [Oh, Jiwon] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Constable, R. Todd] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Evangelou, Nikos; Samaraweera, Amal P. R.] Univ Nottingham, Dept Clin Neurosci, Nottingham, England. [Guttmann, Charles R. G.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Ctr Neurol Imaging, Boston, MA USA. [Henry, Roland G.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Klawiter, Eric C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Mainero, Caterina; Treaba, Constantina A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Massacesi, Luca] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy. [Nelson, Flavia] Univ Texas Hlth Sci Ctr Houston, Multiple Sclerosis Res Grp, Dept Neurol, Houston, TX 77030 USA. [Ontaneda, Daniel] Cleveland Clin Fdn, Mellen Ctr MS Treatment & Res, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Rauscher, Alexander] Univ British Columbia, Dept Pediat, Div Neurol, UBC MRI Res Ctr, Vancouver, BC, Canada. [Rooney, William D.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Shinohara, Russell T.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Solomon, Andrew J.] Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT USA. [Wuerfel, Jens] Univ Basel Hosp, Med Image Anal Ctr, Basel, Switzerland. [Zivadinov, Robert] SUNY Buffalo, Buffalo Neuroimaging Anal Ctr, Dept Neurol, Buffalo, NY USA. [Sicotte, Nancy L.] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Pelletier, Daniel] Univ Southern Calif, Multiple Sclerosis Ctr, Dept Neurol, Keck Sch Med, Los Angeles, CA USA. RP Sati, P (reprint author), NINDS, Translat Neuroradiol Sect, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. EM satip@ninds.nih.gov FU Race to Erase Multiple Sclerosis; Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX The authors would like to thank Christina J. Azevedo, Michael G. Dwyer, Leorah Freeman, Christoph Juchem, Shannon Kolind, Naila Makhani, Govind Nair, Nico Papinutto, Haochang Shou, Daniel Schwartz, Ferdinand Schweser, Elizabeth Sweeney, Ian Tagge, Shahamat Tauhid and Subhash Tummala for their participation in, and contribution to, the group workshop at the NAIMS meeting in Los Angeles. Matthew Schindler is acknowledged for helpful suggestions. The authors also acknowledge Rohit Bakshi, Peter Calabresi, Ciprian Crainiceanu and Jack Simon for their contribution as NAIMS members. The authors, on behalf of the NAIMS Cooperative, would also like to thank the Race to Erase Multiple Sclerosis for financial support, and Joel Arnold, Aracely Delgadillo, and Liz Seares for helping with organization of the NAIMS meeting. This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 67 TC 0 Z9 0 U1 6 U2 6 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 DEC PY 2016 VL 12 IS 12 BP 714 EP 722 DI 10.1038/nrneurol.2016.166 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EE6PP UT WOS:000389735000006 PM 27834394 ER PT J AU Sarkar, J Liu, Y AF Sarkar, Jaya Liu, Yie TI The origin of oxidized guanine resolves the puzzle of oxidation-induced telomere-length alterations SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID DNA-SYNTHESIS; BASE DAMAGE; DELETION; REPAIR; YEAST; TRF2; OGG1 AB Although oxidative stress has long been considered to be a major factor contributing to telomere shortening, recent work has established that oxidative stress and DNA damage are linked to telomere lengthening. Now, Opresko and colleagues resolve this apparent discrepancy by showing that differential modulation of telomerase activity depends on the origin of a common oxidative guanine lesion. C1 [Sarkar, Jaya] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Liu, Yie] Johns Hopkins Univ, Dept Biophys, Baltimore, MD 21218 USA. RP Liu, Y (reprint author), Johns Hopkins Univ, Dept Biophys, Baltimore, MD 21218 USA. EM liuyie@mail.nih.gov NR 20 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 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2016 VL 23 IS 12 BP 1070 EP 1071 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EE4GC UT WOS:000389559300007 PM 27922610 ER PT J AU Bates, MN Reed, BR Liu, S Eisen, EA Hammond, SK AF Bates, Michael N. Reed, Bruce R. Liu, Sa Eisen, Ellen A. Hammond, S. Katharine TI Solvent exposure and cognitive function in automotive technicians SO NEUROTOXICOLOGY LA English DT Article DE Automotive repair; Automotive technician; Cognitive function; Hexane; Occupational exposure; Solvent ID DIGIT SYMBOL; PERFORMANCE; MEMORY; SPEED; AGE AB Automotive technicians are commonly exposed to organic and chlorinated solvents, particularly through use of cleaning products. Occupational solvent exposures have been associated with deficits in cognitive function but, to our knowledge, no previous studies have investigated automotive technicians. The purpose of the present study was to investigate whether previous exposures to n-hexane, in particular, or general solvents posed a persistent neurotoxic hazard to automotive workers. Enrolled in the study were 830 San Francisco Bay Area automotive repair workers. Each participant underwent a battery of cognitive function tests to investigate central nervous system impairment, with a primary focus on the domains of psychomotor speed, fine motor function, memory and mood. Cognitive test results regressed against estimated hexane and total solvent exposures showed little evidence of associations. Exposures to both solvents and hexane were well below the occupational exposure limits. Our results provide some reassurance about persistent neuropsychological effects in automotive workers who use solvent-based products and those who previously used hexane-containing automotive cleaning products, since this solvent is believed no longer to be used in automotive cleaning products. The lack of observed effect in this study may be attributable to low exposures, or it may reflect improved cognitive function since hexane use in automotive cleaning products was discontinued. However, impacts on results of exposure misclassification and/or the healthy worker survivor effect cannot be discounted. Irrespective of the outcome of this study, the main known neurologic effect of n-hexane is peripheral neuropathy, and such an association in automotive technicians is not excluded by these results. (C) 2016 Elsevier B.V. All rights reserved. C1 [Bates, Michael N.; Liu, Sa; Eisen, Ellen A.; Hammond, S. Katharine] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Reed, Bruce R.] Univ Calif Davis, Dept Neurol, Davis, CA USA. [Reed, Bruce R.] Natl Inst Hlth, Ctr Sci Review, Bethesda, MD 20892 USA. RP Bates, MN (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. EM m_bates@berkeley.edu OI Bates, Michael/0000-0003-4122-0715 FU National Institute of Environmental Health Sciences of the National Institutes of Health [R01 ES014049] FX This work was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (grant number R01 ES014049). NR 25 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2016 VL 57 BP 22 EP 30 DI 10.1016/j.neuro.2016.08.009 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA EE3NT UT WOS:000389497000003 PM 27545874 ER PT J AU Golding, J Gregory, S Emond, A Iles-Caven, Y Hibbeln, J Taylor, CM AF Golding, Jean Gregory, Steven Emond, Alan Iles-Caven, Yasmin Hibbeln, Joseph Taylor, Caroline M. TI Prenatal mercury exposure and offspring behaviour in childhood and adolescence SO NEUROTOXICOLOGY LA English DT Article DE ALSPAC; Prenatal mercury exposure; Dietary fish; Child behaviour; Adolescent behaviour ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FISH CONSUMPTION; METHYLMERCURY EXPOSURE; DIFFICULTIES QUESTIONNAIRE; PREGNANT-WOMEN; COHORT; AGE; STRENGTHS; OUTCOMES; CHILDREN AB Background: There is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations. Material: Data were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16-17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10. Results: Prenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16-17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10-11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference. Conclusions: There were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters. (C) 2016 The Author(s). Published by Elsevier B.V. C1 [Golding, Jean; Gregory, Steven; Emond, Alan; Iles-Caven, Yasmin; Taylor, Caroline M.] Univ Bristol, Ctr Child & Adolescent Hlth, Bristol, Avon, England. [Hibbeln, Joseph] NIAAA, NIH, Rockville, MD 20852 USA. RP Golding, J (reprint author), Univ Bristol, Sch Social & Community Med, Ctr Child & Adolescent Hlth, Barley House, Bristol BS8 2BN, Avon, England. EM jean.golding@bristol.ac.uk OI Golding, Jean/0000-0003-2826-3307 FU Wellcome Trust [102215/2/13/2, 104077/Z/14/Z]; NOAA; Intramural Research Program of NIAAA, NIH FX We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol currently provide core support for ALSPAC. CMT was supported by a Wellcome Trust Career Re-Entry Fellowship (Grant ref: 104077/Z/14/Z). This publication is the work of the authors; Jean Golding and Steven Gregory will serve as guarantors for the contents of this paper.; The assays of the maternal blood samples were carried out at the Centers for Disease Control and Prevention with funding from NOAA, and the statistical analyses were carried out in Bristol with funding from NOAA and support from the Intramural Research Program of NIAAA, NIH. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC, NOAA or the NIH. NR 29 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2016 VL 57 BP 87 EP 94 DI 10.1016/j.neuro.2016.09.003 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA EE3NT UT WOS:000389497000011 PM 27633321 ER PT J AU Gage, JC Hunt, WC Schiffman, M Katki, HA Cheung, LA Myers, O Cuzick, J Wentzensen, N Kinney, W Castle, PE Wheeler, CM AF Gage, Julia C. Hunt, William C. Schiffman, Mark Katki, Hormuzd A. Cheung, Li A. Myers, Orrin Cuzick, Jack Wentzensen, Nicolas Kinney, Walter Castle, Philip E. Wheeler, Cosette M. CA New Mexico HPV Pap Registry TI Similar Risk Patterns After Cervical Screening in Two Large US Populations Implications for Clinical Guidelines SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS; UNITED-STATES; CANCER; WOMEN; CYTOLOGY; MANAGEMENT; HPV; PRECANCER AB OBJECTIVE: To compare the risks of histologic high-grade cervical intraepithelial neoplasia (CIN) or worse after different cervical cancer screening test results between two of the largest U.S. clinical practice research data sets. METHODS: The New Mexico Human Papillomavirus (HPV) Pap Registry is a statewide registry representing a diverse population experiencing varied clinical practice delivery. Kaiser Permanente Northern California is a large integrated health care delivery system practicing routine HPV cotesting since 2003. In this retrospective cohort study, a logistic-Weibull survival model was used to estimate and compare the cumulative 3- and 5-year risks of histologic CIN 3 or worse among women aged 21-64 years screened in 2007-2011 in the New Mexico HPV Pap Registry and 2003-2013 in Kaiser Permanente Northern California. Results were stratified by age and baseline screening result: negative cytology, atypical squamous cells of undetermined significance (ASC-US) (with or without HPV triage), low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion. RESULTS: There were 453,618 women in the New Mexico HPV Pap Registry and 1,307,528 women at Kaiser Permanente Northern California. The 5-year CIN 3 or worse risks were similar within screening results across populations: cytology negative (0.52% and 0.30%, respectively, P<001), HPV-negative and ASC-US (0.72% and 0.49%, respectively, P=.5), ASC-US (3.4% and 3.4%, respectively, P=.8), HPV-positive and ASC-US (7.7% and 7.1%, respectively, P=.3), low-grade squamous intraepithelial lesion (6.5% and 5.4%, respectively, P=.009), and high-grade squamous intraepithelial lesion (53.1% and 50.4%, respectively, P=.2). Cervical intraepithelial neoplasia grade 2 or worse risks and 3-year risks had similar trends across populations. Age-stratified analyses showed more variability, especially among women aged younger than 30 years, but patterns of risk stratification were comparable. CONCLUSION: Current U.S. cervical screening and management recommendations are based on comparative risks of histologic high-grade CIN after screening test results. The similar results from these two large cohorts from different real-life clinical practice settings support risk-based management thresholds across U.S. clinical populations and practice settings. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. Univ New Mexico, Hlth Sci Ctr, Dept Internal Med, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. Informat Management Serv Inc, Calverton, MD USA. Queen Mary Univ London, Wolfson Inst Prevent Med, Ctr Canc Prevent, London, England. Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. Albert Einstein Coll Med, New York, NY USA. RP Wheeler, CM (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Pathol, House Prevent Epidemiol HOPE,1816 Sigma Chi Rd NE, Albuquerque, NM 87131 USA. EM cwheeler@salud.unm.edu FU Qiagen; Roche; GenProbe/Hologic; Abbott; BD; Cepheid; Genera; Trovagene; University of New Mexico from Merck and Co., Inc. FX Dr. Schiffman and Dr. Gage have received HPV testing for research at no cost from Roche and BD. Dr. Cuzick has received research funding and reagents from Qiagen, Roche, GenProbe/Hologic, Abbott, BD, Cepheid, Genera, and Trovagene and has been personally compensated for Advisory Boards or Speakers Bureau activities from Trovagene, GenProbe/Hologic, Abbott, BD, Merck, and Cepheid. Dr. Wentzensen has received cervical cancer screening assays in-kind or at reduced cost from BD, Cepheid, Hologic, and Roche. Dr. Castle has received HPV tests and testing for research at a reduced or no cost from Qiagen and Roche, has been compensated for serving as a member on a Data and Safety Monitoring Board for Merck, and as a consultant for BD, Cepheid, Roche, GE Healthcare, ClearPath, Guided Therapeutics, and Gen-Probe/Hologic. Dr. Wheeler has received funding through the University of New Mexico from Merck and Co., Inc. and Glaxo SmithKline for human papillomavirus (HPV) vaccine studies and equipment and reagents from Roche Molecular Systems for HPV genotyping. The remaining authors did not report any potential conflicts of interest. NR 25 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD DEC PY 2016 VL 128 IS 6 BP 1248 EP 1257 DI 10.1097/AOG.0000000000001721 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE5KH UT WOS:000389645200008 PM 27824767 ER PT J AU Blackwell, SC Landon, MB Mele, L Reddy, UM Casey, BM Wapner, RJ Varner, MW Rouse, DJ Thorp, JM Sciscione, A Catalano, P Saade, G Caritis, SN Sorokin, Y Grobman, WA AF Blackwell, Sean C. Landon, Mark B. Mele, Lisa Reddy, Uma M. Casey, Brian M. Wapner, Ronald J. Varner, Michael W. Rouse, Dwight J. Thorp, John M., Jr. Sciscione, Anthony Catalano, Patrick Saade, George Caritis, Steve N. Sorokin, Yoram Grobman, William A. CA Eunice Kennedy Shriver Natl Inst TI Relationship Between Excessive Gestational Weight Gain and Neonatal Adiposity in Women With Mild Gestational Diabetes Mellitus SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BODY-MASS INDEX; PREGNANCY; OBESITY; OUTCOMES; INFANTS; MOTHERS AB OBJECTIVE: To evaluate the relationships among excessive gestational weight gain, neonatal adiposity, and adverse obstetric outcomes in women with mild gestational diabetes mellitus. METHODS: This is a secondary analysis of a multicenter randomized clinical trial of women with mild gestational diabetes mellitus. Based on self-reported prepregnancy body weight, gestational weight gain was categorized as excessive if it was greater than 2009 Institute of Medicine guidelines. Maternal outcomes and neonatal anthropomorphic characteristics were compared between women with excessive weight gain and those without excessive weight gain. Multiple linear and logistic regression analyses were performed to adjust for confounding factors. RESULTS: We studied 841 women who participated in the main trial and had prepregnancy body mass index (BMI) and delivery information available (n=431 treatment group, n=410 no treatment). After adjustment for factors including treatment and prepregnancy BMI, excessive weight gain remained associated with large for gestational age (adjusted odds ratio [OR] 2.94, 95% confidence interval [CI] 1.81-4.93), birth weight greater than 4,000 g (adjusted OR 2.56, 95% CI 1.54-4.40), preeclampsia (adjusted OR 2.96, 95% CI 1.35-7.03), and cesarean delivery for labor arrest (adjusted OR 2.37, 95% CI 1.30-4.44). In addition, excessive weight gain was independently associated with increased total neonatal fat (P<.001) and birth weight (P<. 001). CONCLUSION: In women with both treated and untreated mild gestational diabetes mellitus, excessive gestational weight gain was independently associated with both greater birth weight and adiposity. C1 Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Univ Texas Southwestern Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Drexel Univ, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. George Washington Univ, Dept Obstet & Gynecol, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Obstet & Gynecol, Bethesda, MD USA. RP Blackwell, SC (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, 6431 Fannin,Suite 3-286, Houston, TX 77030 USA. EM Sean.Blackwell@uth.tmc.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801]; General Clinical Research Centers Grant [M01-RR00034]; National Center for Research Resources [UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801), General Clinical Research Centers Grant (M01-RR00034), and the National Center for Research Resources (UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234). Comments and views of the authors do not necessarily represent views of the NICHD. NR 27 TC 0 Z9 0 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD DEC PY 2016 VL 128 IS 6 BP 1325 EP 1332 DI 10.1097/AOG.0000000000001773 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE5KH UT WOS:000389645200013 PM 27824768 ER PT J AU Veerappan, M El-Hage-Sleiman, AKM Tai, V Chiu, SJ Winter, KP Stinnett, SS Hwang, TS Hubbard, GB Michelson, M Gunther, R Wong, WT Chew, EY Toth, CA AF Veerappan, Malini El-Hage-Sleiman, Abdul-Karim M. Tai, Vincent Chiu, Stephanie J. Winter, Katrina P. Stinnett, Sandra S. Hwang, Thomas S. Hubbard, G. Baker, III Michelson, Michelle Gunther, Randall Wong, Wai T. Chew, Emily Y. Toth, Cynthia A. CA Age Related Eye Dis Study Ancillar TI Optical Coherence Tomography Reflective Drusen Substructures Predict Progression to Geographic Atrophy in Age-related Macular Degeneration SO OPHTHALMOLOGY LA English DT Article ID EYE DISEASE; AUTOMATIC SEGMENTATION; COMPLEMENT ACTIVATION; HYPERREFLECTIVE FOCI; IDENTIFICATION; MACULOPATHY; EPITHELIUM; PATHOLOGY; IMAGES; SDOCT AB Purpose: Structural and compositional heterogeneity within drusen comprising lipids, carbohydrates, and proteins have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography-reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)-related features and AMD progression. Design: Retrospective analysis in a prospective study. Participants: Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral-domain optical coherence tomography (SD OCT) study. Methods: Baseline SD OCT scans of 1 eye per patient were analyzed for the presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm-diameter region around individual ODS and corresponding control region without ODS in the same eye. Main Outcome Measures: Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs. Results: Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Among the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001-0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002-0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02-0.03) and (2) development of preatrophy changes at years 2 and 3 within the region (P = 0.008-0.05). Conclusions: Optical coherence tomography-reflective drusen substructures are optical coherence tomography-based biomarkers of progression to GA, but not to CNV, in eyes with intermediate AMD. Optical coherence tomography-reflective drusen substructures may be a clinical entity helpful in monitoring AMD progression and informing mechanisms in GA pathogenesis. (C) 2016 by the American Academy of Ophthalmology C1 [Veerappan, Malini; El-Hage-Sleiman, Abdul-Karim M.; Tai, Vincent; Chiu, Stephanie J.; Winter, Katrina P.; Stinnett, Sandra S.; Hubbard, G. Baker, III; Michelson, Michelle; Chew, Emily Y.] Duke Univ, Med Ctr, Duke Eye Ctr, 2351 Erwin Rd,Box 3802, Durham, NC 27710 USA. [Hwang, Thomas S.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Hubbard, G. Baker, III] Emory Univ, Emory Eye Ctr, Atlanta, GA 30322 USA. [Wong, Wai T.; Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Toth, Cynthia A.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. RP Veerappan, M (reprint author), Duke Univ, Med Ctr, Duke Eye Ctr, 2351 Erwin Rd,Box 3802, Durham, NC 27710 USA. EM malini.veerappan@dm.duke.edu RI Wong, Wai/B-6118-2017; OI Wong, Wai/0000-0003-0681-4016; Sleiman, Karim/0000-0002-4017-4908 FU National Eye Institute; Genentech; Alcon; Bioptigen FX The author(s) have made the following disclosure(s): A-K.M.E-H.S., V.T., K.P.W., S.S.S., T.S.H., G.B.H., M.M., R.G., W.T.W., and E.Y.C.: Grants - National Eye Institute, Genentech, Alcon, and Bioptigen during the conduct of the study.; S.J.C.: Grants - National Eye Institute, Genentech, Alcon, and Bioptigen during the conduct of the study; Patent - segmentation and identification of layered structures in images (US 20110182517 A1).; C.A.T.: Royalties - Alcon; Research grants for this study - National Eye Institute, Alcon, Bioptigen, and Genentech. NR 39 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2016 VL 123 IS 12 BP 2554 EP 2570 DI 10.1016/j.ophtha.2016.08.047 PG 17 WC Ophthalmology SC Ophthalmology GA EE3YZ UT WOS:000389539900023 PM 27793356 ER PT J AU Shantha, JG Crozier, I Varkey, JB Kraft, CS Lyon, GM Mehta, AK Carlson, RD Hill, CE Kumar, G Debiec, MR Patel, PS Olsen, TW Nussenblatt, RB Martin, DF Stroher, U Uyeki, TM Ribner, BS Franzco, JRS Yeh, S AF Shantha, Jessica G. Crozier, Ian Varkey, Jay B. Kraft, Colleen S. Lyon, G. Marshall, III Mehta, Aneesh K. Carlson, Renee Donahue Hill, Charles E. Kumar, Gokul Debiec, Matthew R. Patel, Purnima S. Olsen, Timothy W. Nussenblatt, Robert B. Martin, Daniel F. Stroeher, Ute Uyeki, Timothy M. Ribner, Bruce S. Franzco, Justine R. Smith Yeh, Steven TI Long-term Management of Panuveitis and Iris Heterochromia in an Ebola Survivor SO OPHTHALMOLOGY LA English DT Editorial Material ID VIRUS DISEASE C1 [Shantha, Jessica G.; Kumar, Gokul; Debiec, Matthew R.; Patel, Purnima S.; Olsen, Timothy W.; Yeh, Steven] Emory Univ, Sch Med, Emory Eye Ctr, Dept Ophthalmol, Atlanta, GA USA. [Crozier, Ian] Mulago Hosp Complex, Infect Dis Inst, Kampala, Uganda. [Varkey, Jay B.; Kraft, Colleen S.; Lyon, G. Marshall, III; Mehta, Aneesh K.; Carlson, Renee Donahue; Ribner, Bruce S.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Kraft, Colleen S.; Hill, Charles E.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. [Martin, Daniel F.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Stroeher, Ute; Uyeki, Timothy M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Franzco, Justine R. Smith] Flinders Univ S Australia, Adelaide, SA, Australia. RP Yeh, S (reprint author), 1365B Clifton Rd NE, Atlanta, GA 30322 USA. EM steven.yeh@emory.edu FU NCATS NIH HHS [UL1 TR000454]; NEI NIH HHS [P30 EY006360] NR 5 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2016 VL 123 IS 12 BP 2626 EP 2628 PG 3 WC Ophthalmology SC Ophthalmology GA EE3YZ UT WOS:000389539900031 PM 27594198 ER PT J AU Harrandah, AM Fitzpatrick, SG Smith, MH Wang, DR Cohen, DM Chan, EKL AF Harrandah, Amani M. Fitzpatrick, Sarah G. Smith, Molly H. Wang, Dunrui Cohen, Donald M. Chan, Edward K. L. TI MicroRNA-375 as a biomarker for malignant transformation in oral lesions SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID INHIBITS CELL-PROLIFERATION; PREMALIGNANT LESIONS; MIR-375 EXPRESSION; GASTRIC-CANCER; LEUKOPLAKIA; CARCINOMA; SURVIVAL; MIR-21; SIGNATURE; INVASION AB Objective. Malignant transformation of oral premalignant lesions is the key process in the progression to oral squamous cell carcinoma (OSCC). Previously, we identified miR-7 and miR-21 as candidate oncogenes and miR-375 and miR-494 as candidate tumor suppressors in OSCC. We aim to evaluate these microRNAs as biomarkers of malignant transformation in oral premalignant lesions. Study Design. Formalin-fixed, paraffin-embedded samples from progressive premalignant lesions and paired sequential OSCC tumors at the same site were obtained from same patients (n-31). Total RNA was extracted and analyzed for microRNA levels using real-time polymerase chain reaction. Results. MiR-375 expression in progressive lesions was clearly lower than in nonprogressive control lesions (average eightfold difference, P = .0004). Furthermore, the expression of miR-375 decreased significantly after the progression from premalignant lesion to OSCC (P < .0001). Receiver operating characteristic curve analysis revealed that miR-375 was able to differentiate between progressive and nonprogressive premalignant lesions (P < .0001). Conclusions. MiR-375 downregulation in oral premalignant lesions is associated with a higher risk of malignant transformation. C1 [Harrandah, Amani M.; Chan, Edward K. L.] Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL USA. [Fitzpatrick, Sarah G.; Smith, Molly H.; Cohen, Donald M.] Univ Florida, Coll Dent, Dept Oral & Maxillofacial Diagnost Sci, Gainesville, FL USA. [Wang, Dunrui] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chan, EKL (reprint author), Univ Florida, Dept Oral Biol, 1600 SW Archer Rd, Gainesville, FL 32610 USA. EM Echan@ufl.edu FU University of Florida institutional funds, Andrew J. Semesco Foundation, Ocala, Florida, USA; UMM ALQURA University, Saudi Arabia; Saudi Arabian Cultural Mission FX This study was funded by the University of Florida institutional funds, Andrew J. Semesco Foundation, Ocala, Florida, USA; UMM ALQURA University, Saudi Arabia; and Saudi Arabian Cultural Mission to the United States. NR 41 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 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD DEC PY 2016 VL 122 IS 6 BP 743 EP + DI 10.1016/j.oooo.2016.07.022 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EE3ZC UT WOS:000389540200016 PM 27720656 ER PT J AU Branham, K Matsui, H Biswas, P Guru, AA Hicks, M Suk, JJ Li, H Jakubosky, D Long, T Telenti, A Nariai, N Heckenlively, JR Frazer, KA Sieving, PA Ayyagari, R AF Branham, Kari Matsui, Hiroko Biswas, Pooja Guru, Aditya A. Hicks, Michael Suk, John J. Li, He Jakubosky, David Long, Tao Telenti, Amalio Nariai, Naoki Heckenlively, John R. Frazer, Kelly A. Sieving, Paul A. Ayyagari, Radha TI Establishing the involvement of the novel gene AGBL5 in retinitis pigmentosa by whole genome sequencing SO PHYSIOLOGICAL GENOMICS LA English DT Article DE ophthalmology; whole genome sequencing ID MUTATIONS; DISCOVERY; FRAMEWORK; DEGENERATION; ALIGNMENT; VARIANTS; ACCURATE; TUBULIN AB While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40-50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of IRD in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10. Sequence reads were aligned to hg19 using BWA-MEM and variant calling was performed with Genome Analysis Toolkit. The called variants were annotated with SnpEff v4.11, PolyPhen v2.2.2, and CADD v1.3. Copy number variations were called using Genome STRiP (svtoolkit 2.00.1611) and SpeedSeq software. Variants were filtered to detect rare potentially deleterious variants segregating with disease. Candidate variants were validated by dideoxy sequencing. Clinical evaluation revealed typical adolescent-onset recessive retinitis pigmentosa (arRP) in affected members. WGS identified about 4 million variants in each individual. Two rare and potentially deleterious compound heterozygous variants p.Arg281Cys and p.Arg487* were identified in the gene ATP/GTP binding protein like 5 (AGBL5) as likely causal variants. No additional variants in IRD genes that segregated with disease were identified. Mutation analysis confirmed the segregation of these variants with the IRD in the pedigree. Homology models indicated destabilization of AGBL5 due to the p.Arg281Cys change. Our findings establish the involvement of mutations in AGBL5 in RP and validate the WGS variant filtering pipeline we designed. C1 [Branham, Kari; Heckenlively, John R.] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Matsui, Hiroko; Li, He; Jakubosky, David; Nariai, Naoki; Frazer, Kelly A.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Biswas, Pooja; Guru, Aditya A.; Suk, John J.; Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, 9415 Campus Point Dr,JRC206, La Jolla, CA 92037 USA. [Hicks, Michael; Long, Tao; Telenti, Amalio] Human Longev Inc, San Diego, CA USA. [Frazer, Kelly A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Frazer, Kelly A.] Univ Calif San Diego, Rady Childrens Hosp, Div Genome Informat Sci, La Jolla, CA 92093 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. RP Ayyagari, R (reprint author), Univ Calif San Diego, Shiley Eye Inst, 9415 Campus Point Dr,JRC206, La Jolla, CA 92037 USA. EM rayyagari@ucsd.edu FU Foundation Fighting Blindness; Research to Prevent Blindness; National Eye Institute [EY-21237, P30-EY-22589] FX The Foundation Fighting Blindness, Research to Prevent Blindness (to Department of Ophthalmology at University of California San Diego, La Jolla, CA, and Kellogg Eye Center, University of Michigan, Ann Arbor, MI); National Eye Institute Grants EY-21237, P30-EY-22589. NR 33 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD DEC PY 2016 VL 48 IS 12 BP 922 EP 927 DI 10.1152/physiolgenomics.00101.2016 PG 6 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA EE5IL UT WOS:000389639700005 PM 27764769 ER PT J AU Hotaling, NA Jeon, J Wade, MB Luong, D Palmer, XL Bharti, K Simon, CG AF Hotaling, Nathan A. Jeon, Jun Wade, Mary Beth Luong, Derek Palmer, Xavier-Lewis Bharti, Kapil Simon, Carl G., Jr. TI Training to Improve Precision and Accuracy in the Measurement of Fiber Morphology SO PLOS ONE LA English DT Article ID NANOFIBER SCAFFOLD; IMAGE-ANALYSIS; DIFFERENTIATION; REPRODUCIBILITY; STANDARDS; DIAMETER; CELLS AB An estimated $7.1 billion dollars a year is spent due to irreproducibility in pre-clinical data from errors in data analysis and reporting. Therefore, developing tools to improve measurement comparability is paramount. Recently, an open source tool, DiameterJ, has been deployed for the automated analysis of scanning electron micrographs of fibrous scaffolds designed for tissue engineering applications. DiameterJ performs hundreds to thousands of scaffold fiber diameter measurements from a single micrograph within a few seconds, along with a variety of other scaffold morphological features, which enables a more rigorous and thorough assessment of scaffold properties. Herein, an online, publicly available training module is introduced for educating DiameterJ users on how to effectively analyze scanning electron micrographs of fibers and the large volume of data that a DiameterJ analysis yields. The end goal of this training was to improve user data analysis and reporting to enhance reproducibility of analysis of nanofiber scaffolds. User performance was assessed before and after training to evaluate the effectiveness of the training modules. Users were asked to use DiameterJ to analyze reference micrographs of fibers that had known diameters. The results showed that training improved the accuracy and precision of measurements of fiber diameter in scanning electron micrographs. Training also improved the precision of measurements of pore area, porosity, intersection density, and characteristic fiber length between fiber intersections. These results demonstrate that the DiameterJ training module improves precision and accuracy in fiber morphology measurements, which will lead to enhanced data comparability. C1 [Hotaling, Nathan A.; Palmer, Xavier-Lewis; Simon, Carl G., Jr.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Hotaling, Nathan A.; Jeon, Jun; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Wade, Mary Beth; Luong, Derek] Univ Akron, Dept Polymer Sci, Akron, OH 44325 USA. RP Hotaling, NA (reprint author), NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA.; Hotaling, NA (reprint author), NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. EM Nathan.Hotaling@nih.gov OI Hotaling, Nathan/0000-0001-8423-6464 NR 33 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2016 VL 11 IS 12 AR e0167664 DI 10.1371/journal.pone.0167664 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3JC UT WOS:000389482700221 PM 27907145 ER PT J AU Shevtsova, E Shevtsov, A Mukanov, K Filipenko, M Kamalova, D Sytnik, I Syzdykov, M Kuznetsov, A Akhmetova, A Zharova, M Karibaev, T Tarlykov, P Ramanculov, E AF Shevtsova, Elena Shevtsov, Alexandr Mukanov, Kasim Filipenko, Maxim Kamalova, Dinara Sytnik, Igor Syzdykov, Marat Kuznetsov, Andrey Akhmetova, Assel Zharova, Mira Karibaev, Talgat Tarlykov, Pavel Ramanculov, Erlan TI Epidemiology of Brucellosis and Genetic Diversity of Brucella abortus in Kazakhstan SO PLOS ONE LA English DT Article ID TANDEM-REPEAT ANALYSIS; MELITENSIS; STRAIN; MLVA; REEMERGENCE; COUNTRIES; DISEASE; VACCINE; HEALTH; CATTLE AB Brucellosis is a major zoonotic infection in Kazakhstan. However, there is limited data on its incidence in humans and animals, and the genetic diversity of prevalent strains is virtually unstudied. Additionally, there is no detailed overview of Kazakhstan brucellosis control and eradication programs. Here, we analyzed brucellosis epidemiological data, and assessed the effectiveness of eradication strategies employed over the past 70 years to counteract this infection. We also conducted multiple loci variable-number tandem repeat analysis (MLVA) of Brucella abortus strains found in Kazakhstan. We analyzed official data on the incidence of animal brucellosis in Kazakhstan. The records span more than 70 years of anti-brucellosis campaigns, and contain a brief description of the applied control strategies, their effectiveness, and their impact on the incidence in humans. The MLVA-16 method was used to type 94 strains of B. abortus and serial passages of B. abortus 82, a strain used in vaccines. MLVA-8 and MLVA-11 analyses clustered strains into a total of four and seven genotypes, respectively; it is the first time that four of these genotypes have been described. MLVA-16 analysis divided strains into 28 distinct genotypes having genetic similarity coefficient that varies from 60 to100% and a Hunter & Gaston diversity index of 0.871. MST analysis reconstruction revealed clustering into "Kazakhstani-Chinese (Central Asian)", "European" and "American" lines. Detection of multiple genotypes in a single outbreak confirms that poorly controlled trade of livestock plays a crucial role in the spread of infection. Notably, the MLVA-16 profile of the B. abortus 82 strain was unique and did not change during 33 serial passages. MLVA genotyping may thus be useful for epidemiological monitoring of brucellosis, and for tracking the source(s) of infection. We suggest that countrywide application of MLVA genotyping would improve the control of brucellosis in Kazakhstan. C1 [Shevtsova, Elena; Shevtsov, Alexandr; Mukanov, Kasim; Filipenko, Maxim; Kamalova, Dinara; Tarlykov, Pavel] Natl Biotechnol Ctr, Astana, Kazakhstan. [Filipenko, Maxim] Inst Chem Biol & Fundamental Med, Novosibirsk, Russia. [Filipenko, Maxim] Novosibirsk State Univ, Novosibirsk, Russia. [Sytnik, Igor; Akhmetova, Assel; Zharova, Mira; Karibaev, Talgat] Natl Reference Ctr Vet, Astana, Kazakhstan. [Syzdykov, Marat; Kuznetsov, Andrey] Kazakh Sci Ctr Quarantine & Zoonot Dis, Alma Ata, Kazakhstan. [Ramanculov, Erlan] Nazarbayev Univ, Sch Sci & Technol, Astana, Kazakhstan. RP Shevtsov, A (reprint author), Natl Biotechnol Ctr, Astana, Kazakhstan. EM ncbshevtsov@gmail.com RI Kuznetsov, Andrey/K-8824-2014; Tarlykov, Pavel/C-2587-2012 OI Kuznetsov, Andrey/0000-0003-2354-533X; Tarlykov, Pavel/0000-0003-2075-307X FU Ministry of Education and Science of the Republic of Kazakhstan [N0115RK01870] FX This work was supported by funding received from the Ministry of Education and Science of the Republic of Kazakhstan, grant no. N0115RK01870. AS received the funding. (http://sc.edu.gov.kz/main/?L=2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2016 VL 11 IS 12 AR e0167496 DI 10.1371/journal.pone.0167496 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3JC UT WOS:000389482700170 PM 27907105 ER PT J AU Winther, M Holdfeldt, A Gabl, M Wang, JM Forsman, H Dahlgren, C AF Winther, Malene Holdfeldt, Andre Gabl, Michael Wang, Ji Ming Forsman, Huamei Dahlgren, Claes TI Formylated MHC Class lb Binding Peptides Activate Both Human and Mouse Neutrophils Primarily through Formyl Peptide Receptor 1 SO PLOS ONE LA English DT Article ID CLASS-IB MOLECULE; STAPHYLOCOCCUS-AUREUS; RESPIRATORY BURST; LIGAND; RESPONSES; H2-M3; FPR; TUBERCULOSIS; INFLAMMATION; RECOGNITION AB Two different immune recognition systems have evolved in parallel to recognize peptides starting with an N-formylated methionine, and recognition similarities/differences between these two systems have been investigated. A number of peptides earlier characterized in relation to the H2-M3 complex that presents N-formylated peptides to cytotoxic T cells, have been characterized in relation to the formyl peptide receptors expressed by phagocytic neutrophils in both men (FPRs) and mice (Fprs). FPR1/Fpr1 was identified as the preferred receptor for all fMet-containing peptides examined, but there was no direct correlation between H2-M3 binding and the neutrophil activation potencies. Similarly, there was no direct correlation between the activities induced by the different peptides in human and mouse neutrophils, respectively. The formyl group was important in both H2-M3 binding and FPR activation, but FPR2 was the preferred receptor for the non-formylated peptide. The structural requirements differed between the H2-M3 and FPR/Fpr recognition systems and these data suggest that the two recognition systems have different evolutionary traits. C1 [Winther, Malene; Holdfeldt, Andre; Gabl, Michael; Forsman, Huamei; Dahlgren, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden. [Wang, Ji Ming] Frederick Natl Lab Canc Res, Ctr Canc Res, Frederick, MD USA. RP Dahlgren, C (reprint author), Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden. EM Claes.Dahlgren@microbio.gu.se FU Swedish research council; King Gustaf the Vth 80-year foundation; Clas Groschinsky foundation; Ake Wiberg foundation; IngaBritt and Arne Lundbergs foundation; Sahlgrenska university hospital FX The research was supported by grants from the Swedish research council, The King Gustaf the Vth 80-year foundation, the Clas Groschinsky foundation, the Ake Wiberg foundation, from IngaBritt and Arne Lundbergs foundation, and the Sahlgrenska university hospital through the national ALF-agreement. The funding agencies had no influence on the study design, data collection and analysis, or writing and submission of the report.; We thank the members of the Phagocyte Research Group at the Sahlgrenska Academy for critically discussing the results and the manuscript. The research was supported by grants from the Swedish research council, The King Gustaf the Vth 80-year foundation, the Clas Groschinsky foundation, the Ake Wiberg foundation, from IngaBritt and Arne Lundbergs foundation and, the Sahlgrenska university hospital through the national ALF-agreement. The funding agencies had no influence on the study design, data collection and analysis, or writing and submission of the report. NR 34 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2016 VL 11 IS 12 AR e0167529 DI 10.1371/journal.pone.0167529 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3JC UT WOS:000389482700184 PM 27907124 ER PT J AU Hales, CM Dammer, EB Deng, QD Duong, DM Gearing, M Troncoso, JC Thambisetty, M Lah, JJ Shulman, JM Levey, AI Seyfried, NT AF Hales, Chadwick M. Dammer, Eric B. Deng, Qiudong Duong, Duc M. Gearing, Marla Troncoso, Juan C. Thambisetty, Madhav Lah, James J. Shulman, Joshua M. Levey, Allan I. Seyfried, Nicholas T. TI Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression SO PROTEOMICS LA English DT Article DE Aggregation; Biomedicine; Mass spectrometry; Neurodegeneration; Proteostasis; Spliceosome ID A-BETA; NEURODEGENERATIVE DISEASE; NEUROFIBRILLARY TANGLES; PROTEINS; DEMENTIA; TOXICITY; COMPLEX; THERAPEUTICS; AGGREGATION; ASSOCIATION AB Despite a key role of amyloid-beta (A beta) in Alzheimer's disease (AD), mechanisms that link A beta plaques to tau neurofibrillary tangles and cognitive decline still remain poorly understood. The purpose of this study was to quantify proteins in the sarkosyl-insoluble brain proteome correlated with A beta and tau insolubility in the asymptomatic phase of AD (AsymAD) and through mild cognitive impairment (MCI) and symptomatic AD. Employing label-free mass spectrometry-based proteomics, we quantified 2711 sarkosyl-insoluble proteins across the prefrontal cortex from 35 individual cases representing control, AsymAD, MCI and AD. Significant enrichment of A beta and tau in AD was observed, which correlated with neuropathological measurements of plaque and tau tangle density, respectively. Pairwise correlation coefficients were also determined for all quantified proteins to A beta and tau, across the 35 cases. Notably, six of the ten most correlated proteins to A beta were U1 small nuclear ribonucleoproteins (U1 snRNPs). Three of these U1 snRNPs (U1A, SmD and U1-70K) also correlated with tau consistent with their association with tangle pathology in AD. Thus, proteins that cross-correlate with both A beta and tau, including specific U1 snRNPs, may have potential mechanistic roles in linking A beta plaques to tau tangle pathology during AD progression. C1 [Hales, Chadwick M.; Lah, James J.; Levey, Allan I.; Seyfried, Nicholas T.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Hales, Chadwick M.; Dammer, Eric B.; Deng, Qiudong; Duong, Duc M.; Gearing, Marla; Lah, James J.; Levey, Allan I.; Seyfried, Nicholas T.] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA USA. [Dammer, Eric B.; Deng, Qiudong; Duong, Duc M.; Seyfried, Nicholas T.] Emory Univ, Sch Med, Dept Biochem, 1510 Clifton Rd, Atlanta, GA 30322 USA. [Gearing, Marla] Emory Univ, Sch Med, Dept Expt Pathol, Atlanta, GA USA. [Troncoso, Juan C.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Troncoso, Juan C.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Thambisetty, Madhav] NIA, NIH, Baltimore, MD 21224 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Jan & Dan Duncan Neurol Res Inst, Dept Neurol, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Jan & Dan Duncan Neurol Res Inst, Dept Neurosci, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Jan & Dan Duncan Neurol Res Inst, Dept Mol & Human Genet, Houston, TX 77030 USA. [Shulman, Joshua M.] Texas Childrens Hosp, Baylor Coll Med, Jan & Dan Duncan Neurol Res Inst, Program Dev Biol, Houston, TX 77030 USA. RP Seyfried, NT (reprint author), Emory Univ, Sch Med, Dept Biochem, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM nseyfri@emory.edu FU Accelerating Medicine Partnership AD [U01AG046161-02]; NINDS Emory Neuroscience Core [P30NS055077]; Johns Hopkins Alzheimer's Disease Research Center [P50AG05146]; Emory Alzheimer's Disease Research Center [P50AG025688]; Intramural Research Program of the NIH, National Institute on Aging; NINDS [K08NS087121]; American Brain Foundation; Alzheimer's Association (ALZ); Alzheimer's Research UK (ARUK); Michael J. Fox Foundation for Parkinson's Research (MJFF); Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant [11060]; BrightFocus Foundation [A2015332S] FX We are grateful to participants in the Baltimore Longitudinal Study of Aging (BLSA) and Emory brain bank donors for their invaluable contribution. Funding: Support was provided by the Accelerating Medicine Partnership AD grant U01AG046161-02, the NINDS Emory Neuroscience Core (P30NS055077), the Johns Hopkins Alzheimer's Disease Research Center (P50AG05146), and the Emory Alzheimer's Disease Research Center (P50AG025688). This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. CMH is supported by NINDS K08NS087121 and by the American Brain Foundation. NTS is supported in part by an Alzheimer's Association (ALZ), Alzheimer's Research UK (ARUK), The Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant (11060). JCT was also supported by a BrightFocus Foundation (A2015332S). NR 64 TC 0 Z9 0 U1 10 U2 10 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 DEC PY 2016 VL 16 IS 23 BP 3042 EP 3053 DI 10.1002/pmic.201600057 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ED9VA UT WOS:000389220000013 PM 27718298 ER PT J AU Wood, CS Weis, CP Caro, CM Roe, A AF Wood, Carol S. Weis, Christopher P. Caro, Carla M. Roe, Amy TI A practice analysis of toxicology SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Toxicology; Practice analysis; Delineation; Examination specifications AB In 2015, the American Board of Toxicology (ABT), with collaboration from the Society of Toxicology (SOT), in consultation with Professional Examination Service, performed a practice analysis study of the knowledge required for general toxicology. The purpose of this study is to help assure that the examination and requirements for attainment of Diplomate status are relevant to modern toxicology and based upon an empirical foundation of knowledge. A profile of the domains and tasks used in toxicology practice was developed by subject-matter experts representing a broad range of experiences and perspectives. An on-line survey of toxicologists, including Diplomates of the ABT and SOT members, confirmed the delineation. Results of the study can be used to improve understanding of toxicology practice, to better serve all toxicologists, and to present the role of toxicologists to those outside the profession. Survey results may also be used by the ABT Board of Directors to develop test specifications for the certifying examination and will be useful for evaluating and updating the content of professional preparation, development, and continuing education programs. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Wood, Carol S.] Oak Ridge Natl Lab, POB 2008,Bldg 1507,MS 6407, Oak Ridge, TN 38501 USA. [Weis, Christopher P.] NIEHS, 31 Ctr Dr,Bldg 31,Room B1C02, Bethesda, MD 20892 USA. [Caro, Carla M.] Profess Exam Serv, 475 Riverside Dr,6th Floor, New York, NY 10115 USA. [Roe, Amy] Procter & Gamble Co, 8700 Mason Montgomery Rd, Cincinnati, OH 45040 USA. RP Wood, CS (reprint author), Oak Ridge Natl Lab, POB 2008,Bldg 1507,MS 6407, Oak Ridge, TN 38501 USA. NR 3 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 0273-2300 EI 1096-0295 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD DEC PY 2016 VL 82 BP 140 EP 146 DI 10.1016/j.yrtph.2016.09.017 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA EE6PU UT WOS:000389735500013 PM 27647630 ER PT J AU Ferguson, KK Cantonwine, DE McElrath, TF Mukherjee, B Meeker, JD AF Ferguson, Kelly K. Cantonwine, David E. McElrath, Thomas F. Mukherjee, Bhramar Meeker, John D. TI Repeated measures analysis of associations between urinary bisphenol-A concentrations and biomarkers of inflammation and oxidative stress in pregnancy SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE BPA; Oxidative stress; Inflammation; IL-6; Pregnancy; Biomarkers; Longitudinal ID C-REACTIVE PROTEIN; PHTHALATE METABOLITE; PRETERM BIRTH; HUMAN EXPOSURE; RISK; MARKERS; GROWTH; WOMEN; VARIABILITY; GENERATION AB Bisphenol-A (BPA) exposure occurs commonly and may adversely impact pregnancy. Endocrine disruption is posited as the primary mechanism of action, but oxidative stress and inflammation pathways may also be important. We investigated associations between BPA exposure and oxidative stress and inflammation in 482 pregnant women. Participants were recruited early in pregnancy and provided urine and plasma at up to four visits. We measured total BPA and two biomarkers of oxidative stress (8-hydroxydeoxyguanosine and 8-isoprostane) in urine from each visit. Inflammation markers, including C-reactive protein and four cytokines were measured in plasma from the same time points. In adjusted models, an interquartile range increase in BPA was associated with significant increases in both oxidative stress biomarkers (5-9% increase). Additionally, we observed significantly higher IL-6 concentrations in association with an interquartile range increase in BPA (8.95% increase). These systemic changes consequent to BPA exposure may mediate adverse birth outcomes and/or fetal development. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ferguson, Kelly K.] Natl Inst Environm Hlth Sci, Epidemiol Branch, 111 TW Alexander Dr, Res Triangle Pk, NC USA. [Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Cantonwine, David E.; McElrath, Thomas F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, 75 Francis St, Boston, MA USA. [Mukherjee, Bhramar] Univ Michigan, Sch Publ Hlth, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI 48109 USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI Ferguson, Kelly/0000-0001-8467-3250 FU National Institute of Environmental Health Sciences, National Institutes of Health [R01ES018872, P42ES017198, P30ES017885] FX Funding was provided by the National Institute of Environmental Health Sciences, National Institutes of Health, grant numbers: R01ES018872, P42ES017198, and P30ES017885. NR 40 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 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD DEC PY 2016 VL 66 BP 93 EP 98 DI 10.1016/j.reprotox.2016.10.002 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA EE5XS UT WOS:000389683500010 PM 27751756 ER PT J AU Makanjuola, V Esan, Y Oladeji, B Kola, L Appiah-Poku, J Harris, B Othieno, C Price, L Seedat, S Gureje, O AF Makanjuola, Victor Esan, Yomi Oladeji, Bibilola Kola, Lola Appiah-Poku, John Harris, Benjamin Othieno, Caleb Price, Leshawndra Seedat, Soraya Gureje, Oye TI Explanatory model of psychosis: impact on perception of self-stigma by patients in three sub-saharan African cities SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Explanatory model; Psychosis; Self-stigma; Sub-saharan Africa; Religious theme ID SCHIZOPHRENIA SPECTRUM DISORDERS; COMMON MENTAL-DISORDERS; INTERNALIZED STIGMA; TRADITIONAL HEALERS; ILLNESS-SCALE; SOUTH-INDIA; PEOPLE; COMMUNITY; EXPERIENCES; OUTPATIENTS AB Most cultures in sub-Saharan Africa subscribe to the belief that the root cause of psychosis is supernatural. Individuals in the community who hold a religiomagical explanatory model of causation have been shown to exhibit more stigmatizing attitudes towards people with psychosis. Self-stigma among individuals with psychosis is less frequently studied. We used a mixed-method approach, consisting of key informant's interviews to elicit information on explanatory models of causation of psychosis and questionnaire assessment of internalized stigma with an adapted version of the Scale for Internalized Stigma of Mental Illness. Twenty-four, 31, and 30 subjects with recent experience of utilizing the service of traditional or faith healers for severe mental disorders in Ibadan (Nigeria), Kumasi (Ghana), and Nairobi (Kenya), respectively, were interviewed. About 44 % (42.1 %) of the Nigerian respondents had a high (severe) level of self-stigma with the respective proportions among Ghanaian and Kenyan respondents being 20.7 and 37.5 %. Compared with 4 out of a total of 12 respondents (33.3 %) who reported low self-stigma reported supernatural attribution, 14 out of 20 respondents (70 %) with the highest level of self-stigma reported supernatural attribution across the three sites. When low scorers ascribed supernatural causation, it was often with a religious focus. There is a greater tendency for persons with high levels of self-stigma than those with low levels to ascribe supernatural attribution to their experience of a severe mental health condition. C1 [Makanjuola, Victor; Esan, Yomi; Oladeji, Bibilola; Gureje, Oye] Univ Ibadan, Dept Psychiat, Ibadan, Nigeria. [Kola, Lola] World Hlth Org Country Off, Abuja, Nigeria. [Appiah-Poku, John] Kwame Nkuruma Univ Sci & Technol, Kumasi, Ghana. [Harris, Benjamin] Univ Liberia, Monrovia, Liberia. [Othieno, Caleb] Univ Nairobi, Nairobi, Kenya. [Price, Leshawndra] NIMH, Bethesda, MD 20892 USA. [Seedat, Soraya] Univ Stellenbosch, Stellenbosch, South Africa. RP Makanjuola, V (reprint author), Univ Ibadan, Dept Psychiat, Ibadan, Nigeria. EM vmakanjuola@yahoo.com OI MAKANJUOLA, VICTOR/0000-0001-7449-0506 NR 48 TC 0 Z9 0 U1 8 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD DEC PY 2016 VL 51 IS 12 BP 1645 EP 1654 DI 10.1007/s00127-016-1274-8 PG 10 WC Psychiatry SC Psychiatry GA EE4XL UT WOS:000389608800008 PM 27491966 ER PT J AU Lyden, P Weymer, S Coffey, C Cudkowicz, M Berg, S O'Brien, S Fisher, M Haley, EC Khatri, P Saver, J Levine, S Levy, H Rymer, M Wechsler, L Jadhav, A McNeil, E Waddy, S Pryor, K AF Lyden, Patrick Weymer, Sara Coffey, Chris Cudkowicz, Merit Berg, Samantha O'Brien, Sarah Fisher, Marc Haley, E. Clarke Khatri, Pooja Saver, Jeff Levine, Steven Levy, Howard Rymer, Marilyn Wechsler, Lawrence Jadhav, Ashutosh McNeil, Elizabeth Waddy, Salina Pryor, Kent TI Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection SO STROKE LA English DT Article DE activated protein C; clinical trial; neuroprotective agents; thrombectomy; thrombolysis ID ACUTE ISCHEMIC-STROKE; ACTIVATED PROTEIN-C; TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS THROMBOLYSIS; ANTICOAGULANT ACTIVITY; ENDOVASCULAR TREATMENT; REPERFUSION INJURY; RANDOMIZED-TRIALS; CEREBRAL-ISCHEMIA; ANIMAL-MODELS AB Background and Purpose-The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. Methods-The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. Results-Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. Conclusions-It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. C1 [Lyden, Patrick] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Weymer, Sara; Levy, Howard; Pryor, Kent] ZZ Biotech LLC, Houston, TX USA. [Coffey, Chris; O'Brien, Sarah] Univ Iowa, Dept Biostat, Iowa City, IA USA. [Cudkowicz, Merit; Berg, Samantha] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. [Fisher, Marc] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Haley, E. Clarke] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Khatri, Pooja] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA. [Saver, Jeff] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Levine, Steven] Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY 11203 USA. [Rymer, Marilyn] Univ Kansas Hosp, Dept Neurol, Kansas City, MO USA. [Wechsler, Lawrence; Jadhav, Ashutosh] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [McNeil, Elizabeth; Waddy, Salina] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Weymer, Sara] Fate Therapeut, San Diego, CA USA. [McNeil, Elizabeth] Biogen, Cambridge, MA USA. RP Lyden, P (reprint author), Dept Neurol, 127 S San Vicente Blvd,AHSP A6417, Los Angeles, CA 90048 USA. EM lydenp@cshs.org FU National Institutes of Neurological Disorders and Stroke [U01NS088312]; National Institutes of Neurological Disorders and Stroke (Clinical Coordinating Center) [U01NS077179]; National Institutes of Neurological Disorders and Stroke (Data Coordinating Center) [U01NS077352] FX This study was funded by the National Institutes of Neurological Disorders and Stroke (U01NS088312). The NeuroNEXT Network is supported by the National Institutes of Neurological Disorders and Stroke (Clinical Coordinating Center: U01NS077179; Data Coordinating Center: U01NS077352). NR 39 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 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 2979 EP 2985 DI 10.1161/STROKEAHA.116.013881 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200029 PM 27803392 ER PT J AU Tokar, EJ AF Tokar, Erik J. TI MicroRNAs: small molecules with big effects SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Editorial Material C1 [Tokar, Erik J.] NIEHS, Stem Cell Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Tokar, EJ (reprint author), Div Natl Toxicol Program, Natl Toxicol Program Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM tokare@niehs.nih.gov NR 5 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2016 VL 312 SI SI BP 1 EP 2 DI 10.1016/j.taap.2016.11.004 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE8JA UT WOS:000389870300001 PM 27927287 ER PT J AU Smith, RC Barillas-Mury, C AF Smith, Ryan C. Barillas-Mury, Carolina TI Plasmodium Oocysts: Overlooked Targets of Mosquito Immunity SO TRENDS IN PARASITOLOGY LA English DT Review ID MALARIA PARASITE DEVELOPMENT; IN-VIVO ANALYSIS; ANOPHELES-GAMBIAE; AEDES-AEGYPTI; FUNCTIONAL-CHARACTERIZATION; ANTIPLASMODIAL IMMUNITY; DROSOPHILA MODEL; MIDGUT INVASION; PROTEIN; INFECTION AB Although the ability of mosquitoes to limit Plasmodium infection is well documented, many questions remain as to how malaria parasites are recognized and killed by the mosquito host. Recent evidence suggests that anti Plasmodium immunity is multimodal, with different immune mechanisms regulating ookinete and oocyst survival. However, most experiments determine the number of mature oocysts, without considering that different immune mechanisms may target different developmental stages of the parasite. Complement-like proteins have emerged as important determinants of early immunity targeting the ookinete stage, yet the mechanisms by which the mosquito late-phase immune response limits oocyst survival are less understood. Here, we describe the known components of the mosquito immune system that limit oocyst development, and provide insight into their possible mechanisms of action. C1 [Smith, Ryan C.] Iowa State Univ, Dept Entomol, Ames, IA 50011 USA. [Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Smith, RC (reprint author), Iowa State Univ, Dept Entomol, Ames, IA 50011 USA. EM smithr@iastate.edu FU Agricultural Experiment Station at Iowa State University; 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 Agricultural Experiment Station at Iowa State University (to R.C.S.) and by the intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to C.B.M.), NR 99 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 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD DEC PY 2016 VL 32 IS 12 BP 979 EP 990 DI 10.1016/j.pt.2016.08.012 PG 12 WC Parasitology SC Parasitology GA EE6OZ UT WOS:000389733400010 PM 27639778 ER PT J AU Bartlett, DH Silk, SB AF Bartlett, Doreen H. Silk, Susan B. TI Office of Laboratory Animal Welfare Comments SO ZEBRAFISH LA English DT Article DE PHS Policy; OLAW; vertebrate animal; guide; performance standards; Animal Welfare Assurance AB In support of the new column in Zebrafish dedicated to initiating conversations about animal care policies and compliance for the zebrafish, the Office of Laboratory Animal Welfare (OLAW) has offered the following clarification and guidance. C1 [Bartlett, Doreen H.; Silk, Susan B.] NIH, Off Lab Anim Welf, Bldg 10, Bethesda, MD 20892 USA. RP Bartlett, DH (reprint author), NIH, Off Lab Anim Welf, Bldg 10, Bethesda, MD 20892 USA. EM olawdoa@mail.nih.gov NR 5 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 EI 1557-8542 J9 ZEBRAFISH JI Zebrafish PD DEC PY 2016 VL 13 IS 6 BP 563 EP 564 DI 10.1089/zeb.2016.1344 PG 2 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA EE2MJ UT WOS:000389418100015 PM 27779465 ER PT J AU Landovitz, RJ Tran, TTT Cohn, SE Ofotokun, I Godfrey, C Kuritzkes, DR Lennox, JL Currier, JS Ribaudo, HJ AF Landovitz, Raphael J. Tran, Thuy Tien T. Cohn, Susan E. Ofotokun, Ighovwhera Godfrey, Catherine Kuritzkes, Daniel R. Lennox, Jeffrey L. Currier, Judith S. Ribaudo, Heather J. TI HIV Transmission Risk Behavior in a Cohort of HIV-Infected Treatment-Na < ve Men and Women in the United States SO AIDS AND BEHAVIOR LA English DT Article DE Condom use; HIV transmission; ART-naive; Behavior ID EARLY ANTIRETROVIRAL THERAPY; SEXUAL-BEHAVIOR; PREVENTION; PROPHYLAXIS; INITIATION; IMPACT; ADULTS; KENYA AB Antiretroviral therapy (ART) can minimize HIV transmission. Prevention benefits may be compromised by barriers to virologic suppression, and by increased condomless sex among those initiating ART. We evaluated condomless sex in a cohort of HIVinfected US individuals poised to initiate ART in a clinical trial. We assessed partner and sex act type, condom use, and perception of infectiousness. Six percent of participants reported as not infectious; men who have sex with men were more likely to perceive high infectivity. Prevalence of condomless sex was 44 %; 74 % of those also reported homosexual acquisition of HIV. Predictors of increased risk of condomless sex included greater numbers of lifetime partners, recent stimulant drug use and an HIV-positive or unknown serostatus partner. In the context of serodifferent partners, lower perception of infectiousness was also associated with a higher risk of condomless sex. Results highlight opportunities for prevention education for HIV infected individuals at ART initiation. C1 [Landovitz, Raphael J.; Currier, Judith S.] Univ Calif Los Angeles, Div Infect Dis, UCLA Ctr Clin AIDS Res & Educ, 11075 Santa Monica Blvd,Suite 100, Los Angeles, CA 90025 USA. [Tran, Thuy Tien T.; Ribaudo, Heather J.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Cohn, Susan E.] Northwestern Univ, Sch Med, Div Infect Dis, Chicago, IL USA. [Ofotokun, Ighovwhera; Lennox, Jeffrey L.] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA. [Godfrey, Catherine] NIH, Div Aids, Therapeut Res Branch, Bldg 10, Bethesda, MD 20892 USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Landovitz, RJ (reprint author), Univ Calif Los Angeles, Div Infect Dis, UCLA Ctr Clin AIDS Res & Educ, 11075 Santa Monica Blvd,Suite 100, Los Angeles, CA 90025 USA. EM rlandovitz@mednet.ucla.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR); AIDS Clinical Trials Group; Site Data Management Center Grant [UM1AI68634]; ACTG; CTSA [UL1 TR000445, 1UL1TR001111, UL1 TR001082, UL1TR000124, UL1 TR024160, UL1 TR000454, UL1 TR000170, UL1TR000439, UL1TR001079, UL1TR000058, 5UL1 RR024156, UL1TR000457]; CFAR [P30 AI50410, 5-P30-AI-045008-15, P30 AI050409, P30 AI060354]; Cathi Basler-University of Colorado Hospital CRS [2UM1AI069432]; UCLA CARE Center CRS [A1069424]; Univ. of Rochester ACTG CRS/AIDS CARE CRS/Trillium Health [2UM1 AI069511-08]; Maria Laura Martinez-Houston AIDS Research Team CRS [2 UM1 AI069503-08, 2 UM1 AI068636-08]; CPCRA CTU [UM1 AI069503]; RN- UCSF HIV/AIDS CRS [UM1 AI069496]; UCSF-CTSA [UL1 TR000004]; [AI069439]; [UM1AI069494]; [AI69432]; [2UM1AI069439-08]; [UM1 AI069423-08]; [UM1AI069439]; [2UM1AI069452-08]; [AI069432]; [AI069424]; [UM1-AI069534-08]; [U01 AI069471]; [2UM1AI069415-09]; [5U01 AI069471]; [A1069423-08]; [2UM1A1069412-08]; [2UM1 AI069418-08]; [UM 1 A1069503]; [AI069477]; [UM1AI069472]; [AI 69501]; [2UM1AI069503-08]; [UM1 AI069532]; [UM AI069481]; [2UM1 AI069465]; [AI-069471]; [AI069501]; [1U01AI069494]; [5UM1 AI069484-07]; [2UM1-AI069470-08]; [AI069556]; [U01AI069447]; [UM1AI069419]; [2UM1AI069412-08]; [UM1 AI069494] FX The project described was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). 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. The study team would like to additionally thank the ACTG CRS's that conducted the A5257 protocol and the A5257 study participants. The protocol received support from the AIDS Clinical Trials Group, the Site Data Management Center Grant of UM1AI68634, the ACTG specialty laboratories listed in the manuscript, and the clinical research sites. From the sites we acknowledge the following personnel and AIDS Clinical Trials Unit Grants: Michelle Saemann, RN and Jennifer Baer, RN-Cincinnati CRS (Site 2401) Grant AI069439; Dr. Susan Koletar, Mark Hite RN-Ohio State University CRS (Site 2301) Grant UM1AI069494; Linda Meixner, RN and Edward Seefried, RN-UCSD Antiviral Research Center CRS (Site 701) Grant AI69432; Vicki Bailey, RN and Rebecca Basham, CCRP- Vanderbilt Therapeutics CRS (Site 3652) Grant 2UM1AI069439-08, CTSA Grant UL1 TR000445; David Currin RN and Miriam Chicurel-Bayard RN-Chapel Hill CRS (Site 3201) Grant UM1 AI069423-08, CTSA Grant 1UL1TR001111, CFAR Grant P30 AI50410; Teresa Spitz and Judy Frain-Washington University Therapeutics CRS (Site 2101) Grant UM1AI069439; Elizabeth Lindsey, RN and Tamara James -Alabama Therapeutics CRS (Site 5801) Grant 2UM1AI069452-08; Beverly Putnam and Cathi Basler-University of Colorado Hospital CRS (Site 6101) Grant 2UM1AI069432, CTSA Grant UL1 TR001082; Michael P. Dube, MD and Bartolo Santos, RN-University of Southern California CRS (Site 1201) Grant AI069432; Eric Daar and Sadia Shaik Harbor UCLA CRS (Site 603) Grant AI069424, CTSA Grant UL1TR000124; Pablo TebasMD and Aleshia Thomas RN, BSN-Penn Therapeutics CRS (Site 6201) Grant UM1-AI069534-08, CFAR Grant 5-P30-AI-045008-15; Roger Bedimo, MD and Michelle Mba, MPHTrinity Health and Wellness Center (Site 31443) Grant U01 AI069471; David Cohn MD and Fran Moran RN-Denver Public Health CRS (Site 31470) Grant UM1 AI069503; Jorge L. Santana Bagur, MD and Ileana Boneta Dueno, RN-Puerto Rico AIDS Clinical Trials Unit CRS (Site 5401) Grant 2UM1AI069415-09; Babafemi Taiwo, MBBS, Baiba Berzins, MPH-Northwestern University CRS (Site 2701) Grant 5U01 AI069471; Dr. Emery Chang and Maria Palmer-UCLA CARE Center CRS (Site 601) Grant A1069424; Mary Adams, RN and Christine Hurley, RN - Univ. of Rochester ACTG CRS/AIDS CARE CRS/Trillium Health (Site 1101/Site 1108) Grant 2UM1 AI069511-08, CTSA Grant UL1 TR024160; Timothy Lane and Cornelius Van Dam-Greensboro CRS (Site 3203) Grant A1069423-08; Karen Tashima MD and Helen Patterson LPN - The Miriam Hospital (TMH) CRS (Site 2951) Grant 2UM1A1069412-08; Carlos del Rio, MD & Ericka Patrick, RN- The Ponce de Leon Ctr. CRS (Site 5802) Grant 2UM1 AI069418-08, CFAR Grant P30 AI050409, CTSA Grant UL1 TR000454; Norman Markowitz and Indira Brar-Henry Ford Hosp. CRS (Site 31472) Grant UM 1 A1069503; Roberto C. Arduino, MD, and Maria Laura Martinez-Houston AIDS Research Team CRS (Site 31473) Grant 2 UM1 AI069503-08, 2 UM1 AI068636-08; Rose Kim, MD and Yolanda Smith, BA-Cooper Univ. Hosp. CRS (Site 31476) Grant UM1 AI069503; Hector Bolivar, MD, Margaret A. Fischl, MD Univ.; of Miami AIDS Clinical Research Unit (ACRU) CRS (Site 901) Grant AI069477; Edward Telzak, MD and Richard Cindrich, MD-Bronx-Lebanon Hosp. Ctr. CRS (Site 31469) Grant UM1 AI069503; Paul Sax MD and Cheryl Keenan RN BC- Brigham and Women's Hospital Therapeutics CRS (Site 107) Grant UM1AI069472; CFAR Grant P30 AI060354, CTSA UL1 TR000170; Kim Whitely, RN and Traci Davis, RN- MetroHealth CRS (Site 2503) Grant AI 69501; CTSA Grant UL1TR000439; Dr. Rodger D. MacArthur and Marti Farrough, RN, BSN - Wayne State Univ. CRS (Site 31478) Grant 2UM1AI069503-08; Judith A. Aberg, MD and Michelle S Cespedes, MPH, MD - NY Univ. HIV/AIDS CRS (Site 401) Grant UM1 AI069532; Shelia Dunaway, MD and Sheryl Storey, PA-C-University of Washington AIDS CRS (Site 1401) Grant UM AI069481; Joel Gallant, MD, and Ilene Wiggins, RN -Johns Hopkins University CRS (Site 201) Grant 2UM1 AI069465, CTSA Grant UL1TR001079; Beverly Sha, MD and Veronica Navarro, RN - Rush University CRS (Site 2702) Grant AI-069471; Vicky Watson RN and Daniel Nixon DO, PhD - Virginia Commonwealth Univ. Medical Ctr. CRS (Site 31475) CPCRA CTU award UM1 AI069503, CTSA UL1TR000058; Annie Luetkemeyer, MD and Jay Dwyer, RN- UCSF HIV/AIDS CRS (Site 801) Grant UM1 AI069496, UCSF-CTSA Grant UL1 TR000004; Kristen Allen RN and Patricia Walton RN-Case CRS (Site 2501) Grant AI069501; Dr. Princy Kumar and Dr. Joseph Timpone-Georgetown University CRS (Site 1008) Grant 1U01AI069494; Mehri McKellar, MD and Jacquelin Granholm, RN-Duke Univ. Med. Ctr. Adult CRS (Site 1601) Grant 5UM1 AI069484-07; Michael T Yin, MD MS and Madeline Torres, RN-Columbia Physicians and Surgeons CRS (Site 30329) Grant 2UM1-AI069470-08, CTSA 5UL1 RR024156; Sandra Valle, PA-C and Debbie Slamowitz, RN-Stanford CRS (Site 501) Grant AI069556; Charles E. Davis Jr., M.D. and William A. Blattner, M.D. - IHV Baltimore Treatment CRS (Site 4651) Grant U01AI069447; BMC ACTG CRS (Site 104) Benjamin Linus, MD, UM1 AI069472; Beth Israel Deaconess Med. Ctr., ACTG CRS (Site 103) Mary Albrecht, MD, UM1 AI069472; CFAR Grant P30 AI060354; Christina Megill, PA-C and Valery Hughes, NP-Cornell Chelsea CRS (Site 7804) Grant UM1AI069419, CTSA Grant UL1TR000457; Teri Flynn, MSN, ANP and Amy Sbrolla BSN, RN Massachusetts General Hospital CRS (Site 101) Grant 2UM1AI069412-08; CFAR Grant P30 AI060354; Sharon Riddler, MD and Lisa Klevens, BSN-University of Pittsburgh CRS (Site 1001) Grant UM1 AI069494. NR 31 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 20 IS 12 BP 2983 EP 2995 DI 10.1007/s10461-016-1365-2 PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA ED1AF UT WOS:000388575100020 PM 26979419 ER PT J AU Pfeiffer, CM Sternberg, MR Hamner, HC Crider, KS Lacher, DA Rogers, LM Bailey, RL Yetley, EA AF Pfeiffer, Christine M. Sternberg, Maya R. Hamner, Heather C. Crider, Krista S. Lacher, David A. Rogers, Lisa M. Bailey, Regan L. Yetley, Elizabeth A. TI Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE deficiency; insufficiency; microbiologic assay; NHANES; radioprotein-binding assay ID BIO-RAD RADIOASSAY; WHOLE-BLOOD FOLATE; MICROBIOLOGIC ASSAY; UNITED-STATES; RBC FOLATE; NHANES 1988-2010; NATIONAL-HEALTH; SERUM FOLATE; LC-MS/MS; NUTRITION AB Background: Folate cutoffs for risk of deficiency compared with possible deficiency were originally derived differently (experimental compared with epidemiologic data), and their interpretations are different. The matching of cutoffs derived from one assay with population-based data derived from another assay requires caution. Objective: We assessed the extent of folate-status misinterpretation with the use of inappropriate cutoffs. Design: In the cross-sectional NHANES, serum and red blood cell (RBC) folate were first measured with the use of a radioprotein-binding assay (RPBA) (1988-2006) and, afterwards, with the use of a microbiologic assay (2007-2010). We compared prevalence estimates for assay matched cutoffs (e.g., with the use of an RPBA cutoff with RPBA data) and assay-mismatched cutoffs (e.g., with the use of microbiologic assay cutoff with RPBA data) for risk of deficiency on the basis of megaloblastic anemia as a hematologic indicator in persons y of age (e.g., serum folate concentration <7 nmol/L and RBC folate concentration <305 nmol/L derived with the use of a microbiologic assay), possible deficiency on the basis of rising homocysteine as a metabolic indicator in persons y of age (e.g., serum folate concentration <10 nmol/L and RBC folate concentration <340 nmol/L derived with the use of an RPBA), and insufficiency on the basis of elevated risk of neural tube defects in women 12-49 y old (e.g., RBC folate concentration <906 nmol/L derived with the use of a microbiologic assay). Results: Pre folic acid fortification (1988-1994), risks of deficiency for assay-matched compared with assay-mismatched cutoffs were 5.6% compared with 16% (serum folate), respectively, and 7.4% compared with 28% (RBC folate), respectively; risks declined postfortification (1999-2006) to <1% compared with <1% (serum folate), respectively, and to <1% compared with 2.5% (RBC folate), respectively. Prefortification (1988-1994), risks of possible deficiency for assay-matched compared with assay-mismatched cutoffs were 35% compared with 56% (serum folate), respectively, and 37% compared with 84% (RBC folate), respectively; risks declined post fortification (1999-2006) to 1.9% compared with 7.0% (serum folate), respectively, and to 4.8% compared with 53% (RBC folate), respectively. Postfortification (2007-2010), risks of insufficiency were 3% (assay matched) compared with 39% (assay mismatched), respectively. Conclusions: The application of assay-mismatched cutoffs leads to a misinterpretation of folate status. This confusion likely applies to clinical assays because no comparability data are available, to our knowledge. C1 [Pfeiffer, Christine M.; Sternberg, Maya R.] CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Hamner, Heather C.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Crider, Krista S.] CDC, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Lacher, David A.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Rogers, Lisa M.] WHO Geneva, Geneva, Switzerland. [Bailey, Regan L.] Purdue Univ, Nutr Sci, W Lafayette, IN 47907 USA. [Bailey, Regan L.; Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Pfeiffer, CM (reprint author), CDC, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. EM cfp8@cdc.gov NR 30 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 DEC PY 2016 VL 104 IS 6 BP 1607 EP 1615 DI 10.3945/ajcn.116.138529 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE0RV UT WOS:000389287500014 PM 27680995 ER PT J AU Swanger, SA Chen, WJ Wells, G Burger, PB Tankovic, A Bhattacharya, S Strong, KL Hu, C Kusumoto, H Zhang, J Adams, DR Millichap, JJ Petrovski, S Traynelis, SF Yuan, H AF Swanger, Sharon A. Chen, Wenjuan Wells, Gordon Burger, Pieter B. Tankovic, Anel Bhattacharya, Subhrajit Strong, Katie L. Hu, Chun Kusumoto, Hirofumi Zhang, Jing Adams, David R. Millichap, John J. Petrovski, Slave Traynelis, Stephen F. Yuan, Hongjie TI Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID D-ASPARTATE RECEPTOR; MOLECULAR-DYNAMICS SIMULATIONS; ONSET EPILEPTIC ENCEPHALOPATHY; AUTISM SPECTRUM DISORDERS; SITE-DIRECTED MUTAGENESIS; SUBUNIT MESSENGER-RNAS; DE-NOVO MUTATIONS; LIGAND-BINDING; GLUTAMATE BINDING; ENDOPLASMIC-RETICULUM AB Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain-and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function. C1 [Swanger, Sharon A.; Chen, Wenjuan; Tankovic, Anel; Bhattacharya, Subhrajit; Strong, Katie L.; Hu, Chun; Kusumoto, Hirofumi; Zhang, Jing; Traynelis, Stephen F.; Yuan, Hongjie] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Wells, Gordon; Burger, Pieter B.; Strong, Katie L.] Emory Univ, Dept Chem, 1515 Pierce Dr, Atlanta, GA 30322 USA. [Adams, David R.] NHGRI, Undiagnosed Dis Network, NIH, Bethesda, MD 20892 USA. [Millichap, John J.] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Millichap, John J.] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA. [Millichap, John J.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Petrovski, Slave] Univ Melbourne, Austin Hlth, Dept Med, Melbourne, Vic 3050, Australia. [Petrovski, Slave] Royal Melbourne Hosp, Melbourne, Vic 3050, Australia. [Traynelis, Stephen F.; Yuan, Hongjie] Emory Univ, Sch Med, CFERV, Atlanta, GA 30322 USA. [Chen, Wenjuan] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410013, Hunan, Peoples R China. [Wells, Gordon] Univ Stellenbosch, Dept Biochem, ZA-7602 Stellenbosch, South Africa. RP Traynelis, SF; Yuan, H (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA.; Traynelis, SF; Yuan, H (reprint author), Emory Univ, Sch Med, CFERV, Atlanta, GA 30322 USA. EM strayne@emory.edu; hyuan@emory.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development [R01HD082373]; National Center for Advancing Translational Sciences of the NIH [UL1TR000454]; National Institute of Neurological Disorders and Stroke [F32NS086361, NS036654]; Xiangya-Emory Medical Schools Visiting Student Program; Janssen FX The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at the ExAC website. The authors also thank Dr. Dennis Liotta for generous support of this study. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to H.Y.), the National Center for Advancing Translational Sciences of the NIH (UL1TR000454 to H.Y.), the National Institute of Neurological Disorders and Stroke (F32NS086361 to S.A.S. and NS036654 to S.F.T.), and the Xiangya-Emory Medical Schools Visiting Student Program (to W.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. S.F.T. is co-founder of NeurOp Inc., a consultant of Janssen Pharmaceuticals, Pfizer, and NeurOp Inc., and a PI on a research grant from Janssen to Emory University. S.P. serves on the advisory board of Pairnomix. NR 101 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 1 PY 2016 VL 99 IS 6 BP 1261 EP 1280 DI 10.1016/j.ajhg.2016.10.002 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600003 PM 27839871 ER PT J AU Arno, G Agrawal, SA Eblimit, A Bellingham, J Xu, MC Wang, F Chakarova, C Parfitt, DA Lane, A Burgoyne, T Hull, S Carss, KJ Fiorentino, A Hayes, MJ Munro, PM Nicols, R Pontikos, N Holder, GE Asomugha, C Raymond, FL Moore, AT Plagnol, V Michaelides, M Hardcastle, AJ Li, YM Cukras, C Webster, AR Cheetham, ME Chen, R AF Arno, Gavin Agrawal, Smriti A. Eblimit, Aiden Bellingham, James Xu, Mingchu Wang, Feng Chakarova, Christina Parfitt, David A. Lane, Amelia Burgoyne, Thomas Hull, Sarah Carss, Keren J. Fiorentino, Alessia Hayes, Matthew J. Munro, Peter M. Nicols, Ralph Pontikos, Nikolas Holder, Graham E. Asomugha, Chinwe Raymond, F. Lucy Moore, Anthony T. Plagnol, Vincent Michaelides, Michel Hardcastle, Alison J. Li, Yumei Cukras, Catherine Webster, Andrew R. Cheetham, Michael E. Chen, Rui CA UKIRDC TI Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEINS; OPTIC CUPS; DISEASE; IDENTIFICATION; MECHANISMS; GENES; EXPRESSION; GENOMICS AB Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy. C1 [Arno, Gavin; Bellingham, James; Chakarova, Christina; Parfitt, David A.; Lane, Amelia; Burgoyne, Thomas; Hull, Sarah; Fiorentino, Alessia; Hayes, Matthew J.; Munro, Peter M.; Pontikos, Nikolas; Holder, Graham E.; Moore, Anthony T.; Michaelides, Michel; Hardcastle, Alison J.; Webster, Andrew R.; Cheetham, Michael E.] UCL, Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England. [Arno, Gavin; Hull, Sarah; Holder, Graham E.; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.] Moorfields Eye Hosp, London EC1V 2PD, England. [Agrawal, Smriti A.; Eblimit, Aiden; Xu, Mingchu; Wang, Feng; Li, Yumei; Chen, Rui] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Agrawal, Smriti A.; Eblimit, Aiden; Xu, Mingchu; Wang, Feng; Li, Yumei; Chen, Rui] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Carss, Keren J.; Raymond, F. Lucy] Cambridge Univ Hosp NHS Fdn Trust, NIHR BioResource Rare Dis, Cambridge Biomed Campus, Cambridge CB2 0QQ, England. [Carss, Keren J.] Univ Cambridge, Dept Haematol, NHS Blood & Transplant Ctr, Cambridge CB2 0PT, England. [Nicols, Ralph] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [Asomugha, Chinwe] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Raymond, F. Lucy] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England. [Moore, Anthony T.] UCSF, Sch Med, Dept Ophthalmol, Koret Vis Ctr, San Francisco, CA 94133 USA. [Plagnol, Vincent] UCL, Genet Inst, London WC1E 6BT, England. [Cukras, Catherine] NEI, NIH, Bethesda, MD 20892 USA. RP Cheetham, ME (reprint author), UCL, Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England.; Chen, R (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Chen, R (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. EM michael.cheetham@ucl.ac.uk; ruichen@bcm.edu OI Burgoyne, Thomas/0000-0002-8428-720X; Lord, Emma/0000-0001-9216-7382; Cheetham, Michael/0000-0001-6429-654X FU Foundation Fighting Blindness [BR-GE-0613-0618-BCM]; National Eye Institute [R01EY022356, R01EY020540]; NEI vision core grant [P30EY002520]; RP Fighting Blindness and Fight for Sight; Wellcome Trust [092621]; National Institute for Health Research (UK); Biomedical Research Centre at Moorfields Eye Hospital; UCL Institute of Ophthalmology; Fight for Sight UK; Moorfields Eye Hospital Special Trustees; Foundation Fighting Blindness - USA FX We thank all the individuals and their family members for participating in this study. We also thank the Integrated Microscopy Core at Baylor College of Medicine for OCT experiments. Additionally, we thank Dr. Anand Swaroop for providing the Reep6 antibody and Dr. Peter MacLeish for providing the 7G6 antibody. We would also like to thank the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE) and Amy Turiff, the NEI coordinator, the UK Inherited Retinal Disease Consortium (UKIRDC), and the NIHR BioResource - RareDiseases project (BRIDGE-SPEED). This project was funded by the Foundation Fighting Blindness (BR-GE-0613-0618-BCM) and National Eye Institute (R01EY022356, R01EY020540) to R.C. Sequencing effort is also supported by the NEI vision core grant (P30EY002520). The UKIRDC is funded by RP Fighting Blindness and Fight for Sight. This project was also supported by The Wellcome Trust (092621 to M.E.C.), The National Institute for Health Research (UK), Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Fight for Sight UK, Moorfields Eye Hospital Special Trustees, and Foundation Fighting Blindness - USA. NR 34 TC 0 Z9 0 U1 6 U2 6 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 DEC 1 PY 2016 VL 99 IS 6 BP 1305 EP 1315 DI 10.1016/j.ajhg.2016.10.008 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600006 PM 27889058 ER PT J AU Vince, N Li, HC Ramsuran, V Naranbhai, V Duh, FM Fairfax, BP Saleh, B Knight, JC Anderson, SK Carrington, M AF Vince, Nicolas Li, Hongchuan Ramsuran, Veron Naranbhai, Vivek Duh, Fuh-Mei Fairfax, Benjamin P. Saleh, Bahara Knight, Julian C. Anderson, Stephen K. Carrington, Mary TI HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WHOLE-GENOME ASSOCIATION; NITRIC-OXIDE SYNTHASE; GENE-EXPRESSION; HIV CONTROL; TRANSCRIPTION FACTOR; WIDE ASSOCIATION; OCTAMER MOTIF; PROTEINS; IMMUNOGLOBULIN; ACTIVATION AB Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 x 10(-66)). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1.8 x 10(-20)) and in two cohorts where HLA-C cell surface levels were determined directly by flow cytometry (n = 369 combined, p < 10(-15)). rs2395471 is located in an Oct1 transcription factor consensus binding site motif where the A allele is predicted to have higher affinity for Oct1 than the G allele. Mobility shift electrophoresis demonstrated that Oct1 binds to both alleles in vitro, but decreased HLA-C promoter activity was observed in a luciferase reporter assay for rs2395471_G relative to rs2395471_A on a fixed promoter background. The rs2395471 variant accounts for up to 36% of the explained variation of HLA-C level. These data strengthen our understanding of HLA-C transcriptional regulation and provide a basis for understanding the potential consequences of manipulating HLA-C levels therapeutically. C1 [Vince, Nicolas; Li, Hongchuan; Ramsuran, Veron; Duh, Fuh-Mei; Saleh, Bahara; Anderson, Stephen K.; Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Vince, Nicolas; Ramsuran, Veron; Naranbhai, Vivek; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Naranbhai, Vivek; Fairfax, Benjamin P.; Knight, Julian C.] Univ Oxford, Wellcome Trust, Ctr Human Genet, Oxford OX3 7BN, England. [Naranbhai, Vivek] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, ZA-4091 Durban, South Africa. RP Carrington, M (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.; Carrington, M (reprint author), Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. EM carringm@mail.nih.gov FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH; Frederick National Lab; Center for Cancer Research; European Research Council [281824]; NIHR Oxford Biomedical Research Centre; Wellcome Trust [090532/Z/09/Z, 074318, 088891]; European Research Council under the European Union [281824]; Medical Research Council [98082]; Rhodes Trust FX This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. J.C.K. is supported by European Research Council funding (grant agreement no. 281824) and the NIHR Oxford Biomedical Research Centre and Wellcome Trust (core facilities grant 090532/Z/09/Z). The Oxford cohort was supported by the Wellcome Trust (grants 074318 [J.C.K.], 088891 [B.P.F.], and 090532/Z/09/Z [core facilities Wellcome Trust Centre for Human Genetics including High-Throughput Genomics Group]), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 281824 (J.C.K.), the Medical Research Council (98082 [J.C.K]), and the NIHR Oxford Biomedical Research Centre. V.N. was supported by the Rhodes Trust. NR 40 TC 0 Z9 0 U1 2 U2 2 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 DEC 1 PY 2016 VL 99 IS 6 BP 1353 EP 1358 DI 10.1016/j.ajhg.2016.09.023 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600010 PM 27817866 ER PT J AU George, A Zand, DJ Hufnagel, RB Sharma, R Sergeev, YV Legare, JM Rice, GM Schwoerer, JAS Rius, M Tetri, L Gamm, DM Bharti, K Brooks, BP AF George, Aman Zand, Dina J. Hufnagel, Robert B. Sharma, Ruchi Sergeev, Yuri V. Legare, Janet M. Rice, Gregory M. Schwoerer, Jessica A. Scott Rius, Mariana Tetri, Laura Gamm, David M. Bharti, Kapil Brooks, Brian P. TI Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WAARDENBURG SYNDROME; TFE FAMILY; MOUSE; GENE; MELANOCYTES; HOMOLOG; NETWORK; PROTEIN AB Human MITF is, by convention, called the "microphthalmia-associated transcription factor'' because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations. C1 [George, Aman; Hufnagel, Robert B.; Sergeev, Yuri V.; Rius, Mariana; Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Zand, Dina J.; Brooks, Brian P.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Sharma, Ruchi; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. [Legare, Janet M.; Rice, Gregory M.; Tetri, Laura; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI 53726 USA. [Schwoerer, Jessica A. Scott; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, McPherson Eye Res Inst, Madison, WI 53726 USA. [Schwoerer, Jessica A. Scott; Gamm, David M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Zand, Dina J.] US FDA, Off New Drugs, Off Drug Evaluat 3, Div Gastroenterol & Inborn Errors Prod, Silver Spring, MD 20993 USA. [Rius, Mariana] SUNY Stony Brook, Sch Marine & Atmospher Sci, Stony Brook, NY 11790 USA. RP Brooks, BP (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA.; Brooks, BP (reprint author), Childrens Natl Med Ctr, Washington, DC 20010 USA. EM brian.brooks1@nih.gov FU NEI FX We are grateful to the probands and their families. We thank Dr. Heinz Arnheiter for critical comments on the manuscript, Dr. James Lister (Virginia Commonwealth University, Richmond, VA) for the zebrafish mitfa construct, Drs. Noriko Esumi (Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD) and Sridhar Mani (Albert Einstein College of Medicine, Bronx, NY) for luciferase promoter constructs, Drs. Chun Gao and Robert Farris (Biological Imaging Core, National Eye Institute [NEI]) for expert assistance with confocal laser-scanning microscopy experiments, Ramakrishna Alur for technical assistance, Delphine Blain for genetic counseling, the NEI Clinical Photography Section for outstanding technical assistance, and Anna Larson and Tyler Fayard for zebrafish breeding and maintenance. This work was supported by the intramural program of the NEI. NR 23 TC 0 Z9 0 U1 4 U2 4 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 DEC 1 PY 2016 VL 99 IS 6 BP 1388 EP 1394 DI 10.1016/j.ajhg.2016.11.004 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600014 PM 27889061 ER PT J AU Reynolds, JA Rosenberg, AZ Smith, CK Sergeant, JC Rice, GI Briggs, TA Bruce, IN Kaplan, MJ AF Reynolds, John A. Rosenberg, Avi Z. Smith, Carolyne K. Sergeant, Jamie C. Rice, Gillian I. Briggs, Tracy A. Bruce, Ian N. Kaplan, Mariana J. TI Vitamin D Deficiency Is Associated With Endothelial Dysfunction and Increases Type I Interferon Gene Expression in a Murine Model of Systemic Lupus Erythematosus SO Arthritis & Rheumatology LA English DT Article ID 25-HYDROXYVITAMIN D DEFICIENCY; DISEASE-ACTIVITY INDEX; CARDIOVASCULAR-DISEASE; RISK-FACTOR; SIGNATURE; WOMEN AB Objective. Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD) and impaired endothelial repair. Although vitamin D deficiency is associated with increased CVD risk in the general population, a causal relationship has not been demonstrated. We aimed to determine whether vitamin D deficiency directly modulates endothelial dysfunction and immune responses in a murine model of SLE. Methods. Vitamin D deficiency was induced in lupus-prone MRL/lpr mice by dietary restriction for 6 weeks. Endothelium-dependent vasorelaxation was quantified using aortic ring myography, and endothelial repair mechanisms were assessed by evaluating the phenotype and function of bone marrow endothelial progenitor cells (EPCs) and with the use of an in vivo Matrigel plug model. Lupus disease activity was determined by evaluating expression of interferon-stimulated genes (ISGs) in splenic tissue, positivity for serum autoantibodies, and renal histology. To validate the findings, expression of ISGs was also measured in whole blood from vitamin D-deficient and vitamin D-sufficient patients with SLE. Results. Vitamin D deficiency resulted in impaired endothelium-dependent vasorelaxation and decreases in neoangiogenesis without a change in the total number of EPCs. There were no differences in anti-double-stranded DNA titers, proteinuria, or glomerulonephritis (activity or chronicity) between vitamin D-deficient or sufficient mice. Vitamin D deficiency was associated with a trend toward increased ISG expression both in mice and in patients with SLE. Conclusion. These findings indicate that vitamin D deficiency is associated with hampered vascular repair and reduced endothelial function, and may modulate type I interferon responses. C1 [Reynolds, John A.; Rosenberg, Avi Z.; Smith, Carolyne K.; Kaplan, Mariana J.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Reynolds, John A.; Briggs, Tracy A.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester, Lancs, England. [Reynolds, John A.; Briggs, Tracy A.] Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Rosenberg, Avi Z.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Sergeant, Jamie C.; Bruce, Ian N.] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Sergeant, Jamie C.; Bruce, Ian N.] Univ Manchester, Manchester, Lancs, England. [Rice, Gillian I.] Univ Manchester, Manchester, Lancs, England. RP Kaplan, MJ (reprint author), NIH, System Autoimmun Branch, NIAMSD, 10 Ctr Dr,6D-47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program); North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics - MRC [G1000417/94909]; ICON; GlaxoSmithKline; AstraZeneca; Medicines Evaluation Unit Ltd.; Arthritis Research UK [20380]; NIHR Manchester Biomedical Research Unit; NIHR Manchester Wellcome Trust Clinical Research Facility FX Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program). Dr. Reynolds is an MRC Clinical Training Fellow and his work was supported by the North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the MRC (grant G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca, and the Medicines Evaluation Unit Ltd. Dr. Bruce is an NIHR Senior Investigator and his work was funded by Arthritis Research UK (grant 20380), the NIHR Manchester Biomedical Research Unit, and the NIHR Manchester Wellcome Trust Clinical Research Facility. NR 17 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD DEC PY 2016 VL 68 IS 12 BP 2929 EP 2935 DI 10.1002/art.39803 PG 7 WC Rheumatology SC Rheumatology GA ED8XE UT WOS:000389153400013 PM 27390112 ER PT J AU Wolfe, F Walitt, B AF Wolfe, Frederick Walitt, Brian TI Fibromyalgia is overdiagnosed in the general population: comment on the article by Hootman et al SO Arthritis & Rheumatology LA English DT Letter ID PREVALENCE; ARTHRITIS C1 [Wolfe, Frederick] Natl Data Bank Rheumat Dis, Wichita, KS 67214 USA. [Walitt, Brian] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Wolfe, F (reprint author), Natl Data Bank Rheumat Dis, Wichita, KS 67214 USA. NR 9 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 68 IS 12 BP 3043 EP 3044 DI 10.1002/art.39839 PG 3 WC Rheumatology SC Rheumatology GA ED8XE UT WOS:000389153400028 PM 27564249 ER PT J AU Takahashi, YK Schoenbaum, G AF Takahashi, Yuji K. Schoenbaum, Geoffrey TI Ventral Striatal Lesions Disrupt Dopamine Neuron Signaling of Differences in Cue Value Caused by Changes in Reward Timing but Not Number SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE dopamine; ventral striatum; reward prediction error; single unit; rat ID ORBITOFRONTAL CORTEX; PREDICTION ERRORS; NUCLEUS-ACCUMBENS; IMPULSIVE CHOICE; DORSAL STRIATUM; TEGMENTAL AREA; SIZED REWARDS; AMYGDALA; ENCODE; REPRESENTATION AB We recently showed that ventral striatal (VS) lesions abolished reward prediction errors that reflect changes in reward timing while leaving relatively unaffected errors that reflect changes in reward number. Here we extended those results by examining whether normal learning-related changes in firing to the reward-predictive cues in the same dopamine neurons were also disrupted by VS lesions. This analysis revealed that dopamine neurons recorded in VS-lesioned rats failed to show value-related changes in firing to the cues in timing but showed normal changes in number blocks. This effect suggests that the loss of reward-evoked error signals in the timing blocks impaired encoding of the cue value in downstream areas, which then supply these predictions to dopamine neurons at the time of cue presentation. C1 [Takahashi, Yuji K.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. RP Schoenbaum, G (reprint author), 251 Bayview Blvd,Suite 200,Bldg BRC, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov FU National Institute on Drug Abuse FX This work was supported by funding from the National Institute on Drug Abuse. The opinions expressed in this article are those of the authors' and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 57 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD DEC PY 2016 VL 130 IS 6 BP 593 EP 599 DI 10.1037/bne0000169 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA ED3ID UT WOS:000388741900007 PM 27854448 ER PT J AU George, J Renn, L Verthelyi, D Roederer, M Rabin, RL Mattapallil, JJ AF George, Jeffy Renn, Lynnsey Verthelyi, Daniela Roederer, Mario Rabin, Ronald L. Mattapallil, Joseph J. TI Early treatment with reverse transcriptase inhibitors significantly suppresses peak plasma IFN alpha in vivo during acute simian immunodeficiency virus infection SO CELLULAR IMMUNOLOGY LA English DT Article DE HIV; SIV; IFN alpha; IFN beta; Subtypes; Dendritic cells; Mucosa ID CD4(+) T-CELLS; PATHOGENIC SIV INFECTION; HEPATITIS-C VIRUS; DENDRITIC CELLS; INTERFERON-ALPHA; RHESUS MACAQUES; GASTROINTESTINAL-TRACT; HIV-1 INFECTION; LYMPH-NODES; ANTIRETROVIRAL THERAPY AB Innate interferons (IFN) are comprised of multiple Type I and III subtypes. The in vivo kinetics of subtype responses during human immunodeficiency virus (HIV) infection is not well defined. Using the acute simian immunodeficiency virus (SIV) infection model, we show that plasma IFN alpha levels peak at day 10 post-infection (pi) after which they rapidly declined. The mRNA expression of Type I and III IFN subtypes were significantly elevated in the lymph nodes (LN) at day 10 pi. Though the expression levels of all subtypes declined by day 14-31 pi, numerous subtypes remained elevated suggesting that ongoing viral replication in LN continues to drive induction of these subtypes. Interestingly, treatment with reverse transcriptase (RT) inhibitors at day 7 pi significantly suppressed plasma IFNa responses by day 10 pi that significantly correlated with cell-associated SIV DNA loads suggesting that RT byproducts such as viral DNA likely plays a role in driving IFN responses during acute SIV infection. Quantification of Type I and III subtype transcripts in sorted subsets of LN CD4+ and CD8+ T cells, CD14+/CD14- monocytes/-macrophages, and total CD11c/CD123+ dendritic cells (DC) at day 10 pi showed that DC expressed similar to 3-4 log more subtype transcripts as compared to the other subsets. Taken together, our results provide new insights into the kinetics of innate interferon responses during early stages of infection, and provide evidence that DC's are a major in vivo source of innate IFN during acute SIV infection. Published by Elsevier Inc. C1 [George, Jeffy; Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Renn, Lynnsey; Rabin, Ronald L.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Roederer, Mario] NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM joseph.mattapallil@usuhs.edu FU Uniformed Services University of the Health Sciences FX The described project was supported by funds from the Uniformed Services University of the Health Sciences to JJM. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense, the Uniformed Services University of the Health Sciences or any other agency of the U.S. Government. NR 84 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD DEC PY 2016 VL 310 BP 156 EP 164 DI 10.1016/j.cellimm.2016.09.003 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA ED4MS UT WOS:000388823700017 PM 27622386 ER PT J AU Sertedaki, A Markou, A Vlachakis, D Kossida, S Campanac, E Hoffman, DA Sierra, MD Xekouki, P Stratakis, CA Kaltsas, G Piaditis, GP Chrousos, GP Charmandari, E AF Sertedaki, Amalia Markou, Athina Vlachakis, Dimitrios Kossida, Sophia Campanac, Emilie Hoffman, Dax A. Sierra, Maria De La Luz Xekouki, Paraskevi Stratakis, Constantine A. Kaltsas, Gregory Piaditis, George P. Chrousos, George P. Charmandari, Evangelia TI Functional characterization of two novel germline mutations of the KCNJ5 gene in hypertensive patients without primary aldosteronism but with ACTH-dependent aldosterone hypersecretion SO CLINICAL ENDOCRINOLOGY LA English DT Article ID FAMILIAL HYPERALDOSTERONISM; REMEDIABLE ALDOSTERONISM; HEREDITARY HYPERTENSION; SIGNALING PATHWAYS; POTASSIUM CHANNEL; SECRETION; PREVALENCE; DIAGNOSIS; MODEL; FORM AB BackgroundGermline mutations of the KCNJ5 gene encoding Kir34, a member of the inwardly rectifying K+ channel, have been identified in normal' adrenal glands, patients with familial hyperaldosteronism (FH) type III, aldosterone-producing adenomas (APAs) and sporadic cases of primary aldosteronism (PA). ObjectiveTo present two novel KCNJ5 gene mutations in hypertensive patients without PA, but with Adrenocorticotropic hormone (ACTH)-dependent aldosterone hypersecretion. Design and PatientsTwo hypertensive patients without PA, who exhibited enhanced ACTH-dependent response of aldosterone secretion, underwent genetic testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. Genomic DNA was isolated from peripheral white blood cells, and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials. Structural biology studies were also carried out. ResultsTwo novel germline heterozygous KCNJ5 mutations, p.V259M and p.Y348N, were detected in the two subjects. Electrophysiological studies showed that the Y348N mutation resulted in significantly less negative reversal potentials, suggesting loss of ion selectivity, while the V259M mutation did not affect the Kir3.4 current. In the mutated structural biology model, the N348 mutant resulted in significant loss of the ability for hydrogen bonding, while the M259 mutant was capable of establishing weaker interactions. The CYP11B1/CYP11B2 chimeric gene was not detected. ConclusionsThese findings expand on the clinical spectrum of phenotypes associated with KCNJ5 mutations and implicate these mutations in the pathogenesis of hypertension associated with increased aldosterone response to ACTH stimulation. C1 [Sertedaki, Amalia; Chrousos, George P.; Charmandari, Evangelia] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1,Div Endocrinol Metab & Diabet, Athens, Greece. [Markou, Athina; Piaditis, George P.] G Gennimatas Gen Hosp, Dept Endocrinol & Diabet Ctr, Athens, Greece. [Vlachakis, Dimitrios; Kossida, Sophia] Acad Athens, Biomed Res Fdn, Bioinformat & Med Informat Team, Athens, Greece. [Campanac, Emilie; Hoffman, Dax A.] Natl Inst Hlth, Program Dev Neurosci, Mol Neurophysiol & Biophys Sect, Bethesda, MD USA. [Sierra, Maria De La Luz; Xekouki, Paraskevi; Stratakis, Constantine A.] Natl Inst Hlth, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Kaltsas, Gregory] Univ Athens, Sch Med, Laikon Hosp, Dept Pathophysiol, Athens, Greece. RP Sertedaki, A (reprint author), Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1,Div Endocrinol Metab & Diabet, Athens, Greece. EM aserted@med.uoa.gr RI Charmandari, Evangelia/B-6701-2011; OI Hoffman, Dax/0000-0001-6999-2157; Vlachakis, Dimitrios/0000-0003-1823-6102 FU National and Kapodistrian University of Athens Medical School, Athens, Greece; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA FX A positive control DNA sample for the presence of the CYP11B1/CYP11B2 hybrid gene was kindly provided by Dr Shengxin Xu from Prof RD Gordon. This work was supported in part by the National and Kapodistrian University of Athens Medical School, Athens, Greece, and the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. NR 30 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2016 VL 85 IS 6 BP 845 EP 851 DI 10.1111/cen.13132 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1DU UT WOS:000387844500004 PM 27293068 ER PT J AU Lee, JJ Pedley, A Marqusee, E Sutherland, P Hoffmann, U Massaro, JM Fox, CS AF Lee, Jane J. Pedley, Alison Marqusee, Ellen Sutherland, Patrice Hoffmann, Udo Massaro, Joseph M. Fox, Caroline S. TI Thyroid function and cardiovascular disease risk factors in euthyroid adults: a cross-sectional and longitudinal study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID BODY-MASS INDEX; WEIGHT-LOSS; ADIPOSE-TISSUE; FREE-THYROXINE; SERUM TSH; FREE T4; METABOLIC SYNDROME; HORMONE LEVELS; HEART-DISEASE; ASSOCIATION AB Objective and designWe explored the cross-sectional and longitudinal associations of thyroid function within the normal range with cardiovascular disease (CVD) risk factors and adiposity measures. Patients and measurementsA total of 3483 (504% women) participants for the cross-sectional CVD study and 1630 (412% women) participants for the cross-sectional body composition substudy were drawn from the Framingham Third Generation Exam 1; 2912 participants (501% women) for the longitudinal CVD study and 713 participants (359% women) for the longitudinal body composition substudy were drawn from the Framingham Third Generation Exams 1-2. Thyroid function was assessed by thyrotropin [thyroid-stimulating hormone (TSH)] and free thyroxine (fT4) concentrations within the reference range at Exam 1. The associations between thyroid function and CVD risk factors were modelled via multivariable-adjusted regression models. Multivariable adjustment included age, sex, current smoking, postmenopausal status and BMI. ResultsCross-sectionally, higher TSH concentration was associated with increased odds of hypertriglyceridaemia [odds ratio (OR)=110], and higher BMI ( = 019 kg/m(2)), total cholesterol ( = 005 mmol/l), triglycerides ( = 00006 mmol/l) and subcutaneous adipose tissue (SAT) volume ( = 388 cm(3)) (all P < 005). Cross-sectionally, fT4 was inversely associated with metabolic and adiposity-related CVD risk factors, including obesity (OR = 117), hypertriglyceridaemia (OR = 109), BMI ( = 042 kg/m(2)), total cholesterol ( = 005 mmol/l), triglycerides ( = 00002 mmol/l), visceral adipose tissue (VAT) volume ( = -207 cm(3)) and attenuation (017 HU) and VAT/SAT ratio ( = -001) (all P < 005). However, during 61 years of follow-up, baseline TSH and fT4 levels were not longitudinally associated with CVD risk factors and adiposity measures. ConclusionsThyroid function within the normal range is cross-sectionally, but not longitudinally, associated with CVD risk factors and adiposity measures. C1 [Lee, Jane J.; Pedley, Alison; Sutherland, Patrice; Fox, Caroline S.] Populat Studies Branch, Framingham Heart Study, Div Intramural Res, Natl Heart Lung & Blood Inst, Framingham, MA USA. [Marqusee, Ellen] Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Marqusee, Ellen] Harvard Med Sch, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). NR 34 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2016 VL 85 IS 6 BP 932 EP 941 DI 10.1111/cen.13124 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1DU UT WOS:000387844500015 PM 27256825 ER PT J AU Luiz, HV Yu, R Wolf, K Miao, N Mannes, A Pacak, K AF Luiz, Henrique V. Yu, Run Wolf, Katherine Miao, Ning Mannes, Andrew Pacak, Karel TI The Author's Reply: inappropriate adrenoreceptor blockade prior to pheochromocytoma removal - "A timely reappraisal' SO CLINICAL ENDOCRINOLOGY LA English DT Letter ID CLINICAL-PRACTICE; PARAGANGLIOMA C1 [Luiz, Henrique V.; Wolf, Katherine; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Luiz, Henrique V.] Hosp Garcia de Orta, Dept Endocrinol & Diabetol, Almada, Portugal. [Yu, Run] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol, Los Angeles, CA 90095 USA. [Miao, Ning; Mannes, Andrew] NIH, Dept Perioperat Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. EM karel@mail.nih.gov FU Intramural NIH HHS [ZIA HD008735-15] NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2016 VL 85 IS 6 BP 990 EP 991 DI 10.1111/cen.13234 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1DU UT WOS:000387844500024 PM 27623515 ER PT J AU Liangpunsakul, S Puri, P Shah, VH Kamath, P Sanyal, A Urban, T Ren, XW Katz, B Radaeva, S Chalasani, N Crabb, DW AF Liangpunsakul, Suthat Puri, Puneet Shah, Vijay H. Kamath, Patrick Sanyal, Arun Urban, Thomas Ren, Xiaowei Katz, Barry Radaeva, Svetlana Chalasani, Naga Crabb, David W. CA Translational Res & Evolving Alcoh TI Effects of Age, Sex, Body Weight, and Quantity of Alcohol Consumption on Occurrence and Severity of Alcoholic Hepatitis SO Clinical Gastroenterology and Hepatology LA English DT Article DE TREAT; Alcohol Intake; Gender; TLFB; Alcoholic Hepatitis; Body Weight ID LIVER-CIRRHOSIS MORTALITY; FATTY LIVER; RISK; DISEASE; PNPLA3; METAANALYSIS; POPULATION; DRINKING; PATHOGENESIS; PREDICTORS AB BACKGROUND & AIMS: Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort, consisting of subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. METHODS: We compared data from 145 patients with AH and 124 controls based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the timeline followback method, the Alcohol Use Disorders Identification Test, and the National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses to assess the effects of these factors and their interaction in increasing the risk for All. We also explored the association between PNPLA3 variants and AH. RESULTS: Cases with AH were older (47 vs 44 y; P = .03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with All. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for the severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single-nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P = .007). CONCLUSIONS: Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for All may be associated with the PNPLA3 rs738409 polymorphism. C1 [Liangpunsakul, Suthat; Chalasani, Naga; Crabb, David W.] Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. [Ren, Xiaowei; Katz, Barry] Indiana Univ Sch Med, Richard M Fairbanks Sch Publ Hlth, Dept Biostat, Indianapolis, IN 46202 USA. [Liangpunsakul, Suthat] Richard L Roudebush Vet Adm Med Ctr, Dept Med, Indianapolis, IN USA. [Puri, Puneet; Sanyal, Arun] Virginia Commonwealth Univ, Dept Med, Div Gastroenterol & Hepatol, Med Coll Virginia Campus, Richmond, VA 23298 USA. [Shah, Vijay H.; Kamath, Patrick] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Urban, Thomas] Univ N Carolina, Eshelman Sch Pharm, Ctr Pharmacogen & Individualized Therapy, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Radaeva, Svetlana] NIAAA, NIH, Rockville, MD 20852 USA. [Crabb, David W.] Eskenazi Hlth, Indianapolis, IN USA. RP Liangpunsakul, S (reprint author), Indiana Univ, Div Gastroenterol & Hepatol, 550 North Univ Blvd,UH 4100, Indianapolis, IN 46202 USA. EM sliangpu@iupui.edu OI Puri, Pier Lorenzo/0000-0003-4964-0095 FU National Institute on Alcohol Abuse and Alcoholism [5U01AA021883-04, 5U01AA021891-04, 5U01AA021788-04, 5U01AA021840-04] FX The Translational Research and Evolving Alcoholic Hepatitis Treatment Consortium is supported by the National Institute on Alcohol Abuse and Alcoholism (5U01AA021883-04, 5U01AA021891-04, 5U01AA021788-04, and 5U01AA021840-04). NR 31 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2016 VL 14 IS 12 BP 1831 EP 1838 DI 10.1016/j.cgh.2016.05.041 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE0QD UT WOS:000389283100024 PM 27320325 ER PT J AU De Boer, YS Kosinski, AS Urban, TJ Zhao, Z Long, NY Chalasani, N Kleiner, DE Hoofnagle, JH AF De Boer, Ynto S. Kosinski, Andrzej S. Urban, Thomas J. Zhao, Zhen Long, Nanye Chalasani, Naga Kleiner, David E. Hoofnagle, Jay H. TI Characterizing Drug-Induced Liver Injury With Autoimmune Features Reply SO Clinical Gastroenterology and Hepatology LA English DT Letter C1 [De Boer, Ynto S.] NIDDK, NIH, Bethesda, MD 20892 USA. [De Boer, Ynto S.] Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands. [Kosinski, Andrzej S.] Duke Clin Res Inst, Durham, NC USA. [Urban, Thomas J.; Long, Nanye] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Zhao, Zhen] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Chalasani, Naga] Indiana Univ Sch Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP De Boer, YS (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA.; De Boer, YS (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands. OI de Boer, Ynto/0000-0002-4066-7593 NR 3 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2016 VL 14 IS 12 BP 1845 EP 1846 DI 10.1016/j.cgh.2016.08.011 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE0QD UT WOS:000389283100031 PM 27546581 ER PT J AU McMahon, S AF McMahon, Sheri TI Minimizing Hazards Associated With Live-Virus Immunotherapeutic Cancer Vaccines SO Clinical Journal of Oncology Nursing LA English DT Article DE vaccine; vaccinia; injection; risk; restrictions; safety ID PROSTATE-CANCER AB Therapeutic cancer vaccines that use attenuated vaccinia viruses as delivery vectors are undergoing clinical trials at dozens of sites internationally. Even in an attenuated form, these live viruses can cause severe illness if they are accidentally transmitted to immunocompromised people, pregnant women, or people with certain skin conditions. Oncology nurses should become familiar with how to manage patients' vaccine injection sites to minimize these risks to patients' close contacts and the community at large. At a Glance Immunotherapeutic vaccines in clinical trials show promise in oncology treatments. Viral vector vaccines are generally safe for those working with them, and precautions needed are similar to those of other biohazardous materials, such as chemotherapy. Staff and patient education are important and necessary to minimize potential risks and hazards associated with the administration of immunotherapeutic vaccines. C1 [McMahon, Sheri] NCI, Off Res Nursing, NIH, Bethesda, MD 20892 USA. RP McMahon, S (reprint author), NCI, Off Res Nursing, NIH, Bethesda, MD 20892 USA. EM sheri.mcmahon@nih.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 EI 1538-067X J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD DEC PY 2016 VL 20 IS 6 BP 602 EP 604 DI 10.1188/16.CJON.602-604 PG 3 WC Oncology; Nursing SC Oncology; Nursing GA EE0AA UT WOS:000389234100011 PM 27857270 ER PT J AU Pratt, B Allen, KA Hyder, AA AF Pratt, Bridget Allen, Katharine A. Hyder, Adnan A. TI Health Systems Research Consortia and the Promotion of Health Equity in Low and Middle-Income Countries SO DEVELOPING WORLD BIOETHICS LA English DT Article DE Research ethics; global justice; health equity; health systems research; research consortia; low and middle-income countries ID INTERNATIONAL RESEARCH; RESEARCH ETHICS; GLOBAL JUSTICE; EXPLORATION AB Health systems research is widely identified as an indispensable means to achieve the goal of health equity between and within countries. Numerous health systems research consortia comprised of institutions from high-income countries and low and middle-income countries (LMICs) are currently undertaking programs of research in LMICs. These partnerships differ from collaborations that carry out single projects in the multiplicity of their goals, scope of their activities, and nature of their management. Recent conceptual work has explored what features might be necessary for health systems research consortia and their research programs to promote health equity. Identified features include selecting research priorities that focus on improving access to high-quality health services and/or financial protection for disadvantaged populations in LMICs and conducting research capacity strengthening that promotes the independent conduct of health systems research in LMICs. Yet, there has been no attempt to investigate whether existing consortia have such characteristics. This paper describes the results of a survey undertaken with health systems research consortia leaders worldwide to assess how consistent current practice is with the proposed ethical guidance. The findings suggest that consortia may be fairly well organised to promote health equity, but have scope for improvement, particularly in terms of achieving inclusive priority-setting. C1 [Pratt, Bridget] Univ Melbourne, Nossal Inst Global Hlth, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Allen, Katharine A.] Johns Hopkins Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Hyder, Adnan A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Hyder, Adnan A.] Hlth Syst Program, Baltimore, MD USA. [Hyder, Adnan A.] Int Injury Res Unit, Baltimore, MD USA. [Hyder, Adnan A.] Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. [Hyder, Adnan A.] NIH, Fogarty Int Res Eth Training Program, Bloomberg Sch Publ Health, Bldg 10, Bethesda, MD 20892 USA. RP Pratt, B (reprint author), Univ Melbourne, Nossal Inst Global Hlth, 161 Barry St, Carlton, Vic 3053, Australia. EM bpratt2@jhu.edu FU Australian National Health and Medical Research Council (NHMRC) Early Career Sidney Sax Public Health Overseas Fellowship [1052346]; Future Health Systems Initiative; UK Department for International Development FX Bridget Pratt is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Sidney Sax Public Health Overseas Fellowship (Award No. 1052346). The contents of this article are solely the responsibility of the authors and do not reflect the views of the NHMRC. Adnan A. Hyder and Bridget Pratt are also supported by the Future Health Systems Initiative, which is funded by the UK Department for International Development. NR 27 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1471-8731 EI 1471-8847 J9 DEV WORLD BIOETH JI Dev. World Bioeth. PD DEC PY 2016 VL 16 IS 3 BP 148 EP 157 DI 10.1111/dewb.12116 PG 10 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA EC0LF UT WOS:000387791700005 PM 26990669 ER PT J AU Melnikov, S Mailliot, J Rigger, L Neuner, S Shin, BS Yusupova, G Dever, TE Micura, R Yusupov, M AF Melnikov, Sergey Mailliot, Justine Rigger, Lukas Neuner, Sandro Shin, Byung-Sik Yusupova, Gulnara Dever, Thomas E. Micura, Ronald Yusupov, Marat TI Molecular insights into protein synthesis with proline residues SO EMBO REPORTS LA English DT Article DE hydrolysis-resistant aminoacyl-tRNA analogs; peptide bond formation; proline; protein synthesis; ribosome ID PEPTIDE-BOND FORMATION; AMINOACYL-TRANSFER-RNA; EUKARYOTIC RIBOSOME; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; EFFICIENT ACCESS; EF-P; TRANSLATION; HYDROLYSIS; MIMICS AB Proline is an amino acid with a unique cyclic structure that facilitates the folding of many proteins, but also impedes the rate of peptide bond formation by the ribosome. As a ribosome substrate, proline reacts markedly slower when compared with other amino acids both as a donor and as an acceptor of the nascent peptide. Furthermore, synthesis of peptides with consecutive proline residues triggers ribosome stalling. Here, we report crystal structures of the eukaryotic ribosome bound to analogs of mono- and diprolyl-tRNAs. These structures provide a high-resolution insight into unique properties of proline as a ribosome substrate. They show that the cyclic structure of proline residue prevents proline positioning in the amino acid binding pocket and affects the nascent peptide chain position in the ribosomal peptide exit tunnel. These observations extend current knowledge of the protein synthesis mechanism. They also revise an old dogma that amino acids bind the ribosomal active site in a uniform way by showing that proline has a binding mode distinct from other amino acids. C1 [Melnikov, Sergey; Mailliot, Justine; Yusupova, Gulnara; Yusupov, Marat] CNRS UMR7104, Inst Genet & Mol & Cellular Biol, INSERM UMR964, Illkirch Graffenstaden, France. [Melnikov, Sergey; Mailliot, Justine; Yusupova, Gulnara; Yusupov, Marat] Strasbourg Univ, Strasbourg, France. [Rigger, Lukas; Neuner, Sandro; Micura, Ronald] Leopold Franzens Univ, Inst Organ Chem, Innsbruck, Austria. [Shin, Byung-Sik; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Yusupov, M (reprint author), CNRS UMR7104, Inst Genet & Mol & Cellular Biol, INSERM UMR964, Illkirch Graffenstaden, France.; Yusupov, M (reprint author), Strasbourg Univ, Strasbourg, France.; Micura, R (reprint author), Leopold Franzens Univ, Inst Organ Chem, Innsbruck, Austria.; Dever, TE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM thomas.dever@nih.gov; ronald.micura@uibk.ac.at; marat@igbmc.fr OI Mailliot, Justine/0000-0002-1026-542X FU Foundation pour la Recherche Medicale en France [SPF20111223404]; Austrian Science Fund FWF [P21641, I1040]; French National Research Agency [ANR-15-CE11-0021-01]; European Research Council [294312]; Human Frontier Science Progra [RGP0062/2012] FX We are grateful to Petr Sergiev (Lomonosov Moscow State University) for providing us with sparsomycin; to the staff of Proxima 1 beamline at the synchrotron SOLEIL (France), and in particular to Andrew Thompson and Pierre Legrand for providing rapid access to the beam and for assisting with data collection, and to members of T.D., R.M., and M.Y. teams for insightful and inspiring discussions! We also thank Corwin Miller and members of Tom Steitz and Dieter Sll laboratories (Yale University) for critically reading and commenting on the manuscript. We also thank Catherine Dunlavey (University of St. Andrews, UK) for editorial support during the manuscript preparation. This work was supported by Foundation pour la Recherche Medicale en France SPF20111223404 (to S.M.), the Austrian Science Fund FWF (P21641 and I1040 to R.M.), the French National Research Agency ANR-15-CE11-0021-01 (to G.Y.), the European Research Council advanced grant 294312 and the Human Frontier Science Program grant RGP0062/2012 (both to M.Y.), the Russian Government Program of Competitive Growth of Kazan Federal University (both to M.Y. and G.Y.), and in part by the Intramural Research Program of the National Institutes of Health, NICHD (T.D.). The structures were deposited to the protein data bank with accession codes 5dtv, 5lyb, 5tga, and 5tgm. NR 44 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD DEC PY 2016 VL 17 IS 12 BP 1776 EP 1784 DI 10.15252/embr.201642943 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE1GQ UT WOS:000389329400015 PM 27827794 ER PT J AU Darr, R Nambuba, J Del Rivero, J Janssen, I Merino, M Todorovic, M Balint, B Jochmanova, I Prchal, JT Lechan, RM Tischler, AS Popovic, V Miljic, D Adams, KT Prall, FR Ling, A Golomb, MR Ferguson, M Nilubol, N Chen, CC Chew, E Taieb, D Stratakis, CA Fojo, T Yang, CZ Kebebew, E Zhuang, ZP Pacak, K AF Darr, Roland Nambuba, Joan Del Rivero, Jaydira Janssen, Ingo Merino, Maria Todorovic, Milena Balint, Bela Jochmanova, Ivana Prchal, Josef T. Lechan, Ronald M. Tischler, Arthur S. Popovic, Vera Miljic, Dragana Adams, Karen T. Prall, F. Ryan Ling, Alexander Golomb, Meredith R. Ferguson, Michael Nilubol, Naris Chen, Clara C. Chew, Emily Taieb, David Stratakis, Constantine A. Fojo, Tito Yang, Chunzhang Kebebew, Electron Zhuang, Zhengping Pacak, Karel TI Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome SO ENDOCRINE-RELATED CANCER LA English DT Article DE pheochromocytoma; paraganglioma; somatostatinoma; polycythemia; HIF2A mutation ID HIPPEL-LINDAU-DISEASE; OF-FUNCTION MUTATIONS; HIF2A MUTATIONS; FAMILIAL ERYTHROCYTOSIS; PHEOCHROMOCYTOMA; GENE; HYPOXIA; TUMORS; HYPERTENSION; SUPERIORITY AB Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and bringsinto perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [F-18]- fluorodihydroxyphenylalanine ([F-18]-FDOPA). Therefore, [F-18]-FDOPA PET/CT, not [Ga-68]-(DOTA)-[Tyr3]-octreotate ([Ga-68]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The longterm prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges. C1 [Darr, Roland; Nambuba, Joan; Del Rivero, Jaydira; Janssen, Ingo; Jochmanova, Ivana; Adams, Karen T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. [Merino, Maria] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Todorovic, Milena] Univ Belgrade, Clin Ctr Serbia, Inst Hematol, Belgrade, Serbia. [Todorovic, Milena] Univ Belgrade, Fac Med, Belgrade, Serbia. [Balint, Bela] Univ Belgrade, Mil Med Acad, Inst Transfusiol & Hemobiol, Belgrade, Serbia. [Balint, Bela] Univ Belgrade, Inst Med Res, Belgrade, Serbia. [Jochmanova, Ivana] Pavol Jozef Safarik Univ Kosice, Fac Med, Dept Internal Med 1, Kosice, Slovakia. [Prchal, Josef T.] Univ Utah, Div Hematol, Salt Lake City, UT USA. [Lechan, Ronald M.] Tufts Med Ctr, Tupper Res Inst, Boston, MA USA. [Lechan, Ronald M.] Tufts Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA USA. [Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA USA. [Popovic, Vera; Miljic, Dragana] Univ Belgrade, Fac Med, Clin Ctr Serbia, Inst Endocrinol, Belgrade, Serbia. [Prall, F. Ryan] Indiana Univ Sch Med, Dept Ophthalmol, Indianapolis, IN 46202 USA. [Prall, F. Ryan] Indiana Univ Sch Med, Marilyn Glick Eye Inst, Indianapolis, IN 46202 USA. [Ling, Alexander] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Golomb, Meredith R.] Indiana Univ Sch Med, Dept Neurol, Div Child Neurol, Indianapolis, IN 46202 USA. [Ferguson, Michael] Indiana Univ Hlth, Riley Hosp Children, Indianapolis, IN USA. [Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chew, Emily] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. [Taieb, David] Aix Marseille Univ, Inst Paoli Calmettes, Marseille Cancerol Res Ctr, CERIMED, Marseille, France. [Taieb, David] Aix Marseille Univ, Inst Paoli Calmettes, Marseille Cancerol Res Ctr, Inserm UMR1068, Marseille, France. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, NIH, Bethesda, MD USA. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Yang, Chunzhang; Zhuang, Zhengping] NCI, Neurooncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; German Research Foundation (DFG) [DA 1630/1-1] FX This work was supported by the Intramural Research Program of the National Institutes of Health; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Neurological Disorders and Stroke; and the German Research Foundation (DFG) (grant number DA 1630/1-1 to R D). NR 47 TC 0 Z9 0 U1 3 U2 3 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 DEC PY 2016 VL 23 IS 12 BP 899 EP 908 DI 10.1530/ERC-16-0231 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA ED6BU UT WOS:000388940100014 PM 27679736 ER PT J AU Neelavalli, J Krishnamurthy, U Jella, PK Mody, SS Yadav, BK Hendershot, K Hernandez-Andrade, E Yeo, L Cabrera, MD Haacke, EM Hassan, SS Romero, R AF Neelavalli, Jaladhar Krishnamurthy, Uday Jella, Pavan K. Mody, Swati S. Yadav, Brijesh K. Hendershot, Kelly Hernandez-Andrade, Edgar Yeo, Lami Cabrera, Maria D. Haacke, Ewart M. Hassan, Sonia S. Romero, Roberto TI Magnetic resonance angiography of fetal vasculature at 3.0 T SO EUROPEAN RADIOLOGY LA English DT Article DE Non-contrast magnetic resonance angiography; Time of flight vascular imaging; Placental vasculature; Fetal circulation; Pseudo-triggering ID SPATIOTEMPORAL IMAGE CORRELATION; 4-DIMENSIONAL ULTRASONOGRAPHY; RELAXATION RATES; NEONATAL BRAIN; MR-ANGIOGRAPHY; BLOOD; HEART; ARTERY; SUSCEPTIBILITY; T-2-ASTERISK AB Magnetic resonance angiography has not been used much previously for visualizing fetal vessels in utero for reasons that include a contraindication for the use of exogenous contrast agents, maternal respiratory motion and fetal motion. In this work, we report the feasibility of using an appropriately modified clinical time-of-flight magnetic resonance imaging sequence for non-contrast angiography of human fetal and placental vessels at 3.0 T. Using this 2D angiography technique, it is possible to visualize fetal vascular networks in late pregnancy. aEuro cent 3D-visualization of fetal vasculature is feasible using non-contrast MRA at 3.0 T. aEuro cent Visualization of placental vasculature is also possible with this method. aEuro cent Fetal MRA can serve as a vascular localizer for quantitative MRI studies. aEuro cent This method can be extended to 1.5 T. C1 [Neelavalli, Jaladhar; Krishnamurthy, Uday; Jella, Pavan K.; Mody, Swati S.; Yadav, Brijesh K.; Hendershot, Kelly; Cabrera, Maria D.; Haacke, Ewart M.] Wayne State Univ, Dept Radiol, Sch Med, 4201 St Antoine, Detroit, MI 48201 USA. [Neelavalli, Jaladhar; Krishnamurthy, Uday; Yadav, Brijesh K.; Haacke, Ewart M.] Wayne State Univ, Dept Biomed Engn, Detroit, MI 48202 USA. [Mody, Swati S.] Childrens Hosp Michigan, Dept Radiol, Detroit, MI 48201 USA. [Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Neelavalli, J (reprint author), Wayne State Univ, Dept Radiol, Sch Med, 4201 St Antoine, Detroit, MI 48201 USA.; Neelavalli, J (reprint author), Wayne State Univ, Dept Biomed Engn, Detroit, MI 48202 USA. EM jneelava@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; STTR from the NHLBI [1R42HL112580-01A1]; Wayne State University by W.K. Kellogg Foundation [P3018205] FX The scientific guarantor of this publication is Dr. Jaladhar Neelavalli. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; by the STTR grant from the NHLBI - 1R42HL112580-01A1); and by Wayne State University's Perinatology Virtual Discovery Grant to J.N. (made possible by W.K. Kellogg Foundation award P3018205). No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Parts of the data reported in this paper were presented as an abstract at the 25th World Congress on Ultrasound in Obstetrics and Gynecology, 11-14 October 2015, Montreal, Quebec, Canada. Methodology: prospective, experimental and performed at one institution. NR 36 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD DEC PY 2016 VL 26 IS 12 BP 4570 EP 4576 DI 10.1007/s00330-016-4243-4 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC0SJ UT WOS:000387810700044 PM 27189488 ER PT J AU Ward, H Tang, L Poonia, B Kottilil, S AF Ward, Haley Tang, Lydia Poonia, Bhawna Kottilil, Shyam TI Treatment of hepatitis B virus: an update SO FUTURE MICROBIOLOGY LA English DT Review DE cccDNA; eradication; HBV; hepatitis B; Toll-like receptors; TLRs ID CHRONIC VIRAL-INFECTION; ALPHA-GLUCOSIDASE INHIBITORS; CHRONIC HBV INFECTION; CLOSED CIRCULAR DNA; PLASMACYTOID DENDRITIC CELLS; COMPLEX THERAPEUTIC VACCINE; LARGE ENVELOPE PROTEIN; ZINC-FINGER NUCLEASES; REPLICATION IN-VIVO; TERM-FOLLOW-UP AB Chronic hepatitis B virus infection is a global health concern as it affects over 240 million people worldwide and an estimated 686,000 people die annually as a result of complications of the disease. With the development of newer antiviral drugs, viral suppression of HBV is achievable, however elimination of HBV from infected individuals (functional cure) remains an issue. Due to persistence of HBV DNA (cccDNA) in infected cells, chronically infected patients who discontinue therapy prior to HBsAg loss or seroconversion are likely to relapse. Several novel therapeutic strategies are being researched and studied in clinical trials. Here we review these novel strategies to achieve sustained cure or elimination of HBV. These strategies include the targeting of the host or viral factors required for viral persistence as well as therapeutic vaccines. C1 [Ward, Haley] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Tang, Lydia; Poonia, Bhawna; Kottilil, Shyam] Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. RP Kottilil, S (reprint author), Univ Maryland, Sch Med, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. EM skottilil@ihv.umaryland.edu NR 167 TC 0 Z9 0 U1 10 U2 10 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 EI 1746-0921 J9 FUTURE MICROBIOL JI Future Microbiol. PD DEC PY 2016 VL 11 IS 12 BP 1581 EP 1597 DI 10.2217/fmb-2016-0128 PG 17 WC Microbiology SC Microbiology GA ED2LM UT WOS:000388676400009 PM 27855500 ER PT J AU Dekker, JP Frank, KM AF Dekker, John P. Frank, Karen M. TI Next-Generation Epidemiology: Using Real-Time Core Genome Multilocus Sequence Typing To Support Infection Control Policy SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material ID ESCHERICHIA-COLI; OUTBREAK; RESOLUTION; SURVEILLANCE; TRANSMISSION; STRAIN; SCHEME; MLST AB Multidrug-resistant bacteria are responsible for substantial morbidity and mortality worldwide. Tracking the nosocomial spread of resistant bacteria is critical to infection control. Mellmann et al. (J. Clin. Microbiol. 54: 2874-2881, 2016, http://dx.doi.org/10.1128/JCM.00790-16) have described prospective whole-genome sequencing with core genome multilocus sequencing typing (cgMLST) analysis for real-time surveillance and have addressed the practical aspects of implementing this type of operation in the hospital setting. C1 [Dekker, John P.; Frank, Karen M.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Frank, KM (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Karen.frank@nih.gov NR 28 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2016 VL 54 IS 12 BP 2850 EP 2853 DI 10.1128/JCM.01714-16 PG 4 WC Microbiology SC Microbiology GA ED9RF UT WOS:000389209600003 PM 27629902 ER PT J AU Dekker, JP AF Dekker, John P. TI Molecular Assay Validation Using Genomic Sequence Databases SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material ID CAMPYLOBACTER-JEJUNI; SPECIES CONCEPT; DIVERSITY; MLST; COLI; PCR AB Whole-genome sequence databases offer new in silico approaches for designing and validating PCR assays in the clinical microbiology laboratory. An article in this issue of the Journal of Clinical Microbiology (M. J. Jansen van Rensburg, C. Swift, A. J. Cody, C. Jenkins, and M. C. J. Maiden, J Clin Microbiol, 54: 2882-2890, 2016, http://dx.doi.org/10.1128/JCM.01522-16) demonstrates the use of publicly available genomic sequence data to evaluate a PCR assay for distinguishing Campylobacter species. C1 [Dekker, John P.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Dekker, JP (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM john.dekker@nih.gov NR 25 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2016 VL 54 IS 12 BP 2854 EP 2856 DI 10.1128/JCM.01522-16 PG 3 WC Microbiology SC Microbiology GA ED9RF UT WOS:000389209600004 PM 27733633 ER PT J AU Joo, EE Lombaert, IMA Yamada, KM AF Joo, E. E. Lombaert, I. M. A. Yamada, K. M. TI Hyperacetylation of Microtubules in Mesenchymal Cells Increases Cytokeratin 14-Positive Epithelial Progenitors in Developing Salivary Glands SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE salivary physiology; morphogenesis; cell differentiation; cell signaling; epithelial-mesenchymal interaction; extracellular matrix (ECM) ID STEM-CELLS; BRANCHING MORPHOGENESIS; EXTRACELLULAR-MATRIX; PARASYMPATHETIC INNERVATION; TISSUE ARCHITECTURE; FIBRONECTIN; CANCER; ORGANOGENESIS; REGENERATION; ACETYLATION AB Cells engage in bidirectional communication with their surroundings. This reciprocal dialogue between cells and their cellular microenvironments often governs the maintenance and differentiation of stem/progenitor cells. Here, the authors present evidence that in developing salivary gland explants, a single posttranslational change in microtubules in mesenchymal cells alters the mesenchymal microenvironment and promotes the maintenance and differentiation of a subset of epithelial progenitor cells that impairs branching morphogenesis. Specifically, the authors report that hyperacetylation of microtubules in mesenchymal cells increased cytokeratin 14-positive ( K14(+)) progenitors and their differentiated progeny, myoepithelial cells, in epithelial basal and suprabasal layers in the distal endbud region of developing salivary glands. Mechanistically, this process engages the transforming growth factor beta 1 protein and Notch signaling pathways. This report establishes that a simple posttranslational change in the cytoskeletal system of mesenchyme dictates the maintenance and differentiation of adjacent epithelial progenitor cells to alter branching morphogenesis of the epithelium. C1 [Joo, E. E.; Yamada, K. M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Lombaert, I. M. A.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Matrix & Morphogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Joo, EE; Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. EM jooeu@mail.nih.gov; kenneth.yamada@nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. EEJ and KMY designed studies and EEJ performed experiments. IMAL designed and performed qPCR, recombination, and fluorescence activated cell sorting assays. EEJ, IMAL, and KMY wrote the manuscript. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. IMAL is currently affiliated with the Biologic and Material Sciences, School of Dentistry and Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2016 VL 95 IS 13 BP 1518 EP 1527 DI 10.1177/0022034516662450 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ED4WB UT WOS:000388851500012 PM 27542391 ER PT J AU Doussau, A Grady, C AF Doussau, Adelaide Grady, Christine TI Deciphering assumptions about stepped wedge designs: the case of Ebola vaccine research SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID CLUSTER-RANDOMIZED-TRIALS; EMERGENCY DRUG DISCOVERY; SAMPLE-SIZE CALCULATION; PREVENTIVE THERAPY; CLINICAL SCIENCE; IMPLEMENTATION; EFFICACY; EVALUATE; ETHICS; ISSUES AB Ethical concerns about randomising persons to a no-treatment arm in the context of Ebola epidemic led to consideration of alternative designs. The stepped wedge (SW) design, in which participants or clusters are randomised to receive an intervention at different time points, gained popularity. Common arguments in favour of using this design are (1) when an intervention is likely to do more good than harm, (2) all participants should receive the experimental intervention at some time point during the study and (3) the design might be preferable for practical reasons. We examine these assumptions when considering Ebola vaccine research. First, based on the claim that a stepped wedge design is indicated when it is likely that the intervention will do more good than harm, we reviewed published and ongoing SW trials to explore previous use of this design to test experimental drugs or vaccines, and found that SW design has never been used for trials of experimental drugs or vaccines. Given that Ebola vaccines were all experimental with no prior efficacy data, the use of a stepped wedge design would have been unprecedented. Second, we show that it is rarely true that all participants receive the intervention in SW studies, but rather, depending on certain design features, all clusters receive the intervention. Third, we explore whether the SW design is appealing for feasibility reasons and point out that there is significant complexity. In the setting of the Ebola epidemic, spatiotemporal variation may have posed problematic challenges to a stepped wedge design for vaccine research. Finally, we propose a set of points to consider for scientific reviewers and ethics committees regarding proposals for SW designs. C1 [Doussau, Adelaide; Grady, Christine] NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,Bldg 10-1C118, Bethesda, MD 20892 USA. RP Doussau, A (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,Bldg 10-1C118, Bethesda, MD 20892 USA. EM doussau2.adelaide@gmail.com NR 61 TC 0 Z9 0 U1 4 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD DEC PY 2016 VL 42 IS 12 BP 797 EP 804 DI 10.1136/medethics-2015-103292 PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA ED6PG UT WOS:000388977100009 PM 27754861 ER PT J AU Pan, E Supko, JG Kaley, TJ Butowski, NA Cloughesy, T Jung, J Desideri, S Grossman, S Ye, XB Park, DM AF Pan, Edward Supko, Jeffrey G. Kaley, Thomas J. Butowski, Nicholas A. Cloughesy, Timothy Jung, Jinkyu Desideri, Serena Grossman, Stuart Ye, Xiaobu Park, Deric M. TI Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioma; Notch; Gamma secretase; Bevacizumab; Clinical trial ID GAMMA-SECRETASE INHIBITOR; ADVANCED SOLID TUMORS; CANCER STEM-CELLS; BREAST-CANCER; NOTCH; ACTIVATION; PATHWAY; HIF-1-ALPHA; LUNG; ANGIOGENESIS AB Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered. C1 [Pan, Edward] UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dept Med, Dallas, TX 75390 USA. [Supko, Jeffrey G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kaley, Thomas J.] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA. [Butowski, Nicholas A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Cloughesy, Timothy] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Jung, Jinkyu; Park, Deric M.] NCI, Neurooncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Desideri, Serena; Grossman, Stuart; Ye, Xiaobu] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. RP Pan, E (reprint author), UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dept Med, Dallas, TX 75390 USA.; Park, DM (reprint author), NCI, Neurooncol Branch, CCR, NIH, Bethesda, MD 20892 USA. EM Edward.Pan@UTSouthwestern.edu; deric.park@nih.gov FU [CA UM1 137443] FX CA UM1 137443 awarded to ABTC. NR 35 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 130 IS 3 BP 571 EP 579 DI 10.1007/s11060-016-2263-1 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA ED6FE UT WOS:000388950700020 PM 27826680 ER PT J AU Marosi, K Kim, SW Moehl, K Scheibye-Knudsen, M Cheng, AW Cutler, R Camandola, S Mattson, MP AF Marosi, Krisztina Kim, Sang Woo Moehl, Keelin Scheibye-Knudsen, Morten Cheng, Aiwu Cutler, Roy Camandola, Simonetta Mattson, Mark P. TI 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE bdnf; ketone; mitochondria; nf-kb; p300 ID FACTOR-KAPPA-B; NEUROTROPHIC FACTOR; KETONE-BODIES; DIETARY RESTRICTION; BETA-HYDROXYBUTYRATE; MOUSE MODEL; MOLECULAR-MECHANISMS; ALZHEIMERS-DISEASE; GLUCOSE-METABOLISM; OXIDATIVE STRESS AB During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD(+)/NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain-derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-B, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets. C1 [Marosi, Krisztina; Kim, Sang Woo; Moehl, Keelin; Cheng, Aiwu; Cutler, Roy; Camandola, Simonetta; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Scheibye-Knudsen, Morten] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Hlth Aging, Copenhagen, Denmark. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU Intramural Research Program of the National Institute on Aging FX We thank Erez Eitan for providing assistance with some of the experiments. This research was supported, in its entirety, by the Intramural Research Program of the National Institute on Aging. None of the authors have any conflicts of interest to declare. NR 78 TC 2 Z9 2 U1 10 U2 10 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 DEC PY 2016 VL 139 IS 5 BP 769 EP 781 DI 10.1111/jnc.13868 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ED8QA UT WOS:000389134800009 PM 27739595 ER PT J AU Chittiboina, P Talagala, L Merkle, H Sarlls, JE Montgomery, BK Piazza, MG Scott, G Ray-Chaudhury, A Lonser, RR Oldfield, EH Koretsky, AP Butman, JA AF Chittiboina, Prashant Talagala, Lalith Merkle, Hellmut Sarlls, Joelle E. Montgomery, Blake K. Piazza, Martin G. Scott, Gretchen Ray-Chaudhury, Abhik Lonser, Russell R. Oldfield, Edward H. Koretsky, Alan P. Butman, John A. TI Endosphenoidal coil for intraoperative magnetic resonance imaging of the pituitary gland during transsphenoidal surgery SO JOURNAL OF NEUROSURGERY LA English DT Article DE endosphenoidal coil; transsphenoidal surgery; intraoperative magnetic resonance imaging; pituitary adenoma; pituitary surgery ID CAVERNOUS SINUS INVASION; TO-NOISE RATIO; CUSHINGS-DISEASE; DURAL INVASION; MRI; ADENOMAS; MICROADENOMAS; ULTRASONOGRAPHY; ACQUISITION; BRAIN AB OBJECTIVE Pituitary MR imaging fails to detect over 50% of microadenomas in Cushing's disease and nearly 80% of cases of dural microinvasion. Surface coils can generate exceptionally high-resolution images of the immediately adjacent tissues. To improve imaging of the pituitary gland, a receive-only surface coil that can be placed within the sphenoid sinus (the endosphenoidal coil [Esc]) during transsphenoidal surgery (TSS) was developed and assessed. METHODS Five cadaver heads were used for preclinical testing of the ESC. The ESC (a double-turn, 12-mm-diameter surface coil made from 1-mm-diameter copper wire) was developed to obtain images in a 1.5-T MR scanner. The ESC was placed (via a standard sublabial TSS approach) on the anterior sella face. Clinical MR scans were obtained using the 8-channel head coil and ESC as the receiver coils. Using the ESC, ultra high-resolution, 3D, balanced fast field echo (BFFE) and T1-weighted imaging were performed at resolutions of 0.25 x 0.25 x 0.50 mm(3) and 0.15 x 0.15 x 0.30 mm(3), respectively. RESULTS Region-of-interest analysis indicated a 10-fold increase in the signal-to-noise ratio (SNR) of the pituitary when using the ESC compared with the 8-channel head coil. ESC-related improvements (p < 0.01) in the SNR were inversely proportional to the distance from the ESC tip to the anterior pituitary gland surface. High-resolution BFFE MR imaging obtained using ESC revealed a number of anatomical features critical to pituitary surgery that were not visible on 8-channel MR imaging, including the pituitary capsule, the intercavernous sinus, and microcalcifications in the pars intermedia. These ESC imaging findings were confirmed by the pathological correlation with whole-mount pituitary sections. CONCLUSIONS ESC can significantly improve SNR in the sellar region intraoperatively using current 1.5-T MR imaging platforms. Improvement in SNR can provide images of the sella and surrounding structures with unprecedented resolution. Clinical use of this ESC may allow for MR imaging detection of previously occult pituitary adenomas and identify microscopic invasion of the dura or cavernous sinus. C1 [Chittiboina, Prashant; Montgomery, Blake K.; Piazza, Martin G.; Scott, Gretchen; Ray-Chaudhury, Abhik; Lonser, Russell R.; Oldfield, Edward H.] NINDS, Surg Neurol Branch, 10 Ctr Dr,Rm 3D20, Bethesda, MD 20892 USA. [Talagala, Lalith; Sarlls, Joelle E.] NIH, MRI Res Facil, Bldg 10, Bethesda, MD 20892 USA. [Merkle, Hellmut; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, 10 Ctr Dr,Rm 3D20, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Oldfield, Edward H.] Univ Virginia Hlth Syst, Dept Neurol Surg, Charlottesville, VA USA. RP Chittiboina, P (reprint author), NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Rm 3D20, Bethesda, MD 20892 USA. EM prashant.chittiboina@nih.gov FU intramural research program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH); NIH FX This study was funded by the intramural research program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH. NR 37 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2016 VL 125 IS 6 BP 1451 EP 1459 DI 10.3171/2015.11.JNS151465 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA ED3XY UT WOS:000388783000015 PM 26991390 ER PT J AU Mehta, GU Feldman, MJ Wang, H Ding, D Chittiboina, P AF Mehta, Gautam U. Feldman, Michael J. Wang, Herui Ding, Dale Chittiboina, Prashant TI Unilateral vestibular schwannoma in a patient with schwannomatosis in the absence of LZTR1 mutation SO JOURNAL OF NEUROSURGERY LA English DT Article DE cranial nerve; LZTR1; schwannomatosis; vestibular schwannoma ID DIAGNOSTIC-CRITERIA AB The presence of vestibular schwannomas has long been considered an exclusion criterion for the diagnosis of schwannomatosis. Recently, 2 cases of vestibular schwannoma were reported in patients with schwannomatosis, leading to a revision of the diagnostic criteria for this genetic disorder. Overall, the relative infrequency of vestibular schwannomas in schwannomatosis is unexplained, and the genetics of this uncommon phenomenon have not been described. The authors report on a family with clinical manifestations consistent with schwannomatosis, including 4 affected members, that was identified as having an affected member harboring a unilateral cerebellopontine angle mass with extension into the internal auditory canal. Radiologically, this mass was consistent with a vestibular schwannoma and resulted in a symptomatic change in ipsilateral hearing (word recognition 86% at 52 dB) and increased latency of the wave I V interval on auditory brainstem response testing. The patient was found to be negative for a germline mutation of NF2 and LZTR1, and her affected mother was found to harbor neither NF2 nor SMARCB1 mutations on genetic testing. Although vestibular schwannomas have been classically considered to not occur in the setting of schwannomatosis, this patient with schwannomatosis and a vestibular schwannoma further confirms that schwannomas can occur on the vestibular nerve in this syndrome. Further, this is the first such case found to be negative for a mutation on the LZTR1 gene. C1 [Mehta, Gautam U.; Feldman, Michael J.; Wang, Herui; Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, 10 Ctr Dr,Rm 3D20, Bethesda, MD 20892 USA. [Mehta, Gautam U.; Ding, Dale] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA. RP Mehta, GU (reprint author), NINDS, Surg Neurol Branch, 10 Ctr Dr,Rm 3D20, Bethesda, MD 20892 USA. EM gautam.mehta@nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2016 VL 125 IS 6 BP 1469 EP 1471 DI 10.3171/2015.11.JNS151766 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA ED3XY UT WOS:000388783000017 PM 26848914 ER PT J AU Jahns, L Johnson, LK Scheett, AJ Stote, KS Raatz, SK Subar, AF Tande, D AF Jahns, Lisa Johnson, LuAnn K. Scheett, Angela J. Stote, Kim S. Raatz, Susan K. Subar, Amy F. Tande, Desiree TI Measures of Diet Quality across Calendar and Winter Holiday Seasons among Midlife Women: A 1-Year Longitudinal Study Using the Automated Self-Administered 24-Hour Recall SO Journal of the Academy of Nutrition and Dietetics LA English DT Article DE Season; Holiday; Diet quality; Healthy Eating Index 2010 (HEI-2010); Automated Self-Administered 24-Hour Recall (ASA24) ID WEIGHT-GAIN; NUTRIENT INTAKE; ENERGY-INTAKE; BODY-WEIGHT; MEN; CONSUMPTION; POPULATION; OVERWEIGHT; AMERICANS; RESOURCE AB Background Systematic seasonal bias may confound efforts to estimate usual dietary intake and diet quality. Little is known about dietary quality over the winter holiday season. Objectives The aims of this study were to test for differences in intakes of energy, percentage of energy from macronutrients, fruits and vegetables, and diet quality measured using the Healthy Eating Index 2010 (HEI-2010) by calendar and winter holiday seasons. Design Longitudinal cohort design. Participants/setting Data were derived from the Life in All Seasons study. Two cohorts of women aged 40 to 60 years (N=52) from the greater Grand Forks, ND, area were followed for 1 year each between July 2012 and July 2014. Each woman completed an online diet recall using the Automated Self-Administered 24-Hour Recall every 10 days during the year, with a 92% response rate. Statistical analyses Effects of calendar and winter holiday seasons on intakes of energy, percent energy from macronutrients, HEI-2010 total and component scores, and grams per day of individual fruits and vegetables were tested using mixed linear models. Results The mean total HEI-2010 score was 60.1 +/- 1.4. There were seasonal differences in some HEI-2010 component scores, but not in total scores. More lettuce or mixed lettuce salad was consumed during summer than during winter (P=0.034), and more fresh tomatoes were consumed during summer and fall compared with winter (P=0.001). More corn, berries, peaches and nectarines, and melons (P<0.001) were consumed during summer. There was no seasonal difference in reported intakes of energy (P=0.793). The total HEI-2010 score for dietary intake observed over the winter holiday season was lower than the rest of the year (P<0.001). Reported energy intake was not different (P=0.228). Conclusions In this population, diet quality is significantly lower during the winter holiday period, but mostly consistent by season. Multiple recalls in any season can give a reasonable representation of usual overall diet quality throughout the year. C1 [Jahns, Lisa; Johnson, LuAnn K.; Scheett, Angela J.; Raatz, Susan K.] ARS, USDA, Grand Forks Human Nutr Res Ctr, 2420 2nd Ave N, Grand Forks, ND 58203 USA. [Stote, Kim S.] SUNY Empire State Coll, Hlth Sci, Saratoga Springs, NY 12866 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Tande, Desiree] Univ North Dakota, Dept Nutr & Dietet, Grand Forks, ND 58201 USA. RP Jahns, L (reprint author), ARS, USDA, Grand Forks Human Nutr Res Ctr, 2420 2nd Ave N, Grand Forks, ND 58203 USA. EM lisa.jahns@ars.usda.gov FU US Department of Agriculture (USDA), Agricultural Research Service [USDA 5450-51000-48-00D, USDA 3062-51000-51-00D] FX This study was funded by the US Department of Agriculture (USDA), Agricultural Research Service (USDA 5450-51000-48-00D and USDA 3062-51000-51-00D). The contents of this publication do not necessarily reflect the views or policies of the USDA or the Agricultural Research Service, nor does mention of trade names, commercial products, or organizations imply endorsement from the US government. NR 31 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 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD DEC PY 2016 VL 116 IS 12 BP 1961 EP 1969 DI 10.1016/j.jand.2016.07.013 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA ED9QY UT WOS:000389208800011 PM 27618574 ER PT J AU Goldstein, BI Blanco, C He, JP Merikangas, K AF Goldstein, Benjamin I. Blanco, Carlos He, Jian-Ping Merikangas, Kathleen TI Correlates of Overweight and Obesity Among Adolescents With Bipolar Disorder in the National Comorbidity Survey-Adolescent Supplement (NCS-A) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar disorder; obesity; overweight; epidemiologic ID MAJOR DEPRESSIVE DISORDER; BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; CARDIOVASCULAR-DISEASE; WEIGHT-GAIN; I-DISORDER; SPECTRUM DISORDERS; EATING-DISORDER; UNITED-STATES; MENTAL-HEALTH AB Objective: Despite substantial evidence on the prevalence and correlates of overweight and obesity (OW/OB) in adults with bipolar disorder (BD), little is known about this topic in adolescents with BD. Method: The method consisted of the National Comorbidity Survey Adolescent Supplement, a face-to-face survey of mental disorders from 2001 through 2004, using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. Participants were adolescents 13 to 17 years of age, with bipolar disorder I or II (n = 295), major depressive disorder (n = 1,112), or controls with neither mood disorder (n = 8,716). Analyses examined for group differences in the prevalence of OW/OB and for correlates of OW/OB in the group with BD. Results: There were no significant differences in weight categories across groups. OW and OB in adolescents with BD were associated with significantly higher lifetime rates of suicide attempt (odds ratio 3.02, 95% CI 1.11-8.24), physical or sexual abuse (2.82, 1.20-6.60), binge eating or bulimia (2.66, 1.13-6.26), and conduct disorder (2.60, 1.10-6.13) in covariate-adjusted analyses. OW and 0)3 also were significantly associated with seeing a professional for depression, being hospitalized overnight for depression, and receiving general medical treatment. Conclusion: The similar prevalence of OW/OB in adolescents with and without BD suggests that this potent association in adults likely comprises a consequence of BD or its correlates. In contrast, the strong association of OW/OB with proxies for depression severity, including suicide attempts and hospitalization, is already evident even in this young, nonclinical sample. Studies are warranted to determine whether early intervention of OW/OB in BD might optimize physical and mental health. C1 [Goldstein, Benjamin I.] Sunnybrook Hlth Sci Ctr, Ctr Youth Bipolar Disorder, Toronto, ON, Canada. [Goldstein, Benjamin I.] Univ Toronto, Toronto, ON, Canada. [Blanco, Carlos] NIMH, Natl Inst Drug Abuse & Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [He, Jian-Ping; Merikangas, Kathleen] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [He, Jian-Ping; Merikangas, Kathleen] NIMH, Dev Trajectories Mental Disorders Branch, Bethesda, MD 20892 USA. RP Goldstein, BI (reprint author), Sunnybrook Hlth Sci Ctr, 2075 Bayview Ave,Room FG-53, Toronto, ON M4N 3M5, Canada. FU Intramural Research Program of the National Institute of Mental Health [ZIAMH002808] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (ZIAMH002808). The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US Government. NR 61 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 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD DEC PY 2016 VL 55 IS 12 BP 1020 EP 1026 DI 10.1016/j.jaac.2016.08.010 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EE0UF UT WOS:000389293700004 PM 27871636 ER PT J AU Gold, AL Brotman, MA Adleman, NE Lever, SN Steuber, ER Fromm, SJ Mueller, SC Pine, DS Leibenluft, E AF Gold, Andrea L. Brotman, Melissa A. Adleman, Nancy E. Lever, Sara N. Steuber, Elizabeth R. Fromm, Stephen J. Mueller, Sven C. Pine, Daniel S. Leibenluft, Ellen TI Comparing Brain Morphometry Across Multiple Childhood Psychiatric Disorders SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE voxel-based morphometry; bipolar disorder; disruptive mood dysregulation disorder; anxiety disorders; prefrontal cortex ID SEVERE MOOD DYSREGULATION; VOXEL-BASED MORPHOMETRY; GRAY-MATTER VOLUME; GENERALIZED ANXIETY DISORDER; PEDIATRIC BIPOLAR DISORDER; MAJOR DEPRESSIVE DISORDER; CORTICAL THICKNESS; HEALTHY-CHILDREN; RATING-SCALE; SEX-DIFFERENCES AB Objective: In both children and adults, psychiatric illness is associated with structural brain alterations, particularly in the prefrontal cortex (PFC). However, most studies compare gray matter volume (GMV) in healthy volunteers (HVs) to one psychiatric group. We compared GMV among youth with anxiety disorders, bipolar disorder (BD), disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), and HVs. Method: 3-Tesla T1-weighted magnetic resonance imaging scans were acquired in 184 youths (39 anxious, 20 BD, 52 DMDD, 20 ADHD, and 53 HV). Voxel-based morphometry analyses were conducted. One-way analysis of variance tested GMV differences with whole-brain familywise error (p < .05) correction; secondary, exploratory whole-brain analyses used a threshold of p < .001, >= 200 voxels. Given recent frameworks advocating dimensional approaches in psychopathology research, we also tested GMV associations with continuous anxiety, irritability, and inattention symptoms. Results: Specificity emerged in the left dorsolateral PFC (d1PFC), which differed among youth with BD, anxiety, and HVs; GMV was increased in youth with anxiety, but decreased in BD, relative to HVs. Secondary analyses revealed BD-specific GMV decreases in the right lateral PFC, right d1PFC, and dorsomedial PFC, and also anxiety specific GMV increases in the left d1PFC, right ventrolateral PFC, frontal pole, and right parahippocampal gyrus/lingual gyrus. Both BD and DMDD showed decreased GMV relative to HVs in the right d1PFC/superior frontal gyrus. GMV was not associated with dimensional measures of anxiety, irritability, or ADHD symptoms. Conclusion: Both disorder-specific and shared GMV differences manifest in pediatric psychopathology. Some differences were specific to anxiety disorders, others specific to BD, and others shared between BD and DMDD. Further developmental research might map commonalities and differences of structure and function in diverse pediatric psychopathologies. C1 [Gold, Andrea L.; Brotman, Melissa A.; Adleman, Nancy E.; Lever, Sara N.; Steuber, Elizabeth R.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. [Adleman, Nancy E.] Catholic Univ Amer, Washington, DC 20064 USA. [Fromm, Stephen J.] Vantiv Inc, Lowell, MA USA. [Mueller, Sven C.] Univ Ghent, B-9000 Ghent, Belgium. RP Gold, AL (reprint author), Bldg 1-5K,MSC-2670, Bethesda, MD 20892 USA. RI Brotman, Melissa/H-7409-2013; OI Gold, Andrea/0000-0003-4447-776X FU Intramural Research Program of the National Institute of Mental Health/National Institutes of Health (NIMH/NIH) [ZIAMH002781, ZIAMH002778-15, ZIAMH002786-13, 01-M-0192, 00-M-0198, 02-M-0021] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health/National Institutes of Health (NIMH/NIH), ZIAMH002781 (Pine), ZIAMH002778-15 (Leibenluft), ZIAMH002786-13 (Leibenluft), and based on Clinical Study Protocols 01-M-0192, 00-M-0198, and 02-M-0021. NR 63 TC 0 Z9 0 U1 20 U2 20 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 DEC PY 2016 VL 55 IS 12 BP 1027 EP 1037 DI 10.1016/j.jaac.2016.08.008 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EE0UF UT WOS:000389293700005 PM 27871637 ER PT J AU Palumbo, P Klenk, J Cattelani, L Bandinelli, S Ferrucci, L Rapp, K Chiari, L Rothenbacher, D AF Palumbo, Pierpaolo Klenk, Jochen Cattelani, Luca Bandinelli, Stefania Ferrucci, Luigi Rapp, Kilian Chiari, Lorenzo Rothenbacher, Dietrich TI Predictive Performance of a Fall Risk Assessment Tool for Community-Dwelling Older People (FRAT-up) in 4 European Cohorts SO Journal of the American Medical Directors Association LA English DT Article DE Older people; falls; FRAT-up; prediction model; validation ID INDIVIDUAL PROGNOSIS; EXTERNAL VALIDATION; DIAGNOSIS TRIPOD; META-ANALYSIS; GO TEST; MODELS; METAANALYSIS; ADULTS; POPULATION; ACCURACY AB Background and objective: The fall risk assessment tool (FRAT-up) is a tool for predicting falls in community-dwelling older people based on a meta-analysis of fall risk factors. Based on the fall risk factor profile, this tool calculates the individual risk of falling over the next year. The objective of this study is to evaluate the performance of FRAT-up in predicting future falls in multiple cohorts. Methods: Information about fall risk factors in 4 European cohorts of older people [Activity and Function in the Elderly (ActiFE), Germany; English Longitudinal Study of Aging (ELSA), England; Invecchiare nel Chianti (InCHIANTI), Italy; Irish Longitudinal Study on Aging (TILDA), Ireland] was used to calculate the FRAT-up risk score in individual participants. Information about falls that occurred after the assessment of the risk factors was collected from subsequent longitudinal follow-ups. We compared the performance of FRAT-up against those of other prediction models specifically fitted in each cohort by calculation of the area under the receiver operating characteristic curve (AUC). Results: The AUC attained by FRAT-up is 0.562 [95% confidence interval (CI) 0.530-0.594] for ActiFE, 0.699 (95% CI 0.680-0.718) for ELSA, 0.636 (95% CI 0.594-0.681) for InCHIANTI, and 0.685 (95% CI 0.660-0.709) for TILDA. Mean FRAT-up AUC as estimated from meta-analysis is 0.646 (95% CI 0.584-0.708), with substantial heterogeneity between studies. In each cohort, FRAT-up discriminant ability is surpassed, at most, by the cohort-specific risk model fitted on that same cohort. Conclusions: We conclude that FRAT-up is a valid approach to estimate risk of falls in populations of community-dwelling older people. However, further studies should be performed to better understand the reasons for the observed heterogeneity across studies and to refine a tool that performs homogeneously with higher accuracy measures across different populations. (C) 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. C1 [Palumbo, Pierpaolo; Chiari, Lorenzo] Univ Bologna, Dept Elect Elect & Informat Engn Guglielmo Marcon, Bologna, Italy. [Klenk, Jochen; Rapp, Kilian] Robert Bosch Krankenhaus, Dept Geriatr, Stuttgart, Germany. [Klenk, Jochen; Rapp, Kilian] Robert Bosch Krankenhaus, Clin Geriatr Rehabil, Stuttgart, Germany. [Klenk, Jochen; Rothenbacher, Dietrich] Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany. [Cattelani, Luca] Univ Bologna, Dept Comp Sci & Engn DISI, Bologna, Italy. [Bandinelli, Stefania] Tuscany Ctr, Local Hlth Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Chiari, Lorenzo] Univ Bologna, Hlth Sci & Technol Interdept Ctr Ind Res, Bologna, Italy. RP Palumbo, P (reprint author), Univ Bologna, Biolab, Dept Elect Elect & Informat Engn Guglielmo Marcon, Viale Risorgimento 2, I-40136 Bologna, BO, Italy. EM pierpaolo.palumbo@unibo.it RI Klenk, Jochen/C-2164-2012; OI Klenk, Jochen/0000-0002-5987-447X; Palumbo, Pierpaolo/0000-0002-4438-1787 FU Ministry of Science, Research and Arts, state of Baden-Wuerttemberg, Germany, as part of the Geriatric Competence Center, Ulm University; National Institute of Aging in the United States; National Institute on Aging (National Institutes of Health, National Institute on Aging, Bethesda, MD); Italian Health Ministry; National Institutes of Health contract; Government of Ireland through the Office of the Minister for Health and Children; Atlantic Philanthropies; Irish Life FX The ActiFE study was supported by grants from the Ministry of Science, Research and Arts, state of Baden-Wuerttemberg, Germany, as part of the Geriatric Competence Center, Ulm University.; The data relative to ELSA were made available through the United Kingdom Data Archive. ELSA was developed by a team of researchers based at the NatCen Social Research, University College London and the Institute for Fiscal Studies. The data were collected by NatCen Social Research. The funding is provided by the National Institute of Aging in the United States, and a consortium of United Kingdom government departments coordinated by the Office for National Statistics. The developers and funders of ELSA and the Archive do not bear any responsibility for the analyses or interpretations presented here.; The InCHIANTI study is currently supported by a grant from the National Institute on Aging (National Institutes of Health, National Institute on Aging, Bethesda, MD) and is coordinated by the Tuscany Regional Health Agency in a partnership with the Florence Health Care Agency, the local Administrators, and the primary care physicians of Greve in Chianti and Bagno a Ripoli. The study was initially managed by the National Institute on Research and Care of the Elderly (Ancona, Italy), and it was funded by Italian Health Ministry and by a National Institutes of Health contract. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. TILDA is an interinstitutional initiative led by Trinity College Dublin.; TILDA data have been co-funded by the Government of Ireland through the Office of the Minister for Health and Children, by Atlantic Philanthropies, and by Irish Life; have been collected under the Statistics Act, 1993, of the Central Statistics Office. The project has been designed and implemented by the TILDA study team, Department of Health and Children. Copyright and all other intellectual property rights relating to the data are vested in TILDA. Ethical approval for each wave of data collection is granted by the Trinity College Research Ethics Committee. TILDA data is accessible for free from the following sites: Irish Social Science Data Archive at University College Dublin http://www.ucd.ie/issda/data/tilda/; Interuniversity Consortium for Political and Social Research at the University of Michigan (http://www.icpsr.umich.edu/icpsrweb/ICPSR/studies/34315). NR 61 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 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD DEC 1 PY 2016 VL 17 IS 12 BP 1106 EP 1113 DI 10.1016/j.jamda.2016.07.015 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA ED9NM UT WOS:000389198200007 PM 27594522 ER PT J AU Ritt, DA Abreu-Blanco, MT Bindu, L Durrant, DE Zhou, M Specht, SI Stephen, AG Holderfield, M Morrison, DK AF Ritt, Daniel A. Abreu-Blanco, Maria T. Bindu, Lakshman Durrant, David E. Zhou, Ming Specht, Suzanne I. Stephen, Andrew G. Holderfield, Matthew Morrison, Deborah K. TI Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit SO MOLECULAR CELL LA English DT Article ID FEEDBACK PHOSPHORYLATION; MYELODYSPLASTIC SYNDROME; KINASE PHOSPHORYLATION; PROTEIN-KINASES; CELL-DEATH; RIGOSERTIB; ERK; TRANSDUCTION; ACTIVATION; MECHANISM AB Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals. This phospho-regulatory circuit is engaged by cancer therapeutics, such as rigosertib and paclitaxel/Taxol, that activate JNK through mitotic and oxidative stress as well as by physiological regulators of the JNK cascade and may function as a signaling checkpoint to suppress the Ras pathway during conditions of cellular stress. C1 [Ritt, Daniel A.; Durrant, David E.; Specht, Suzanne I.; Morrison, Deborah K.] NCI Frederick, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Abreu-Blanco, Maria T.; Bindu, Lakshman; Zhou, Ming; Stephen, Andrew G.; Holderfield, Matthew] NCI Ras Initiat, Canc Res Technol Program, Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI Frederick, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM morrisod@mail.nih.gov FU National Cancer Institute, National Institutes of Health [ZIA BC 010329, HHSN261200800001E] FX This project was supported by federal funds from the National Cancer Institute, National Institutes of Health, under project number ZIA BC 010329 and contract number HHSN261200800001E. NR 32 TC 4 Z9 4 U1 8 U2 8 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 DEC 1 PY 2016 VL 64 IS 5 BP 875 EP 887 DI 10.1016/j.molcel.2016.10.029 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE3RS UT WOS:000389515500005 PM 27889448 ER PT J AU Choi, S Hedman, AC Sayedyahossein, S Thapa, N Sacks, DB Anderson, RA AF Choi, Suyong Hedman, Andrew C. Sayedyahossein, Samar Thapa, Narendra Sacks, David B. Anderson, Richard A. TI Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases SO NATURE CELL BIOLOGY LA English DT Article ID FOCAL ADHESION KINASE; 3-KINASE PATHWAY; PHOSPHATE KINASE; EXOCYST COMPLEX; CELL REGULATION; INSULIN ACTION; BREAST-CANCER; LEADING-EDGE; IQGAP1; MEMBRANE AB Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P-3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P-3 generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIII alpha and PIPKI alpha, which sequentially generate PtdIns(3,4,5) P3 from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P-2 generated is selectively used by PI(3)K for PtdIns(3,4,5)P-3 generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI(3) K signalling complex. Blockade of IQGAP1 interaction with PIPKI alpha or PI(3)K inhibited PtdIns(3,4,5)P-3 generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy. C1 [Choi, Suyong; Thapa, Narendra; Anderson, Richard A.] Univ Wisconsin, Sch Med & Publ Hlth, 1300 Univ Ave, Madison, WI 53706 USA. [Hedman, Andrew C.; Sayedyahossein, Samar; Sacks, David B.] NIH, Dept Lab Med, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Anderson, RA (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, 1300 Univ Ave, Madison, WI 53706 USA. EM raanders@wisc.edu OI Anderson, Richard/0000-0001-6265-8359 FU National Institutes of Health (NIH); Intramural Research Program of the NIH; American Heart Association fellowships FX We would like to thank T. Balla for the PH domain constructs, and all members of the R.A.A. and D.B.S. laboratories, A. Rapreager, P. Lambert, M. Sussman and R. Kimple (University of Wisconsin-Madison) for helpful discussions. This work was supported by National Institutes of Health (NIH) grants to R.A.A., the Intramural Research Program of the NIH to D.B.S. and American Heart Association fellowships to S.C. NR 78 TC 2 Z9 2 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD DEC PY 2016 VL 18 IS 12 BP 1324 EP + DI 10.1038/ncb3441 PG 59 WC Cell Biology SC Cell Biology GA ED8PY UT WOS:000389134600010 PM 27870828 ER PT J AU de Cabo, R Navas, P AF de Cabo, Rafael Navas, Pacido TI Spermidine to the rescue for an aging heart SO NATURE MEDICINE LA English DT Editorial Material ID AUTOPHAGY; RESVERATROL; POLYAMINES; LONGEVITY C1 [de Cabo, Rafael] NIA, US NIH, Baltimore, MD 21224 USA. [Navas, Pacido] Univ Pablo de Olavide, Ctr Andaluz Biol Desarrollo, Inst Carlos III, CABD,CSIC,CIBERER, Seville, Spain. RP de Cabo, R (reprint author), NIA, US NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov OI , rafael/0000-0003-2830-5693 NR 10 TC 1 Z9 1 U1 4 U2 4 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 DEC PY 2016 VL 22 IS 12 BP 1389 EP 1390 DI 10.1038/nm.4243 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000014 PM 27923032 ER PT J AU Khurana, S Fuentes, S Coyle, EM Ravichandran, S Davey, RT Beigel, JH AF Khurana, Surender Fuentes, Sandra Coyle, Elizabeth M. Ravichandran, Supriya Davey, Richard T., Jr. Beigel, John H. TI Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies SO NATURE MEDICINE LA English DT Article ID PROTECTS NONHUMAN-PRIMATES; RANDOMIZED CLINICAL-TRIAL; INFLUENZA VACCINE; MEDIATED PROTECTION; AFFINITY MATURATION; B-CELLS; INFECTION; RESPONSES; GLYCOPROTEIN; CHALLENGE AB Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola. C1 [Khurana, Surender; Fuentes, Sandra; Coyle, Elizabeth M.; Ravichandran, Supriya] US FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. [Davey, Richard T., Jr.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Beigel, John H.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD USA. RP Khurana, S (reprint author), US FDA, Div Viral Prod, CBER, Silver Spring, MD 20993 USA. EM surender.khurana@fda.hhs.gov FU US National Institute of Allergy and Infectious Diseases; FDA-MCMi-Ebola funds; US National Cancer Institute [HHSN261200800001E]; US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland FX We thank S. Rubin and H. Golding for reviewing the manuscript and J. Voell, P. Munoz, R. McConnell, H. Baus, C. Rehm and J. Metcalf for help with clinical studies. We thank J. Crowe (Vanderbilt University) for the gift of MAb 289 and MAb 324. The clinical trial from which the test sera were derived was funded partly by the US National Institute of Allergy and Infectious Diseases. The antibody characterization work described in this manuscript was supported by FDA-MCMi-Ebola funds to S.K. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This project was funded in whole or in part with federal funds from the US National Cancer Institute under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. We thank the US Army Medical Research Institute of Infectious Diseases team, including S. Kwilas, M. Wisniewski and J. Hooper, for providing the pseudovirion neutralization assay data used in this study. The pseudovirion work was funded by the US Department of Defense (DoD) Medical Countermeasures Systems' Joint Vaccine Acquisition Program at Fort Detrick, Maryland. The opinions, interpretations, conclusions and recommendations contained herein are those of the authors and are not necessarily endorsed by the US DoD. NR 40 TC 1 Z9 1 U1 4 U2 4 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 DEC PY 2016 VL 22 IS 12 BP 1439 EP + DI 10.1038/nm.4201 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000021 PM 27798615 ER PT J AU Osuna, CE Lim, SY Deleage, C Griffin, BD Stein, D Schroeder, LT Omange, RW Best, K Luo, M Hraber, PT Andersen-Elyard, H Ojeda, EFC Huang, S Vanlandingham, DL Higgs, S Perelson, AS Estes, JD Safronetz, D Lewis, MG Whitney, JB AF Osuna, Christa E. Lim, So-Yon Deleage, Claire Griffin, Bryan D. Stein, Derek Schroeder, Lukas T. Omange, Robert Were Best, Katharine Luo, Ma Hraber, Peter T. Andersen-Elyard, Hanne Ojeda, Erwing Fabian Cardozo Huang, Scott Vanlandingham, Dana L. Higgs, Stephen Perelson, Alan S. Estes, Jacob D. Safronetz, David Lewis, Mark G. Whitney, James B. TI Zika viral dynamics and shedding in rhesus and cynomolgus macaques SO NATURE MEDICINE LA English DT Article ID NATURAL-KILLER-CELLS; WEST NILE VIRUS; SEXUAL TRANSMISSION; DENGUE VIRUS; INFECTION; BRAZIL; MOSQUITOS; OUTBREAK; SERUM; EXPRESSION AB Infection with Zika virus has been associated with serious neurological complications and fetal abnormalities. However, the dynamics of viral infection, replication and shedding are poorly understood. Here we show that both rhesus and cynomolgus macaques are highly susceptible to infection by lineages of Zika virus that are closely related to, or are currently circulating in, the Americas. After subcutaneous viral inoculation, viral RNA was detected in blood plasma as early as 1 d after infection. Viral RNA was also detected in saliva, urine, cerebrospinal fluid (CSF) and semen, but transiently in vaginal secretions. Although viral RNA during primary infection was cleared from blood plasma and urine within 10 d, viral RNA was detectable in saliva and seminal fluids until the end of the study, 3 weeks after the resolution of viremia in the blood. The control of primary Zika virus infection in the blood was correlated with rapid innate and adaptive immune responses. We also identified Zika RNA in tissues, including the brain and male and female reproductive tissues, during early and late stages of infection. Re-infection of six animals 45 d after primary infection with a heterologous strain resulted in complete protection, which suggests that primary Zika virus infection elicits protective immunity. Early invasion of Zika virus into the nervous system of healthy animals and the extent and duration of shedding in saliva and semen underscore possible concern for additional neurologic complications and nonarthropod-mediated transmission in humans. C1 [Osuna, Christa E.; Lim, So-Yon; Whitney, James B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA. [Deleage, Claire; Estes, Jacob D.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. [Griffin, Bryan D.; Stein, Derek; Schroeder, Lukas T.; Omange, Robert Were; Luo, Ma; Safronetz, David] Natl Microbiol Lab, Winnipeg, MB, Canada. [Best, Katharine; Hraber, Peter T.; Ojeda, Erwing Fabian Cardozo; Perelson, Alan S.] Los Alamos Natl Lab, Los Alamos, NM USA. [Andersen-Elyard, Hanne; Lewis, Mark G.] Bioqual, Rockville, MD USA. [Huang, Scott; Vanlandingham, Dana L.; Higgs, Stephen] Kansas State Univ, Biosecur Res Inst, Manhattan, KS 66506 USA. [Whitney, James B.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. RP Whitney, JB (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA.; Whitney, JB (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. EM jwhitne2@bidmc.harvard.edu OI Osuna, Christa/0000-0003-2761-2456; Hraber, Peter/0000-0002-2920-4897 FU National Cancer Institute ( NIH Contract) [HHSN261200800001E]; NIH [AI028433, OD0110995]; Public Health Agency of Canada FX We thank B. Finneyfrock, Z. Pippin, A. Dodson and A. Cook for their expert animal husbandry and care, and J. Guedj for suggestions about the model simulations. CD38 antibodies were obtained from the NIH Nonhuman Primate Reagent Resource supported by HHSN272200900037C and OD010976. The data presented in this study are tabulated in the main paper and in the supplementary materials. This work was supported in part by federal funds from the National Cancer Institute ( NIH Contract HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. A.S.P. acknowledges support from NIH grants AI028433 and OD0110995. D.S. acknowledges support from the Public Health Agency of Canada. NR 54 TC 8 Z9 8 U1 11 U2 11 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 DEC PY 2016 VL 22 IS 12 BP 1448 EP + DI 10.1038/nm.4206 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000022 PM 27694931 ER PT J AU Lee, J Boutz, DR Chromikova, V Joyce, MG Vollmers, C Leung, K Horton, AP DeKosky, BJ Lee, CH Lavinder, JJ Murrin, EM Chrysostomou, C Hoi, KH Tsybovsky, Y Thomas, PV Druz, A Zhang, BS Zhang, Y Wang, LS Kong, WP Park, D Popova, LI Dekker, CL Davis, MM Carter, CE Ross, TM Ellington, AD Wilson, PC Marcotte, EM Mascola, JR Ippolito, GC Krammer, F Quake, SR Kwong, PD Georgiou, G AF Lee, Jiwon Boutz, Daniel R. Chromikova, Veronika Joyce, M. Gordon Vollmers, Christopher Leung, Kwanyee Horton, Andrew P. DeKosky, Brandon J. Lee, Chang-Han Lavinder, Jason J. Murrin, Ellen M. Chrysostomou, Constantine Hoi, Kam Hon Tsybovsky, Yaroslav Thomas, Paul V. Druz, Aliaksandr Zhang, Baoshan Zhang, Yi Wang, Lingshu Kong, Wing-Pui Park, Daechan Popova, Lyubov I. Dekker, Cornelia L. Davis, Mark M. Carter, Chalise E. Ross, Ted M. Ellington, Andrew D. Wilson, Patrick C. Marcotte, Edward M. Mascola, John R. Ippolito, Gregory C. Krammer, Florian Quake, Stephen R. Kwong, Peter D. Georgiou, George TI Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination SO NATURE MEDICINE LA English DT Article ID MONOCLONAL-ANTIBODIES; IN-VIVO; NEUTRALIZING EPITOPE; VIRUS HEMAGGLUTININ; ELECTRON-MICROSCOPY; H5N1 VACCINATION; GLOBULAR HEAD; B VIRUSES; PROTECTION; VACCINES AB Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for similar to 60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine. C1 [Lee, Jiwon; DeKosky, Brandon J.; Lee, Chang-Han; Lavinder, Jason J.; Murrin, Ellen M.; Chrysostomou, Constantine; Park, Daechan; Georgiou, George] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA. [Boutz, Daniel R.; Horton, Andrew P.; Ellington, Andrew D.; Marcotte, Edward M.; Georgiou, George] Univ Texas Austin, Ctr Syst & Synthet Biol, Austin, TX 78712 USA. [Chromikova, Veronika; Krammer, Florian] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Joyce, M. Gordon; Leung, Kwanyee; Thomas, Paul V.; Druz, Aliaksandr; Zhang, Baoshan; Zhang, Yi; Wang, Lingshu; Kong, Wing-Pui; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Vollmers, Christopher; Quake, Stephen R.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Hoi, Kam Hon; Georgiou, George] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Tsybovsky, Yaroslav] Frederick Natl Lab Canc Res, Electron Microscopy Lab, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD USA. [Popova, Lyubov I.; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Gwen Knapp Ctr Lupus & Immunol Res, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Dekker, Cornelia L.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Davis, Mark M.; Quake, Stephen R.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Carter, Chalise E.; Ross, Ted M.] Univ Georgia, Dept Infect Dis, Ctr Vaccines & Immunol, Athens, GA 30602 USA. [Ellington, Andrew D.; Marcotte, Edward M.; Ippolito, Gregory C.; Georgiou, George] Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA. [Quake, Stephen R.] Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA. [DeKosky, Brandon J.] NIAID, Vaccine Res Ctr, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hoi, Kam Hon] Genentech Inc, Antibody Engn Dept, San Francisco, CA 94080 USA. [Popova, Lyubov I.] SRI Int, Div Infect Dis, Harrisonburg, VA USA. RP Georgiou, G (reprint author), Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA.; Georgiou, G (reprint author), Univ Texas Austin, Ctr Syst & Synthet Biol, Austin, TX 78712 USA.; Georgiou, G (reprint author), Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA.; Georgiou, G (reprint author), Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA. EM gg@che.utexas.edu OI Park, Daechan/0000-0003-4991-5247 FU NIH [5U19AI057234-09, PO1 AI089618, U19 AI109946]; NIH-NCRR CTSA award [UL1 RR025744]; Intramural Research Program of the Vaccine Research Center, NIAID, NIH; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Leidos Biomedical Research, Inc.; DTRA contract [HDTRA1-12-C-0105]; CPRIT grant [673 RP100890]; Clayton Foundation; Centers of Influenza Virus Research and Surveillance (CEIRS) [HHSN272201400008C, HHSN272201400005C]; Welch Foundation [F1515, F1654] FX We are grateful to C. Das for help with monoclonal antibody expression, G. Wu, S. Schatzle and Y. Wine for preliminary experiments and advice, and S. Harrison and A. Schmidt (Harvard Medical School) for providing rHAs and critical comments on the manuscript. We are indebted to Sanofi-Pasteur for their kind gift of IIV1s and to BEI Resources for rHAs. We also thank our study volunteers and S. Mackey for clinical project management, and regulatory and data management support, and S. Swope for conducting the study visits. This work was supported by NIH grants 5U19AI057234-09 (G. G.), PO1 AI089618 (G. G.) and U19 AI109946 (F.K. and P.C.W.), NIH-NCRR CTSA award number UL1 RR025744 (C.L.D.), the Intramural Research Program of the Vaccine Research Center, NIAID, NIH (M.G.J., K.L., P.V.T., A.D., B.Z., Y.Z., L.W., W.-P.K., J.R.M. and P.D.K.), federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E and Leidos Biomedical Research, Inc. (Y.T.), DTRA contract HDTRA1-12-C-0105 (G.G.), CPRIT grant 673 RP100890 for LC-MS/MS instrumentation at University of Texas at Austin (G. G.), the Clayton Foundation (G. G.), the Centers of Influenza Virus Research and Surveillance (CEIRS) contracts HHSN272201400008C (F.K.) and HHSN272201400005C (P.C.W.), and Welch Foundation grants F1515 (E.M.Marcotte) and F1654 (A.D.E.). NR 59 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 22 IS 12 BP 1456 EP + DI 10.1038/nm.4224 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000023 ER PT J AU Jarret, A McFarland, AP Horner, SM Kell, A Schwerk, J Hong, M Badil, S Joslyn, RC Baker, DP Carrington, M Hagedorn, CH Gale, M Savan, R AF Jarret, Abigail McFarland, Adelle P. Horner, Stacy M. Kell, Alison Schwerk, Johannes Hong, MeeAe Badil, Samantha Joslyn, Rochelle C. Baker, Darren P. Carrington, Mary Hagedorn, Curt H. Gale, Michael, Jr. Savan, Ram TI Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling SO NATURE MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; RECEPTOR MESSENGER-RNA; GENETIC-VARIATION; HCV INFECTION; IFN THERAPY; III IFN; EXPRESSION; IL28B; LIVER; ALPHA AB Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients(1-3). We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes(4). These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection. C1 [Jarret, Abigail; McFarland, Adelle P.; Horner, Stacy M.; Kell, Alison; Schwerk, Johannes; Hong, MeeAe; Badil, Samantha; Joslyn, Rochelle C.; Gale, Michael, Jr.; Savan, Ram] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Baker, Darren P.] Biogen Idec Inc, Cambridge, MA USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Leidos Biomed Res Frederick, Frederick, MD USA. [Carrington, Mary] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. [Hagedorn, Curt H.] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Hagedorn, Curt H.] Univ Arkansas Med Sci, Genet Program, Little Rock, AR 72205 USA. [Hagedorn, Curt H.] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [McFarland, Adelle P.] Univ Washington, Dept Microbiol, Mol & Cellular Biol Program, Seattle, WA 98195 USA. [Horner, Stacy M.] Duke Univ, Med Ctr, Ctr Virol, Dept Mol Genet & Microbiol, Durham, NC USA. [Baker, Darren P.] Sanofi Genzyme, Cambridge, MA USA. RP Savan, R (reprint author), Univ Washington, Dept Immunol, Seattle, WA 98195 USA. EM savanram@uw.edu FU NIAID NIH HHS [R01 AI108765] NR 41 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 22 IS 12 BP 1475 EP + DI 10.1038/nm.4211 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000026 PM 27841874 ER PT J AU Parkman, HP Hallinan, EK Hasler, WL Farrugia, G Koch, KL Calles, J Snape, WJ Abell, TL Sarosiek, I McCallum, RW Nguyen, L Pasricha, PJ Clarke, J Miriel, L Lee, L Tonascia, J Hamilton, F AF Parkman, H. P. Hallinan, E. K. Hasler, W. L. Farrugia, G. Koch, K. L. Calles, J. Snape, W. J. Abell, T. L. Sarosiek, I. McCallum, R. W. Nguyen, L. Pasricha, P. J. Clarke, J. Miriel, L. Lee, L. Tonascia, J. Hamilton, F. CA NIDDK Gastroparesis Clinical Res C TI Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE diabetic gastroparesis; gastric emptying; gastroparesis; Nausea; vomiting ID UPPER GASTROINTESTINAL DISORDERS; SYMPTOM SEVERITY; GASTRIC RETENTION; VALIDATION; INDEX; MEAL AB BackgroundNausea and vomiting are classic symptoms of gastroparesis. It remains unclear if characteristics of nausea and vomiting are similar in different etiologies of gastroparesis. The aims of this article were as follows: to describe characteristics of nausea and vomiting in patients with gastroparesis and to determine if there are differences in nausea and vomiting in diabetic (DG) and idiopathic gastroparesis (IG). MethodsGastroparetic patients enrolling in the NIDDK Gastroparesis Registry underwent assessment with history and questionnaires assessing symptoms, quality of life, and a questionnaire characterizing nausea and vomiting. Key ResultsOf 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting. Nausea was predominant symptom in 28% and vomiting was predominant in 4%. Nausea was severe or very severe in 41%. PAGI-SYM nausea/vomiting subscore was greater with increased vomiting severity, but not nausea severity in DG than IG. Nausea was related to meals in 71%; lasting most of the day in 41%. Increasing nausea severity was related to decreased quality of life. Nausea often preceded vomiting in 82% of patients and vomiting often relieved nausea in 30%. Vomiting was more common in DG (81%) compared to IG (57%; p=0.004). Diabetic patients more often had vomiting in the morning before eating, during the night, and when not eating. Conclusions & InferencesNausea is present in essentially all patients with gastroparesis irrespective of cause and associated with decreased quality of life. In contrast, vomiting was more prevalent, more severe, and occurred more often in DG than IG. Thus, characteristics of vomiting differ in IG vs DG. C1 [Parkman, H. P.] Temple Univ, Philadelphia, PA 19122 USA. [Hallinan, E. K.; Pasricha, P. J.; Clarke, J.; Miriel, L.; Lee, L.; Tonascia, J.] Johns Hopkins Univ, Baltimore, MD USA. [Hasler, W. L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Farrugia, G.] Mayo Clin, Rochester, MN USA. [Koch, K. L.; Calles, J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Snape, W. J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Abell, T. L.] Univ Louisville, Louisville, KY 40292 USA. [Sarosiek, I.; McCallum, R. W.] Texas Tech Univ, El Paso, TX USA. [Nguyen, L.] Stanford Univ, Palo Alto, CA 94304 USA. [Hamilton, F.] NIDDK, Bethesda, MD 20892 USA. RP Parkman, HP (reprint author), Temple Univ, Sch Med, Gastroenterol Sect, Parkinson Pavil,8th Floor,3401 North Broad St, Philadelphia, PA 19140 USA. EM henry.parkman@temple.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX The Gastroparesis Clinical Research Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008). NR 25 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD DEC PY 2016 VL 28 IS 12 BP 1902 EP 1914 DI 10.1111/nmo.12893 PG 13 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA ED8VD UT WOS:000389148100014 PM 27350152 ER PT J AU Basuli, F Zhang, X Jagoda, EM Choyke, PL Swenson, RE AF Basuli, Falguni Zhang, Xiang Jagoda, Elaine M. Choyke, Peter L. Swenson, Rolf E. TI Facile room temperature synthesis of fluorine-18 labeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester without azeotropic drying of fluorine-18 SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; LATE-STAGE FLUORINATION; IONIC LIQUID; RADIOPHARMACEUTICALS; RADIOFLUORINATION; RADIOSYNTHESES; BIOMOLECULES; SYSTEM; RANGE; PET AB Fluorine-18 labeled fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester has been successfully synthesized in an unprecedented way by flowing an acetonitrile solution of its quaternary ammonium salt precursor (N,N,N-trimethy1-5-((2,3,5,6-tetrafluorophenoxy)carbonyl)pyridin-2-aminium trifluoromethanesulfonate, 1) through an anion exchange cartridge. The fluorination reaction proceeded at room temperature without azeotropic drying of the fluoride. Over 75% conversion was observed with 10 mg of precursor in 2:8, acetonitrile: t-butanol in 1 min. The total synthesis time was 5 min which is similar to 30 min shorter than the current literature method. Published by Elsevier Inc. C1 [Basuli, Falguni; Zhang, Xiang; Swenson, Rolf E.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20852 USA. [Jagoda, Elaine M.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Basuli, F (reprint author), NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20852 USA. EM bhattacharyyaf@mail.nih.gov FU federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD DEC PY 2016 VL 43 IS 12 BP 770 EP 772 DI 10.1016/j.nucmedbio.2016.08.008 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE0TB UT WOS:000389290700004 PM 27693671 ER PT J AU Kim, H Lee, SJ Kim, JS Davies-Venn, C Cho, HJ Won, SJ Dejene, E Yao, ZS Kim, I Paik, CH Bluemke, DA AF Kim, Heejung Lee, Sung-Jin Kim, Jin Su Davies-Venn, Cynthia Cho, Hong-Jun Won, Samuel J. Dejene, Eden Yao, Zhengsheng Kim, Insook Paik, Chang H. Bluemke, David A. TI Pharmacokinetics and microbiodistribution of Cu-64-labeled collagen-binding peptides in chronic myocardial infarction SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE collagen-specific peptides; extracellular space fraction; fibrosis; myocardial infarction; PET imaging ID ENERGY COMPUTED-TOMOGRAPHY; MAGNETIC-RESONANCE; GLYCOPROTEIN-VI; CONTRAST AGENT; GD-DOTA; FIBROSIS; PET; IDENTIFICATION; RAT AB ObjectivesThe aim of the study is to evaluate the pharmacokinetics and microbiodistribution of Cu-64-labeled collagen-binding peptides.MethodsThe affinity constant (K-D), association (k(a)), and dissociation rate constant (k(d)) for the peptide collagelin or its analog (named CRPA) binding to collagen were measured by biolayer interferometric analysis. Rats (n=4-5) with myocardial infarction or normal were injected intravenously with the Cu-64-labeled peptides or Cu-64-DOTA as a control. Dynamic PET imaging was performed for 60min at 7-8 weeks after infarct. Fluorine-18 fluorodeoxyglucose PET imaging was performed to identify the viable myocardium. To validate the PET images, slices of heart samples from the base to the apex were analyzed using autoradiography and histology.ResultThe peptides bound to collagen with a K-D of approximate to 0.9 mu mol/l. The Cu-64-peptides and Cu-64-DOTA accumulated in the infarct area (confirmed by autoradiography and histology images) within 1min of injection and were excreted rapidly through the renal system. The blood clearance curves were biphasic with elimination half-lives of 21.92.4, 26.2 +/- 4.6, and 21.2 +/- 2.1min for Cu-64-CRPA, Cu-64-collagelin, and the control Cu-64-DOTA, respectively. The clearance half-lives from the focal fibrotic tissue (24.1 +/- 1.5, 25.6 +/- 8.0, and 21.4 +/- 1.3min, respectively) and remote myocardium (20.8 +/- 0.7, 21.0 +/- 5.5, and 19.1 +/- 2.4min, respectively) were not significantly different. The uptake ratios of infarct-to-remote myocardium (1.93 +/- 0.18, 2.15 +/- 0.38, and 1.88 +/- 0.08, respectively) for Cu-64-CRPA, Cu-64-collagelin, and Cu-64-DOTA remained stable for the time period between 10 and 60min.ConclusionThe distribution of the Cu-64-collagelin probes corresponds to the heterogeneous distribution of expanded extracellular space in the setting of myocardial infarction. The overall washout rate from the fibrous tissue was determined by the slow washout rate (t(1/2)20min) of the peptides from the extracellular space to the vasculature, not by the dissociation rate (t(1/2)<2min) of the Cu-64-peptides from collagen. C1 [Kim, Heejung; Lee, Sung-Jin; Kim, Jin Su; Davies-Venn, Cynthia; Cho, Hong-Jun; Won, Samuel J.; Dejene, Eden; Yao, Zhengsheng; Paik, Chang H.; Bluemke, David A.] NIH, Radiopharmaceut Lab, Dept Radiol & Imaging Sci, Ctr Clin,Nucl Med Div, Bldg 10, Bethesda, MD 20892 USA. [Kim, Insook] Frederick Natl Lab, Leidos Biomed Res Inc, Appl & Dev Res Directorate, Frederick, MD USA. [Kim, Jin Su] Korea Inst Radiol & Med Sci, Mol Imaging Res Ctr, Seoul, South Korea. RP Paik, CH (reprint author), NIH, Radiopharmaceut Lab, Dept Radiol & Imaging Sci, Ctr Clin,Nucl Med Div, Bldg 10, Bethesda, MD 20892 USA. EM cpaik@mail.nih.gov FU Intramural Research Program of Clinical Center, NIH; NCI [HHSN261200800001E] FX This research was supported by the Intramural Research Program of Clinical Center, NIH and NCI contract no. HHSN261200800001E. NR 26 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 0143-3636 EI 1473-5628 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD DEC PY 2016 VL 37 IS 12 BP 1306 EP 1317 DI 10.1097/MNM.0000000000000590 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC0RS UT WOS:000387809000014 PM 27623511 ER PT J AU Li, WY Dorans, KS Wilker, EH Rice, MB Schwartz, J Coull, BA Koutrakis, P Gold, DR Fox, CS Mittleman, MA AF Li, Wenyuan Dorans, Kirsten S. Wilker, Elissa H. Rice, Mary B. Schwartz, Joel Coull, Brent A. Koutrakis, Petros Gold, Diane R. Fox, Caroline S. Mittleman, Murray A. TI Residential Proximity to Major Roadways, Fine Particulate Matter, and Adiposity: The Framingham Heart Study SO Obesity LA English DT Article ID AEROSOL OPTICAL DEPTH; LONG-TERM EXPOSURE; BODY-MASS INDEX; AIR-POLLUTION; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; PM2.5 CONCENTRATIONS; LONGITUDINAL COHORT; TISSUE COMPARTMENTS; OXIDATIVE STRESS AB Objective: Higher traffic-related air pollution has been associated with higher body mass index (BMI) among children. However, few studies have assessed the associations among adults. Methods: Participants (N = 2,372) from the Framingham Offspring and Third Generation cohorts who underwent multidetector-computed tomography scans (2002-2005) were included. Residential-based proximity to the nearest major roadway and 1-year average levels of fine particulate matter (PM2.5) air pollution were estimated. BMI was measured at Offspring examination 7 (1998-2001) and Third Generation examination 1 (2002-2005); subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured using multidetector-computed tomography. Linear regression models were used for continuous BMI, SAT, and VAT and logistic models for the binary indicator of obesity (BMI >= 30 kg/m(2)), adjusting for demographic variables, individual- and area-level measures of socioeconomic position, and clinical and lifestyle factors. Results: Participants who lived 60 m from a major roadway had 0.37 kg/m(2) higher BMI (95% CI: 0.10 to 0.65 kg/m(2)), 78.4 cm(3) higher SAT (95% CI: 4.5 to 152.3 cm(3)), and 41.8 cm(3) higher VAT (95% CI: -4.7 to 88.2 cm(3)) than those who lived 440 m away. Conclusions: Living closer to a major roadway was associated with higher overall and abdominal adiposity. C1 [Li, Wenyuan; Dorans, Kirsten S.; Wilker, Elissa H.; Schwartz, Joel; Mittleman, Murray A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Li, Wenyuan; Dorans, Kirsten S.; Wilker, Elissa H.; Rice, Mary B.; Mittleman, Murray A.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiol, Cardiovasc Epidemiol Res Unit, Boston, MA 02115 USA. [Rice, Mary B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA USA. [Schwartz, Joel; Koutrakis, Petros; Gold, Diane R.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Coull, Brent A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Gold, Diane R.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Gold, Diane R.] Harvard Med Sch, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Mittleman, MA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Mittleman, MA (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Cardiol, Cardiovasc Epidemiol Res Unit, Boston, MA 02115 USA. EM mmittlem@hsph.harvard.edu OI Li, Wenyuan/0000-0001-6196-9964 FU USEPA [RD-83479801]; National Heart, Lung, and Blood Institute of the National Institutes of Health [HHSN268201500001I, N01-HC-25195, T32HL007575]; National Institutes of Environmental Health Sciences [P01 ES09825, K23ES026204, P30ES000002] FX This publication was made possible by USEPA grant RD-83479801. Further, USEPA does not endorse the purchase of any commercial products or services mentioned in the publication. 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 U.S. Department of Health and Human Services. This work was further supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health contracts and grants HHSN268201500001I, N01-HC-25195, and T32HL007575 and National Institutes of Environmental Health Sciences grants P01 ES09825, K23ES026204, and P30ES000002. NR 37 TC 2 Z9 2 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD DEC PY 2016 VL 24 IS 12 BP 2593 EP 2599 DI 10.1002/oby.21630 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA ED8VH UT WOS:000389148500023 PM 27804220 ER PT J AU Mendoza-Villanueva, D Balamurugan, K Ali, HR Kim, SR Sharan, S Johnson, RC Merchant, AS Caldas, C Landberg, G Sterneck, E AF Mendoza-Villanueva, D. Balamurugan, K. Ali, H. R. Kim, S-R Sharan, S. Johnson, R. C. Merchant, A. S. Caldas, C. Landberg, G. Sterneck, E. TI The C/EBP delta protein is stabilized by estrogen receptor alpha activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer SO ONCOGENE LA English DT Article ID CCAAT/ENHANCER-BINDING PROTEINS; MAMMARY-GLAND INVOLUTION; GENE-EXPRESSION; TUMOR PROGRESSION; CELL-STATE; CYCLIN D1; SLUG; PATHWAY; BETA; IDENTIFICATION AB Hypoxia and inflammatory cytokines like interleukin-6 (IL-6, IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer-binding protein d (C/EBPd, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPd in breast cancer. We found that the C/EBPd protein is expressed in normal breast epithelial cells and in low-grade cancers. C/EBPd protein (but not mRNA) expression correlates with estrogen receptor (ER+) and progesterone receptor (PGR) expression and longer progression-free survival of breast cancer patients. Specifically in ER+ breast cancers, CEBPD-but not the related CEBPB-mRNA in combination with IL6 correlated with lower risk of progression. Functional studies in cell lines showed that ERa promotes C/EBPd expression at the level of protein stability by inhibition of the FBXW7 pathway. Furthermore, we found that C/EBPd attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, which leads to expression of the cyclin-dependent kinase inhibitor CDKN1A (p21(CIP1/WAF1)). These findings identify a molecular mechanism by which ERa signaling reduces the aggressiveness of cancer cells, and demonstrate that C/EBPd can have different functions in different types of cancer. Furthermore, our results support a potentially beneficial role for the IL-6 pathway specifically in ER+ breast cancer and call for further evaluation of the role of intra-tumoral IL-6 expression and of which cancers might benefit from current attempts to target the IL-6 pathway as a therapeutic strategy. C1 [Mendoza-Villanueva, D.; Balamurugan, K.; Kim, S-R; Sharan, S.; Sterneck, E.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, POB B, Frederick, MD 21702 USA. [Ali, H. R.; Caldas, C.] Univ Cambridge, Cambridge Inst, Dept Oncol, Canc Res UK,Li Ka Shing Ctr, Cambridge, England. [Johnson, R. C.; Merchant, A. S.] Frederick Natl Lab, CCR Collaborat Bioinformat Resource, Adv Biomed Comp Ctr, Leidos Biomed, Frederick, MD USA. [Landberg, G.] Univ Manchester, Breakthrough Breast Canc Unit, Inst Canc Sci, Paterson Inst Canc Res, Manchester, Lancs, England. [Kim, S-R] US FDA, Div Biotechnol Review & Res 4, Off Biotechnol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Landberg, G.] Gothenburg Univ, Dept Pathol, Sahlgrenska Canc Ctr, Medicinaregatan 1F, S-40530 Gothenburg, Sweden. RP Sterneck, E (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM sternecg@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute; Frederick National Laboratory (NIH) [HHSN261200800001E]; National Council on Science and Technology (CONACYT), Mexico FX We are thankful to the Laboratory Animal Sciences Program (Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for excellent support, especially Donna Butcher and Glenn Summers for superb services, and Bao Tran and Jyoti Shetty (Leidos Biomedical Research, Inc.) for mRNA-Seq data. We also thank Elise Nilsson for excellent technical assistance. We thank student interns Katherine L Zhou and Yasmin Y Lachir for their valuable contributions, Linda Miller for preparation of plasmids, and Allen Kane and Joseph Meyer (Leidos Biomedical Research, Inc.) for preparing the figures for publication. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute and in part with Federal Funds from the Frederick National Laboratory (NIH) under contract no. HHSN261200800001E. DM-V was supported in part by a scholarship from the National Council on Science and Technology (CONACYT), Mexico. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 58 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 1 PY 2016 VL 35 IS 48 BP 6166 EP 6176 DI 10.1038/onc.2016.156 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED4YH UT WOS:000388857700002 PM 27181204 ER PT J AU Venturutti, L Russo, RIC Rivas, MA Mercogliano, MF Izzo, F Oakley, RH Pereyra, MG De Martino, M Proietti, CJ Yankilevich, P Roa, JC Guzman, P Cortese, E Allemand, DH Huang, TH Charreau, EH Cidlowski, JA Schillaci, R Elizalde, PV AF Venturutti, L. Russo, R. I. Cordo Rivas, M. A. Mercogliano, M. F. Izzo, F. Oakley, R. H. Pereyra, M. G. De Martino, M. Proietti, C. J. Yankilevich, P. Roa, J. C. Guzman, P. Cortese, E. Allemand, D. H. Huang, T. H. Charreau, E. H. Cidlowski, J. A. Schillaci, R. Elizalde, P. V. TI MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1 SO ONCOGENE LA English DT Article ID ELEMENT-BINDING PROTEIN-1; GROWTH-HORMONE RECEPTOR; NF-KAPPA-B; CELL-PROLIFERATION; TYROSINE KINASE; UP-REGULATION; EXPRESSION; RESISTANCE; MYC; MICRORNA AB ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ-and lapatinib-resistant ErbB-2-positive BC and GC. C1 [Venturutti, L.; Russo, R. I. Cordo; Mercogliano, M. F.; Izzo, F.; Pereyra, M. G.; De Martino, M.; Proietti, C. J.; Charreau, E. H.; Schillaci, R.; Elizalde, P. V.] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Lab Mol Mech Carcinogenesis, Buenos Aires, DF, Argentina. [Rivas, M. A.] Weill Cornell Med, Dept Med, New York, NY USA. [Oakley, R. H.; Cidlowski, J. A.] NIEHS, US Dept HHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Pereyra, M. G.] Hosp Gen Agudos Juan A Fernandez, Serv Anat Patol, Buenos Aires, DF, Argentina. [Yankilevich, P.] Max Planck Gesell, Inst Invest Biomed Buenos Aires, CONICET, Partner Inst, Buenos Aires, DF, Argentina. [Roa, J. C.; Guzman, P.] Univ La Frontera, Dept Anat Patol BIOREN, Temuco, Chile. [Roa, J. C.] Pontificia Univ Catolica Chile, Escuela Med, Dept Anat Patol, Santiago, Chile. [Roa, J. C.] Pontificia Univ Catolica Chile, Adv Ctr Chron Dis ACCDIS, Santiago, Chile. [Cortese, E.] Hosp Aeronaut Cent, Serv Ginecol, Buenos Aires, DF, Argentina. [Allemand, D. H.] Hosp Gen Agudos Juan A Fernandez, Unidad Patol Mamaria, Buenos Aires, DF, Argentina. [Huang, T. H.] Univ Texas San Antonio, Dept Mol Med, Inst Biotechnol Canc Therapy & Res Expt IBYME, San Antonio, TX USA. RP Elizalde, PV (reprint author), Consejo Nacl Invest Cient & Tecn, Lab Mol Mech Carcinogenesis, Inst Biol & Med Expt IBYME, Vuelta Obligado 2490, RA-1428 Buenos Aires, DF, Argentina. EM patriciaelizalde@ibyme.conicet.gov.ar FU Susan G Komen for the Cure [KG090250]; National Institute of Cancer (INC, Argentina); National Agency of Scientific Promotion of Argentina (ANPCyT) [IDB/PICT 2012-668, PID 2012-066]; ANPCyT [IDB/PICT 2012-382, IDB/PICT 2008-189, 2012-1017]; Henry Moore Institute of Argentina [Oncomed-Reno CONICET 1819/03]; CONICET [PIP 59] FX We thank AA Molinolo (UCSD, San Diego, CA, USA) for his constant help. This work was supported by KG090250 investigator-initiated research grant from Susan G Komen for the Cure, Financial Assistance for National Research Projects from the National Institute of Cancer (INC, Argentina), IDB/PICT 2012-668 and PID 2012-066 from National Agency of Scientific Promotion of Argentina (ANPCyT), awarded to PVE; IDB/PICT 2012-382 from ANPCyT, awarded to RS; Oncomed-Reno CONICET 1819/03, from Henry Moore Institute of Argentina, awarded to PVE and RS; IDB/PICT 2008-189 and 2012-1017 from ANPCyT, PIP 59 from CONICET, awarded to CJP. NR 76 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 1 PY 2016 VL 35 IS 48 BP 6189 EP 6202 DI 10.1038/onc.2016.151 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED4YH UT WOS:000388857700004 PM 27157613 ER PT J AU Tang, W Wang, H Ha, HL Tassi, I Bhardwaj, R Claudio, E Siebenlist, U AF Tang, W. Wang, H. Ha, H. L. Tassi, I. Bhardwaj, R. Claudio, E. Siebenlist, U. TI The B-cell tumor promoter Bcl-3 suppresses inflammation associated colon tumorigenesis in epithelial cells SO ONCOGENE LA English DT Article ID NF-KAPPA-B; COLITIS-ASSOCIATED TUMORIGENESIS; GERMINAL CENTER REACTIONS; NECROSIS-FACTOR-ALPHA; SPLENIC MICROARCHITECTURE; COLORECTAL-CANCER; MICE DEFICIENT; CARCINOGENESIS; ONCOPROTEIN; ACTIVATION AB Bcl-3 is an atypical member of the inhibitor of kappa light polypeptide gene enhancer in B-cells (I.B) family. It associates with p50/nuclear factor-kappa B1 (NF-kappa B1) and p52/NF-kappa B2 homodimers in nuclei where it modulates transcription in a context-dependent manner. A subset of B-cell tumors exhibits recurrent translocations of Bcl-3, resulting in overexpression. Elevated expression without translocations is also observed in various B-cell lymphomas and even some solid tumors. Here we investigated the role of Bcl-3 in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors, a mouse model for colitis-associated colorectal cancers in humans. Contrary to expectations, Bcl-3 suppressed colorectal tumor formation: Bcl-3-deficient mice were relatively protected from DSS-induced epithelial damage and developed more polyps after AOM/DSS treatment, although polyp size was unaffected. DSSchallenged mutant mice exhibited increased recruitment of myeloid-derived suppressor cells, consistent with protection of the epithelium. Loss of Bcl-3 in intestinal epithelial cells was sufficient to increase tumorigenesis. The added tumor burden in mutant mice was dependent on tumor necrosis factor-a (TNF alpha), a tumorigenic, NF-kappa B-mediated signaling pathway that was dampened by Bcl-3. These findings reveal a tumor-suppressive role for Bcl-3 in this inflammation-associated cancer model. Bcl-3 thus functions as a tumor promoter or suppressor, depending on the cellular and environmental context. C1 [Tang, W.; Wang, H.; Ha, H. L.; Tassi, I.; Bhardwaj, R.; Claudio, E.; Siebenlist, U.] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIH, Bldg 10,Room 11N210, Bethesda, MD 20892 USA. EM usiebenlist@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX We greatly appreciate the constructive inputs provided by all members of the Siebenlist laboratory. This research was supported by the Intramural Research Program of NIAID, NIH. NR 34 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 1 PY 2016 VL 35 IS 48 BP 6203 EP 6211 DI 10.1038/onc.2016.152 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED4YH UT WOS:000388857700005 PM 27132515 ER PT J AU Li, Y Bouchlaka, MN Wolff, J Grindle, KM Lu, L Qian, S Zhong, X Pflum, N Jobin, P Kahl, BS Eickhoff, JC Wuerzberger-Davis, SM Miyamoto, S Thomas, CJ Yang, DT Capitini, CM Rui, L AF Li, Y. Bouchlaka, M. N. Wolff, J. Grindle, K. M. Lu, L. Qian, S. Zhong, X. Pflum, N. Jobin, P. Kahl, B. S. Eickhoff, J. C. Wuerzberger-Davis, S. M. Miyamoto, S. Thomas, C. J. Yang, D. T. Capitini, C. M. Rui, L. TI FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma SO ONCOGENE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BRUTONS TYROSINE KINASE; FACTOR-KAPPA-B; FOLLICULAR LYMPHOMA; RECEPTOR; IBRUTINIB; THERAPY; APOPTOSIS; SURVIVAL; MALIGNANCIES AB Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-kappa B activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib. C1 [Li, Y.; Wolff, J.; Grindle, K. M.; Pflum, N.; Jobin, P.; Kahl, B. S.; Rui, L.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Li, Y.; Bouchlaka, M. N.; Grindle, K. M.; Kahl, B. S.; Wuerzberger-Davis, S. M.; Miyamoto, S.; Yang, D. T.; Capitini, C. M.; Rui, L.] Univ Wisconsin, Carbone Canc Ctr, Sch Med & Publ Hlth, Madison, WI USA. [Bouchlaka, M. N.; Capitini, C. M.] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. [Lu, L.; Qian, S.; Zhong, X.] Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI USA. [Lu, L.; Qian, S.; Zhong, X.] Univ Wisconsin, Genet Lab, Madison, WI USA. [Eickhoff, J. C.] Univ Wisconsin, Dept Biostat & Med Informat, Sch Med & Publ Hlth, Madison, WI USA. [Wuerzberger-Davis, S. M.; Miyamoto, S.] Univ Wisconsin, Dept Oncol, Sch Med & Publ Hlth, Madison, WI USA. [Thomas, C. J.] NIH, Div Preclin Innovat, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Yang, D. T.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI USA. [Kahl, B. S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. RP Yang, DT; Capitini, CM; Rui, L (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Div Hematol Oncol, Dept Med, 1111 Highland Ave, Madison, WI 53705 USA. EM dtyang@wisc.edu; ccapitini@pediatrics.wisc.edu; lrui@medicine.wisc.edu FU UW-Madison Start-up funds; KL2 Scholar Award [UL1TR0000427, KL2TR000428]; NIH [R01 CA187299]; MACC fund; National Institutes of Health/National Cancer Institute [K08 CA174750]; USDA National Institute of Food and Agriculture [Hatch 1002874]; UW Forward Lymphoma Fund; University of Wisconsin Carbone Cancer Center (UWCCC); NIH/NCI UW Comprehensive Cancer Center Support [P30 CA014520] FX We thank Dr Louis Staudt for providing the reagents, Dr Sameer Mathur for providing peripheral blood mononuclear cells, Dr Wei Huang for helping with analysis of immunohistochemical data, Drs Debra Bloom and Peiman Hematti for providing CD40, BAFF and BAFF receptor antibody, and Kirsti Walker for monitoring xenografted mice. This work was supported by the UW-Madison Start-up funds, KL2 Scholar Award (UL1TR0000427 and KL2TR000428), and NIH R01 CA187299 to LR, the MACC fund and the National Institutes of Health/National Cancer Institute (K08 CA174750) to CMC, the UW-Madison Start-up funds and USDA National Institute of Food and Agriculture (Hatch 1002874) to XZ, and the UW Forward Lymphoma Fund. We thank the University of Wisconsin Carbone Cancer Center (UWCCC) for the funds to complete this project. This work was also supported in part by NIH/NCI P30 CA014520- UW Comprehensive Cancer Center Support. NR 55 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 1 PY 2016 VL 35 IS 48 BP 6223 EP 6234 DI 10.1038/onc.2016.155 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ED4YH UT WOS:000388857700007 PM 27157620 ER PT J AU Marques, EA Gudnason, V Lang, T Sigurdsson, G Sigurdsson, S Aspelund, T Siggeirsdottir, K Launer, L Eiriksdottir, G Harris, TB AF Marques, E. A. Gudnason, V. Lang, T. Sigurdsson, G. Sigurdsson, S. Aspelund, T. Siggeirsdottir, K. Launer, L. Eiriksdottir, G. Harris, T. B. TI Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Aging; Bone turnover; Endosteal bone loss; Fracture risk; Periosteal apposition; QCT ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; BIOCHEMICAL MARKERS; FEMORAL-NECK; TRABECULAR BONE; ELDERLY-WOMEN; OSTEOPOROSIS; PREDICTION; RESORPTION; SURFACE; METABOLISM AB Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum. C1 [Marques, E. A.; Launer, L.; Harris, T. B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Gudnason, V.; Sigurdsson, G.; Sigurdsson, S.; Aspelund, T.; Siggeirsdottir, K.; Eiriksdottir, G.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Gudnason, V.; Sigurdsson, G.] Univ Iceland, Reykjavik, Iceland. [Lang, T.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sigurdsson, G.] Landspitalinn Univ Hosp, Reykjavik, Iceland. [Aspelund, T.] Univ Iceland, Ctr Publ Hlth Sci, Reykjavik, Iceland. RP Marques, EA (reprint author), NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM elisa.marques@nih.gov FU National Institutes of Health [N01-AG-012100]; National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament) FX This study was funded by the National Institutes of Health contract N01-AG-012100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). EAM and TBH were supported in part by and the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 38 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 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD DEC PY 2016 VL 27 IS 12 BP 3485 EP 3494 DI 10.1007/s00198-016-3675-7 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED6GI UT WOS:000388953700009 PM 27341810 ER PT J AU Ovejero, D Lim, YH Boyce, AM Gafni, RI McCarthy, E Nguyen, TA Eichenfield, LF DeKlotz, CMC Guthrie, LC Tosi, LL Thornton, PS Choate, KA Collins, MT AF Ovejero, D. Lim, Y. H. Boyce, A. M. Gafni, R. I. McCarthy, E. Nguyen, T. A. Eichenfield, L. F. DeKlotz, C. M. C. Guthrie, L. C. Tosi, L. L. Thornton, P. S. Choate, K. A. Collins, M. T. TI Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Epidermal nevus syndrome; FGF23; Hypophosphatemic rickets; RASopathies; Skeletal dysplasia ID EPIDERMAL NEVUS-SYNDROME; D-RESISTANT RICKETS; CONGENITAL MELANOCYTIC NEVI; POLYOSTOTIC FIBROUS DYSPLASIA; FIBROBLAST GROWTH FACTOR-23; TUMOR-INDUCED OSTEOMALACIA; CENTRAL PRECOCIOUS PUBERTY; POSTZYGOTIC HRAS MUTATION; FEUERSTEIN-MIMS-SYNDROME; PHAKOMATOSIS PIGMENTOKERATOTICA AB Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients. C1 [Ovejero, D.; Boyce, A. M.; Gafni, R. I.; Guthrie, L. C.; Collins, M. T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, 30 Convent Dr,Room 228,MSC 4320, Bethesda, MD 20892 USA. [Ovejero, D.] Univ Autonoma Barcelona, Dept Med, Barcelona, Spain. [Lim, Y. H.; Choate, K. A.] Yale Univ, Dept Dermatol, Sch Med, New Haven, CT USA. [McCarthy, E.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Nguyen, T. A.] Albert Einstein Coll Med, Bronx, NY USA. [Nguyen, T. A.; Eichenfield, L. F.] Univ Calif San Diego, Dept Dermatol & Pediat, San Diego & Rady Childrens Hosp, San Diego, CA USA. [DeKlotz, C. M. C.] Georgetown Univ, Div Dermatol, Dept Med, Med Ctr, Washington, DC USA. [DeKlotz, C. M. C.] Georgetown Univ, Dept Pediat, Med Ctr, Washington, DC USA. [Tosi, L. L.] Childrens Natl Hlth Syst, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC USA. [Thornton, P. S.] Cook Children Med Ctr, Dept Endocrinol & Diabet, Ft Worth, TX USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, 30 Convent Dr,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov OI DeKlotz, Cynthia/0000-0002-6410-8710 FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health; Department of Health and Human Services, Bethesda, MD; Doris Duke Charitable Foundation Clinical Scientist Development Award; Doris Duke Charitable Foundation; Yale Center for Mendelian Genomics (NIH) [U54 HG006504]; Medical Scientist Training Program at Yale University FX This study was supported in part by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD (D.O., A.M.B., R.I.G., L.G.C., and M.T.C.). K.A.C. was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, and Y.H.L. by a Doris Duke Charitable Foundation Medical Student Research Fellowship and the Yale Center for Mendelian Genomics (NIH U54 HG006504). YHL is also supported by the Medical Scientist Training Program at Yale University. NR 65 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD DEC PY 2016 VL 27 IS 12 BP 3615 EP 3626 DI 10.1007/s00198-016-3702-8 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED6GI UT WOS:000388953700023 PM 27497815 ER PT J AU Kaplan, SL Edgar, JC Ford, EG Adgent, MA Schall, JI Kelly, A Umbach, DM Rogan, WJ Stallings, VA Darge, K AF Kaplan, Summer L. Edgar, J. Christopher Ford, Eileen G. Adgent, Margaret A. Schall, Joan I. Kelly, Andrea Umbach, David M. Rogan, Walter J. Stallings, Virginia A. Darge, Kassa TI Size of testes, ovaries, uterus and breast buds by ultrasound in healthy full-term neonates ages 0-3 days SO PEDIATRIC RADIOLOGY LA English DT Article DE Breast; Measurements; Neonate; Ovary; Testis; Uterus; Ultrasound ID TESTICULAR VOLUME; GIRLS; UTERINE; NEWBORN; BIRTH; BOYS; INFANTS; PUBERTY AB Hormonally sensitive organs in the neonate can change size within days of birth as circulating maternal estrogen wanes. Although several reports document the size of these organs through infancy, few focus attention on the near-birth period. Clinical and research evaluation of hormonal and genitourinary disorders would benefit from reference size standards. We describe the size of the uterus, ovaries, testes and breast buds in healthy term neonates. As part of the Infant Feeding and Early Development (IFED) study, we sonographically measured the largest diameter of these organs in sagittal, transverse and anterior-posterior planes for 194 female and 204 male newborns up to 3 days old. We calculated mean, median and percentiles for longest axis length and for volume calculated from measured diameters. We evaluated size differences by laterality, gender and race and compared our observations against published values. Mean length and mean volume were as follows: uterus, 4.2 cm and 10.0 cm(3); ovary, 1.0 cm and 0.2 cm(3); testis, 1.1 cm and 0.3 cm(3) (0.4 cm(3) Lambert volume); female breast bud, 1.2 cm and 0.7 cm(3); male breast bud, 1.1 cm and 0.6 cm(3). Breast buds were larger in females than males. Laterality differences were typically below the precision of clinical measurement. No significant race differences were detected. Using data from our large cohort together with published values, we provide guidelines for evaluating the size of reproductive organs within the first 3 days of age. Discrepancies between our results and published values are likely attributable to technique. C1 [Kaplan, Summer L.; Edgar, J. Christopher; Darge, Kassa] Childrens Hosp Philadelphia, Dept Radiol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Edgar, J. Christopher; Kelly, Andrea; Stallings, Virginia A.; Darge, Kassa] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ford, Eileen G.; Schall, Joan I.; Stallings, Virginia A.] Childrens Hosp Philadelphia, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Adgent, Margaret A.; Rogan, Walter J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Kelly, Andrea] Childrens Hosp Philadelphia, Dept Pediat, Div Endocrinol, Philadelphia, PA 19104 USA. [Umbach, David M.] NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kaplan, SL (reprint author), Childrens Hosp Philadelphia, Dept Radiol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM kaplans2@email.chop.edu RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 24 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 EI 1432-1998 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD DEC PY 2016 VL 46 IS 13 BP 1837 EP 1847 DI 10.1007/s00247-016-3681-0 PG 11 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA ED3IO UT WOS:000388743000010 PM 27580909 ER PT J AU Sesma, JI Weitzer, CD Livraghi-Butrico, A Dang, H Donaldson, S Alexis, NE Jacobson, KA Harden, TK Lazarowski, ER AF Sesma, Juliana I. Weitzer, Clarissa D. Livraghi-Butrico, Alessandra Dang, Hong Donaldson, Scott Alexis, Neil E. Jacobson, Kenneth A. Harden, T. Kendall Lazarowski, Eduardo R. TI UDP-glucose promotes neutrophil recruitment in the lung SO Purinergic Signalling LA English DT Article DE UDP-glucose; P2Y(14) receptor; Purinergic receptors; Neutrophils; Lung inflammation ID PROTEIN-COUPLED RECEPTOR; CHANNEL-OVEREXPRESSING MICE; HUMAN AIRWAY EPITHELIA; P2Y(14) RECEPTOR; CYSTIC-FIBROSIS; NUCLEOSIDE DIPHOSPHOKINASE; SIGNALING MOLECULES; INTERNATIONAL UNION; SURFACE DEHYDRATION; ADENOSINE RECEPTORS AB In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y(14) receptors (P2Y(14)R). However, the physiological/pathophysiological consequences of UDP-sugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the beta ENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was co-instilled with the P2Y(14)R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to beta ENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation. C1 [Sesma, Juliana I.; Livraghi-Butrico, Alessandra; Dang, Hong; Donaldson, Scott; Lazarowski, Eduardo R.] Univ N Carolina, Sch Med, Marsico Lung Inst, Cyst Fibrosis Res Ctr, 6007 Thurston Bowles Bldg,CB 7248, Chapel Hill, NC 27599 USA. [Weitzer, Clarissa D.; Harden, T. Kendall] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC USA. [Alexis, Neil E.] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Sch Med, Chapel Hill, NC USA. [Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Lazarowski, ER (reprint author), Univ N Carolina, Sch Med, Marsico Lung Inst, Cyst Fibrosis Res Ctr, 6007 Thurston Bowles Bldg,CB 7248, Chapel Hill, NC 27599 USA. EM eduardo_lazarowski@med.unc.edu OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health (NIH) National Institute of General Medical Sciences [R01-GM38213]; NIH National Heart, Lung, and Blood Institute [P01-HL110873]; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program; NIH Specialized Centers of Clinically Orientated Research [P50-HL084934]; US EPA cooperative agreement [CR 833463015-35475, NHLBI-RO1 HL080337]; American Cystic Fibrosis Foundation [SESMA1510]; North Carolina Translational & Clinical Science [NCTraCS 550KR101513]; NIH [P30-DK065988] FX This work was supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences [R01-GM38213] (TKH), the NIH National Heart, Lung, and Blood Institute [P01-HL110873] (ERL), the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (KAJ), the NIH Specialized Centers of Clinically Orientated Research [P50-HL084934] (SD), the US EPA cooperative agreement CR 833463015-35475 and NHLBI-RO1 HL080337 (NEA), and the American Cystic Fibrosis Foundation [SESMA1510] and North Carolina Translational & Clinical Science [NCTraCS 550KR101513] (JIS). The Histology/Microscopy and Mouse Cores were supported by NIH P30-DK065988. NR 54 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 EI 1573-9546 J9 PURINERG SIGNAL JI Purinergic Signal. PD DEC PY 2016 VL 12 IS 4 BP 627 EP 635 DI 10.1007/s11302-016-9524-5 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EE1IX UT WOS:000389335800004 PM 27421735 ER PT J AU Schmitz-Valckenberg, S Sadda, S Staurenghi, G Chew, EY Fleckenstein, M Holz, FG AF Schmitz-Valckenberg, Steffen Sadda, Srinivas Staurenghi, Giovanni Chew, Emily Y. Fleckenstein, Monika Holz, Frank G. CA CAM Grp TI GEOGRAPHIC ATROPHY Semantic Considerations and Literature Review SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Review DE age-related macular degeneration; geographic atrophy; retinal imaging; fundus grading; color fundus photography; spectral domain optical coherence tomography; confocal scanning laser ophthalmoscopy ID RETINAL-PIGMENT EPITHELIUM; SENILE MACULAR DEGENERATION; AREOLAR CHOROIDAL DYSTROPHY; FUNDUS AUTOFLUORESCENCE; EYE DISEASE; PROGRESSION; SECONDARY; MACULOPATHY; PATTERNS; OUTCOMES AB Purpose: There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals. Methods: We reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration. Results: According to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged. Conclusion: Reconsideration of the application of the term "geographic atrophy" in the context of age-related macular degeneration seems to be prudent given ongoing advances in multimodal retinal imaging technology with identification of various phenotypic characteristics, and the observation of atrophy development in eyes under antiangiogenic therapy. C1 [Schmitz-Valckenberg, Steffen; Fleckenstein, Monika; Holz, Frank G.] Univ Bonn, GRADE Reading Ctr, Dept Ophthalmol, Bonn, Germany. [Sadda, Srinivas] Univ Southern Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA USA. [Staurenghi, Giovanni] Univ Milan, Luigi Sacco Hosp, Eye Clin, Dept Biomed & Clin Sci Luigi Sacco, Milan, Italy. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Holz, FG (reprint author), Univ Bonn, Dept Ophthalmol, Ernst Abbe Str 2, D-53127 Bonn, Germany. EM frank.holz@ukb.uni-bonn.de FU Intramural NIH HHS [Z99 EY999999] NR 92 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 BP 2250 EP 2264 DI 10.1097/IAE.0000000000001258 PG 15 WC Ophthalmology SC Ophthalmology GA ED6DB UT WOS:000388944100002 PM 27552292 ER PT J AU Cukras, C Flamendorf, J Wong, WT Ayyagari, R Cunningham, D Sieving, PA AF Cukras, Catherine Flamendorf, Jason Wong, Wai T. Ayyagari, Radha Cunningham, Denise Sieving, Paul A. TI LONGITUDINAL STRUCTURAL CHANGES IN LATE-ONSET RETINAL DEGENERATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE late-onset retinal degeneration; fundus autofluorescence; optical coherence tomography; retinal atrophy; reticular pseudodrusen ID OPTICAL COHERENCE TOMOGRAPHY; RETICULAR MACULAR DISEASE; SUBRETINAL DRUSENOID DEPOSITS; ANTERIOR LENS ZONULES; AUTOFLUORESCENCE CHARACTERISTICS; PSEUDOXANTHOMA ELASTICUM; GEOGRAPHIC ATROPHY; S163R MUTATION; L-ORD; PSEUDODRUSEN AB Purpose: To characterize longitudinal structural changes in early stages of late-onset retinal degeneration to investigate pathogenic mechanisms. Methods: Two affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence images, near-infrared reflectance fundus images, and spectral domain optical coherence tomography scans were acquired during follow-up. Results: Both patients, aged 45 and 50 years, had good visual acuities (>20/20) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on fundus autofluorescence and near-infrared reflectance imaging. Baseline spectral domain optical coherence tomography imaging revealed subretinal deposits that resemble reticular pseudodrusen described in age-related macular degeneration. During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt retinal pigment epithelium and outer retinal atrophy. Conclusion: Structural changes in early stages of late-onset retinal degeneration, revealed by multimodal imaging, resemble those of reticular pseudodrusen observed in age-related macular degeneration and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations. C1 [Cukras, Catherine; Flamendorf, Jason; Wong, Wai T.; Cunningham, Denise; Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Ayyagari, Radha] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA. RP Cukras, C (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM cukrasc@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program; NIH; Pfizer Inc; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc; Howard Hughes Medical Institute FX Supported by the National Eye Institute Intramural Research Program. Portions of this research were made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH, and generous contributions to the Foundation for the NIH from Pfizer Inc, The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. NR 34 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 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 BP 2348 EP 2356 DI 10.1097/IAE.0000000000001113 PG 9 WC Ophthalmology SC Ophthalmology GA ED6DB UT WOS:000388944100013 PM 27388725 ER PT J AU Soucy, K Fairhurst, RM Lynn, GM Fomalont, K Wynn, TA Siegel, RM AF Soucy, Katie Fairhurst, Rick M. Lynn, Geoffrey M. Fomalont, Kevin Wynn, Thomas A. Siegel, Richard M. TI Breaking the Mold: Partnering with the National Institutes of Health Intramural Research Program to Accelerate PhD Training SO TRENDS IN IMMUNOLOGY LA English DT Letter ID PLURIPOTENT STEM-CELLS; FIBROSIS AB Immunology is an increasingly interdisciplinary field. Here we describe a new model for interinstitutional graduate training as partnerships between complementary laboratories. This collaborative model reduces time to graduation without compromising productivity or alumni outcomes. We offer our experience with one such program and thoughts on the ingredients for their success. Despite tremendous recent advances in technology, communications, and the translation of basic scientific discoveries into new diagnostics and therapies for human diseases, graduate training in immunology and other areas of biomedical research in the_ United States has remained remarkably unchanged since the early 20th century, with coursework and laboratory rotations taking up much of the first 2 years, and a single mentor shepherding the student through a research project over 3 or more subsequent years. The time to graduation still averages more than 6 years in the biomedical sciences field (http://www.nsf.govistatistics/2016/nsf16300/), with uncertain benefit of this extended time to research productivity and career advancement. C1 [Soucy, Katie; Fairhurst, Rick M.; Lynn, Geoffrey M.; Fomalont, Kevin; Wynn, Thomas A.] Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD 20892 USA. [Siegel, Richard M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis, NIH, Bethesda, MD 20892 USA. EM SiegelR@mail.nih.gov NR 12 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 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD DEC PY 2016 VL 37 IS 12 BP 813 EP 815 DI 10.1016/j.it.2016.10.005 PG 3 WC Immunology SC Immunology GA EE2ET UT WOS:000389397200001 PM 27838188 ER PT J AU Fessler, MB AF Fessler, Michael B. TI The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response SO TRENDS IN IMMUNOLOGY LA English DT Review ID LIPID-METABOLISM; NLRP3 INFLAMMASOME; STEROL-METABOLISM; ADAPTIVE IMMUNITY; CELL-MIGRATION; LXR-ALPHA; KEY ROLE; T-CELLS; 25-HYDROXYCHOLESTEROL; INTERFERON AB Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon (IFN) response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, 'professional' role for sterols and oxysterols in macrophage and T-cell immunity. Host defense may have been the original selection pressure behind the development of mechanisms for intracellular cholesterol homeostasis. Functional coupling between sterol metabolism and immunity has fundamental implications for health and disease. C1 [Fessler, Michael B.] Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, MD 27709 USA. RP Fessler, MB (reprint author), Natl Inst Environm Hlth Sci, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, MD 27709 USA. EM fesslerm@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Heath Sciences [Z01 ES102005] FX The author thanks Paul Windsor for assistance with figure production. This work was supported by the National Institutes of Health, National Institute of Environmental Heath Sciences (Z01 ES102005). NR 76 TC 1 Z9 1 U1 9 U2 9 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 DEC PY 2016 VL 37 IS 12 BP 819 EP 830 DI 10.1016/j.it.2016.09.001 PG 12 WC Immunology SC Immunology GA EE2ET UT WOS:000389397200003 PM 27692616 ER PT J AU Basavalingappa, RH Massilamany, C Krishnan, B Gangaplara, A Kang, GB Khanzad-Sharghi, V Han, ZJ Othman, S Li, QS Riethoven, JJ Sobel, RA Steffen, D Reddy, J AF Basavalingappa, Rakesh H. Massilamany, Chandirasegaran Krishnan, Bharathi Gangaplara, Arunakumar Kang, Guobin Khanzad-Sharghi, Vahid Han, Zhongji Othman, Shadi Li, Qingsheng Riethoven, Jean-Jack Sobel, Raymond A. Steffen, David Reddy, Jay TI Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; EXPERIMENTAL AUTOIMMUNE MYOCARDITIS; IDIOPATHIC DILATED CARDIOMYOPATHY; CENTRAL-NERVOUS-SYSTEM; T-CELLS; TRANSGENIC OVEREXPRESSION; EPITHELIAL-CELLS; ADP/ATP CARRIER; DISEASE; PEPTIDES AB Heart failure, a leading cause of death in humans, can emanate from myocarditis. Although most individuals with myocarditis recover spontaneously, some develop chronic dilated cardiomyopathy. Myocarditis may result from both infectious and noninfectious causes, including autoimmune responses to cardiac antigens. In support of this notion, intracellular cardiac antigens, like cardiac myosin heavy chain-alpha, cardiac troponin-I, and adenine nucleotide translocator 1 (ANT(1).), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT(1) can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANTI encompasses multiple immunodominant epitopes (namely, ANT(1) 21-40, ANT(1). 31-50, ANT(1) 171-190, and ANT(1) 181-200). Although all four peptides induce comparable T-cell responses, only ANT(1). 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT(1) 21-40 was associated with the generation of T cells producing predominantly IL-17A, and the antigen-sensitized T cells could transfer the disease to naive recipients. These data indicate that cardiac mitochondrial proteins can be target autoantigens in myocarditis, supporting the notion that the antigens released as a result of primary damage may contribute to the persistence of chronic inflammation through auto-immunity. C1 [Basavalingappa, Rakesh H.; Massilamany, Chandirasegaran; Krishnan, Bharathi; Gangaplara, Arunakumar; Steffen, David; Reddy, Jay] Univ Nebraska, Sch Vet Med & Biomed Sci, Bldg VBS,Room 202, Lincoln, NE 68583 USA. [Kang, Guobin; Li, Qingsheng] Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE USA. [Kang, Guobin; Li, Qingsheng] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. [Khanzad-Sharghi, Vahid; Han, Zhongji; Othman, Shadi] Univ Nebraska, Dept Biol Syst Engn, Lincoln, NE USA. [Riethoven, Jean-Jack] Univ Nebraska, Ctr Biotechnol, Lincoln, NE USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Gangaplara, Arunakumar] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Reddy, J (reprint author), Univ Nebraska, Sch Vet Med & Biomed Sci, Bldg VBS,Room 202, Lincoln, NE 68583 USA. EM nreddy2@unl.edu OI Gangaplara, Arunakumar/0000-0001-6307-9391 FU NIH [HL114669]; National Institute of General Medical Science, Nebraska Center for the Prevention of Obesity Diseases, University of Nebraska-Lincoln [P20GM104320] FX Supported by NIH grant HL114669 (J.R.), and the National Institute of General Medical Science grant P20GM104320, Nebraska Center for the Prevention of Obesity Diseases, University of Nebraska-Lincoln. NR 65 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2016 VL 186 IS 12 BP 3160 EP 3175 DI 10.1016/j.ajpath.2016.08.005 PG 16 WC Pathology SC Pathology GA ED8EC UT WOS:000389103800009 PM 27876151 ER PT J AU Blanco, C Wall, MM Okuda, M Wang, S Iza, M Olfson, M AF Blanco, Carlos Wall, Melanie M. Okuda, Mayumi Wang, Shuai Iza, Miren Olfson, Mark TI Pain as a Predictor of Opioid Use Disorder in a Nationally Representative Sample SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ALCOHOL-USE DISORDER; INTERVIEW SCHEDULE AUDADIS; DRUG-USE DISORDERS; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; QUALITY-OF-LIFE; UNITED-STATES; EPIDEMIOLOGIC-SURVEY; INDUCED HYPERALGESIA; NONMEDICAL USE AB Objective: The authors sought to ascertain the relationship between moderate and more severe pain and prescription opioid use disorders in the noninstitutionalized U.S. population. Method: A structural equation model was used to assess prospectively the interdependency of pain and prescription opioid use disorder at waves 1(2001-2002) and 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. Pain was measured with a 5-point scale of pain-related interference in daily activities and dichotomized as "no pain" (no or little interference) or "pain" (moderate to extreme interference). Prescription opioid use disorder was assessed with a structured interview (the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV version). Other covariates included age, sex, anxiety or mood disorders, and family history of drug, alcohol, and behavioral problems. Results: In the structural equation model, pain and prescription opioid use disorders were significantly associated with one another at baseline and at 3-year follow-up. However, whereas pain at baseline was also significantly associated with prescription opioid use disorder at follow-up, prescription opioid use disorder at baseline was not associated with pain at follow-up. These associations were independent of several background demographic and clinical characteristics. The path for pain interference was associated with a 41% relative increase in the risk of developing a prescription opioid use disorder. Conclusions: Painful conditions contribute to the risk of prescription opioid use disorders. To help reduce the incidence of prescription opioid abuse and dependence among adults with moderate to severe pain, careful monitoring and consideration of nonopioid alternative treatments is warranted. C1 [Olfson, Mark] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, Dept Psychiat, New York, NY 10032 USA. Columbia Univ, New York, NY USA. Fdn Jimenez Diaz, Dept Psychiat, Madrid, Spain. RP Olfson, M (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. EM mo49@cumc.columbia.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Program, NIAAA; NIH [MH076051, MH082773, CA133050]; New York State Psychiatric Institute FX The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and funded in part by the Intramural Program, NIAAA. Work on this manuscript was supported by NIH grants MH076051, MH082773, and CA133050 and the New York State Psychiatric Institute (Drs. Blanco, Olfson, and Wall). NR 45 TC 3 Z9 3 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2016 VL 173 IS 12 BP 1189 EP 1195 DI 10.1176/appi.ajp.2016.15091179 PG 7 WC Psychiatry SC Psychiatry GA ED7CB UT WOS:000389012200008 PM 27444794 ER PT J AU Kabakus, IM Borofsky, S Mertan, FV Greer, M Daar, D Wood, BJ Pinto, PA Choyke, PL Turkbey, B AF Kabakus, Ismail M. Borofsky, Samuel Mertan, Francesca V. Greer, Matthew Daar, Dagane Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Does Abstinence From Ejaculation Before Prostate MRI Improve Evaluation of the Seminal Vesicles? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ejaculation; MRI; prostate; seminal vesicles AB OBJECTIVE. The purpose of the present study is to determine whether abstinence from ejaculation before undergoing multiparametric prostate MRI increases seminal vesicle (SV) volume and therefore improves diagnostic interpretation of the SVs. MATERIALS AND METHODS. This retrospective study included 238 patients who underwent 3-T MRI of the prostate over a 4-month period. Patients were requested to complete a questionnaire that asked how long it had been since their last ejaculation (i.e., < 3 days vs >= 3 days). Forty-two patients (mean patient age, 62.0 years) indicated that it had been less than 3 days since their last ejaculation and were designated as group 1, whereas the remainder indicated an interval of 3 days or more since their last ejaculation. A group of 42 age-matched subjects (mean patient age, 62.1 years) were randomly selected from the remaining 196 patients and were designated as group 2. SV volumes were measured manually. Two radiologists who were blinded to group assignment and patient characteristics scored the right and left SVs separately to determine diagnostic interpretability, which was scored on a 3-point scale as follows: a score of 1 denoted that the SVs were not dilated and the score was nondiagnostic, a score of 2 indicated that the SVs were not dilated but the score was diagnostic, and a score of 3 denoted that the SVs were dilated and the score was diagnostic. Volume differences and interpretability scores were analyzed using a t test. Interobserver agreement was analyzed using the Cohen kappa statistic. A separate analysis was performed to evaluate differences in diagnostic interpretability for patients 60 years and younger versus patients older than 60 years, by use of the chi-square test and relative risk ratio analysis. RESULTS. The right, left, and total SV volumes for group 1 were 3.1 mL, 2.9 mL, and 6.0 mL, respectively, whereas those for group 2 were 4.7 mL, 4.1 mL, and 8.8 mL, respectively (p = 0.011). The mean interpretability scores for group 1 and group 2 were 2.0 and 2.5, respectively. For group 1, reader 1 and reader 2 assigned a nondiagnostic score for 10 and 13 patients, respectively, whereas for group 2, they assigned a nondiagnostic score for two and five patients, respectively (p = 0.01, for reader 1; and p = 0.03, for reader 2). For men in group 1 who were older than 60 years, reader 1 and reader 2 gave a nondiagnostic score for nine and 11 patients, respectively; whereas for men in group 2 who were older than 60 years, the readers gave a nondiagnostic score for two and five patients, respectively (p = 0.01, for reader 1; and p = 0.05, for reader 2). CONCLUSION. For men older than 60 years, abstinence from ejaculation for 3 or more days before undergoing MRI examination resulted in larger SV volumes and lower rates of nondiagnostic evaluation and therefore might improve evaluation of SV invasion on multiparametric MRI. The difference is less striking in men 60 years and younger. C1 [Kabakus, Ismail M.] Hacettepe Univ, Dept Radiol, Ankara, Turkey. [Borofsky, Samuel] George Washington Univ, Dept Radiol, Washington, DC USA. [Mertan, Francesca V.; Greer, Matthew; Daar, Dagane; Choyke, Peter L.; Turkbey, Baris] NIH, Mol Imaging Program, 10 Ctr Dr,Bldg 10,Rm B3B85, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Dept Intervent Radiol, Bldg 10, Bethesda, MD 20892 USA. [Pinto, Peter A.] NIH, Dept Urol, Bldg 10, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NIH, Mol Imaging Program, 10 Ctr Dr,Bldg 10,Rm B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Greer, Matthew/0000-0003-4409-4398 NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2016 VL 207 IS 6 BP 1205 EP 1209 DI 10.2214/AJR.16.16278 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED2MS UT WOS:000388681400016 PM 27657193 ER PT J AU Lim, H Linet, MS Van Dyke, ME Miller, DL Simon, SL Sigurdson, AJ Kitahara, CM AF Lim, Hyeyeun Linet, Martha S. Van Dyke, Miriam E. Miller, Donald L. Simon, Steven L. Sigurdson, Alice J. Kitahara, Cari M. TI Changing Patterns in the Performance of Fluoroscopically Guided Interventional Procedures and Adherence to Radiation Safety Practices in a US Cohort of Radiologic Technologists SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE cardiovascular catheterizations; fluoroscopically guided procedures; radiation safety practices; radiologic technologists ID AMERICAN-HEART-ASSOCIATION; IONIZING-RADIATION; CANCER-RISKS; CARDIOLOGISTS; DISEASE; HEALTH; PROTECTION; HAZARDS; WORKING; UPDATE AB OBJECTIVE. Information is limited on changes over time in the types of fluoroscopically guided interventional procedures performed and associated radiation safety practices used by radiologic technologists. MATERIALS AND METHODS. Our study included 12,571 U.S. radiologic technologists who were certified for at least 2 years in 1926-1982 and who reported in a 2012-2013 survey that they ever performed or assisted with fluoroscopically guided interventional procedures. They completed a mailed questionnaire in 2013-2014 describing their detailed work practices for 21 fluoroscopically guided interventional procedures and associated radiation safety practices from the 1950s through 2009. RESULTS. Overall, the proportion of technologists who reported working with therapeutic fluoroscopically guided interventional procedures, including percutaneous coronary interventions, increased over time, whereas the proportion of technologists who worked with diagnostic fluoroscopically guided interventional procedures, including diagnostic cardiovascular catheterization and neuroangiographic procedures, decreased. We also observed substantial increases in the median number of times per month that technologists worked with diagnostic cardiovascular catheterizations and percutaneous coronary interventions. In each time period, most technologists reported consistently (>= 75% of work time) wearing radiation monitoring badges and lead aprons during fluoroscopically guided interventional procedures. However, fewer than 50% of the technologists reported consistent use of thyroid shields, lead glasses, and room shields during fluoroscopically guided interventional procedures, even in more recent time periods. CONCLUSION. This study provides a detailed historical assessment of fluoroscopically guided interventional procedures performed and radiation safety practices used by radiologic technologists from the 1950s through 2009. Results can be used in conjunction with badge dose data to estimate organ radiation dose for studies of radiation-related health risks in radiologic technologists who have worked with fluoroscopically guided interventional procedures. C1 [Lim, Hyeyeun; Linet, Martha S.; Simon, Steven L.; Sigurdson, Alice J.; Kitahara, Cari M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9069 Med Ctr Dr, Rockville, MD 20850 USA. [Van Dyke, Miriam E.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Miller, Donald L.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Lim, H (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 9069 Med Ctr Dr, Rockville, MD 20850 USA. EM Hyeyeun.lim@nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services FX Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. NR 35 TC 0 Z9 0 U1 7 U2 7 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2016 VL 207 IS 6 BP 1350 EP 1359 DI 10.2214/AJR.15.15979 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED2MS UT WOS:000388681400037 PM 27575031 ER PT J AU Amano, M Salcedo-Gomez, PM Zhao, R Yedidi, RS Das, D Bulut, H Delino, NS Sheri, VR Ghosh, AK Mitsuya, H AF Amano, Masayuki Salcedo-Gomez, Pedro Miguel Zhao, Rui Yedidi, Ravikiran S. Das, Debananda Bulut, Haydar Delino, Nicole S. Sheri, Venkata Reddy Ghosh, Arun K. Mitsuya, Hiroaki TI A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DRUG DISCOVERY; ANTIRETROVIRAL THERAPY; BIS-TETRAHYDROFURAN; CRYSTAL-STRUCTURES; X-RAY; LIGAND; POTENT; PI; REPLICATION AB We report here that GRL-10413, a novel nonpeptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a hydroxyethylamine sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50] of 0.00035 to 0.0018 mu M), with minimal cytotoxicity (50% cytotoxic concentration [CC50] =35.7 mu M). GRL-10413 blocked the infectivity and replication of HIV-1NL4-3 variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 mu M(EC50 =0.0021 to 0.0023 mu M). GRL-10413 also maintained its strong antiviral activity against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that against APV. In addition, GRL-10413 showed favorable central nervous system (CNS) penetration properties as assessed with an in vitro blood-brain barrier (BBB) reconstruction system. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants, with favorable CNS penetration capability, and that the newly modified P1 moiety may confer desirable features in designing novel anti-HIV-1 PIs. C1 [Amano, Masayuki; Salcedo-Gomez, Pedro Miguel; Zhao, Rui; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto, Japan. [Amano, Masayuki; Salcedo-Gomez, Pedro Miguel; Zhao, Rui; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto, Japan. [Yedidi, Ravikiran S.; Das, Debananda; Bulut, Haydar; Delino, Nicole S.; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Yedidi, Ravikiran S.] GSL Med Coll & Gen Hosp, Dept Pharmacol, Rajahmundry, Andhra Pradesh, India. [Sheri, Venkata Reddy; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Sheri, Venkata Reddy; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Mitsuya, Hiroaki] Natl Ctr Global Hlth, Tokyo, Japan. [Mitsuya, Hiroaki] Med Res Inst, Tokyo, Japan. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto, Japan. EM hm21q@nih.gov RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU HHS \ National Institutes of Health (NIH) [GM53386]; Ministry of Health, Labor and Welfare (MHLW) FX This work, including the efforts of Arun K. Ghosh, was funded by HHS vertical bar National Institutes of Health (NIH) (GM53386). This work, including the efforts of Hiroaki Mitsuya, was funded by Ministry of Health, Labor and Welfare (MHLW). NR 54 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2016 VL 60 IS 12 BP 7046 EP 7059 DI 10.1128/AAC.01428-16 PG 14 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7QO UT WOS:000389064300005 PM 27620483 ER PT J AU Lestner, JM Groll, AH Aljayyoussi, G Seibel, NL Shad, A Gonzalez, C Wood, LV Jarosinski, PF Walsh, TJ Hope, WW AF Lestner, Jodi M. Groll, Andreas H. Aljayyoussi, Ghaith Seibel, Nita L. Shad, Aziza Gonzalez, Corina Wood, Lauren V. Jarosinski, Paul F. Walsh, Thomas J. Hope, William W. TI Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LIPOPROTEINS; DISEASES; SERUM; TRIAL; ASPERGILLOSIS; AMBISOME; THERAPY; SAFETY AB Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg(-1) daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = 35 patients) and on the final day of therapy (n = 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n = 13) having significantly higher maximum serum concentrations (C-max) and areas under the concentration-time curve from 0 to 24 h (AUC(0-24)) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC(0-24) and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P = 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors. C1 [Lestner, Jodi M.; Hope, William W.] Univ Liverpool, Antimicrobial Pharmacodynam & Therapeut, Liverpool, Merseyside, England. [Groll, Andreas H.] Univ Childrens Hosp Munster, Ctr Bone Marrow Transplantat, Dept Pediat Hematology Oncol, Munster, Germany. [Aljayyoussi, Ghaith] Univ Liverpool Liverpool Sch Trop Med, Liverpool, Merseyside, England. [Seibel, Nita L.; Walsh, Thomas J.] NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD USA. [Seibel, Nita L.] Childrens Natl Med Ctr & George Washington Univ S, Washington, DC USA. [Shad, Aziza] NCI, Clin Investigat Branch, Canc Treatment Evaluat Program, Bethesda, MD USA. [Gonzalez, Corina] Univ Med Ctr, Dept Pediat, Div Pediat Hematology Oncol, Washington, DC USA. [Wood, Lauren V.] NCI, Ctr Canc Res, Bethesda, MD USA. [Jarosinski, Paul F.] Natl Inst Hlth Clin Ctr, Dept Pharm, Bethesda, MD USA. [Walsh, Thomas J.] Weill Cornell Med Ctr, Transplantat Oncol Infect Dis Program, New York, NY USA. [Walsh, Thomas J.] Weill Cornell Med Ctr, Dept Pediat, New York, NY USA. [Walsh, Thomas J.] Weill Cornell Med Ctr, Dept Microbiol, New York, NY USA. RP Lestner, JM (reprint author), Univ Liverpool, Antimicrobial Pharmacodynam & Therapeut, Liverpool, Merseyside, England. EM jlestner@liverpool.ac.uk OI Hope, William/0000-0001-6187-878X FU Astellas Pharma (Astellas) FX This work, including the efforts of Thomas J. Walsh, was funded by Astellas Pharma (Astellas). NR 18 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2016 VL 60 IS 12 BP 7340 EP 7346 DI 10.1128/AAC.01427-16 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7QO UT WOS:000389064300037 PM 27697762 ER PT J AU Kharfan-Dabaja, MA Kumar, A Hamadani, M Stilgenbauer, S Ghia, P Anasetti, C Dreger, P Montserrat, E Perales, MA Alyea, EP Awan, FT Ayala, E Barrientos, JC Brown, JR Castro, JE Furman, RR Gribben, J Hill, BT Mohty, M Moreno, C O'Brien, S Pavletic, SZ Pinilla-Ibarz, J Reddy, NM Sorror, M Bredeson, C Carpenter, P Savani, BN AF Kharfan-Dabaja, Mohamed A. Kumar, Ambuj Hamadani, Mehdi Stilgenbauer, Stephan Ghia, Paolo Anasetti, Claudio Dreger, Peter Montserrat, Emili Perales, Miguel-Angel Alyea, Edwin P. Awan, Farrukh T. Ayala, Ernesto Barrientos, Jacqueline C. Brown, Jennifer R. Castro, Januario E. Furman, Richard R. Gribben, John Hill, Brian T. Mohty, Mohamad Moreno, Carol O'Brien, Susan Pavletic, Steven Z. Pinilla-Ibarz, Javier Reddy, Nishitha M. Sorror, Mohamed Bredeson, Christopher Carpenter, Paul Savani, Bipin N. TI Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic lymphocytic leukemia; Allogeneic hematopoietic cell transplantation; BCR inhibitors; BCL-2 inhibitors ID RICHTER-SYNDROME; REDUCED-INTENSITY; FLOW-CYTOMETRY; 17P DELETION; FOLLOW-UP; MUTATIONAL STATUS; PERIPHERAL-BLOOD; BONE-MARROW; SINGLE-ARM; CLL AB We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations high-light the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Kharfan-Dabaja, Mohamed A.; Anasetti, Claudio; Ayala, Ernesto] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Kharfan-Dabaja, Mohamed A.; Anasetti, Claudio; Ayala, Ernesto; Pinilla-Ibarz, Javier] Univ S Florida, Morsani Coll Med, Dept Oncol Sci, Tampa, FL USA. [Kumar, Ambuj] Univ S Florida, Coll Med, Program Comparat Effectiveness Res, Tampa, FL USA. [Hamadani, Mehdi] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Stilgenbauer, Stephan] Univ Ulm, Internal Med 3, Ulm, Germany. [Ghia, Paolo] IRCCS San Raffaele Hosp, Dept Oncohaematol, Milan, Italy. [Ghia, Paolo] IRCCS San Raffaele Hosp, Div Expt Oncol, Milan, Italy. [Ghia, Paolo] Univ Vita Salute San Raffaele, Milan, Italy. [Dreger, Peter] Heidelberg Univ, Dept Med 5, Heidelberg, Germany. [Montserrat, Emili] Univ Barcelona, Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Adult Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Alyea, Edwin P.; Brown, Jennifer R.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Awan, Farrukh T.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Barrientos, Jacqueline C.] Hofstra Northwell Sch Med, CLL Res & Treatment Program, New Hyde Pk, NY USA. [Castro, Januario E.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Furman, Richard R.] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY USA. [Gribben, John] Queen Mary Univ London, John Vane Canc Ctr, Barts Canc Inst, Charterhouse Sq, London, England. [Hill, Brian T.] Cleveland Clin, Dept Hematol & Med Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. [Mohty, Mohamad] Univ Paris 06, St Antoine Hosp, Dept Haematol, Paris, France. [Mohty, Mohamad] INSERM, UMRs938, Paris, France. [Moreno, Carol] Hosp Santa Creu St Pau, Barcelona, Spain. [O'Brien, Susan] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Pavletic, Steven Z.] NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Pinilla-Ibarz, Javier] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL USA. [Reddy, Nishitha M.; Savani, Bipin N.] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37212 USA. [Sorror, Mohamed; Carpenter, Paul] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Sorror, Mohamed; Carpenter, Paul] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Bredeson, Christopher] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher] Ottawa Hosp Res Inst, Ottawa, ON, Canada. RP Kharfan-Dabaja, MA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, 12902 Magnolia Dr,FOB 3, Tampa, FL 33612 USA. EM Mohamed.Kharfan-Dabaja@Moffitt.org FU Takeda Oncology; Sanofi; Otsuka; AbbVie; Amgen; Boehringer-Ingelheim; Celgene; Genentech; Genzyme; Gilead; GlaxoSmithKline; Janssen; Mundipharma; Novartis; Pharmacyclics; Hoffmann La-Roche; GSK; Roche; Acerta; TG Therapeutics; Regeneron; ProNAi FX The authors have nothing to disclose. Conflict of interest statement: M.H.: Research funding by Takeda Oncology, Sanofi, and Otsuka; Honoraria from Celgene; Consultancy by Medimmune, Pharmacyclics and Cellerant. S.S.: Honoraria for consultancy, research support, and travel support from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi. P.G.: Advisory board for AbbVie, Adaptive Biotechnologies, Gilead, Janssen, Pharmacyclics, and Roche; Research funding from Gilead, GSK, and Roche. P.D.: Research support from Janssen and and Gilead; Honoraria for speaker and advisory board services from Janssen, Gilead, Novartis, and Roche. F.T.A.: Advisory boards for Gilead and Novartis Oncology. J.G.: Honoraria from Janssen, Roche/Genentech, Abbie, Pharmacyclics, Gilead, and Celgene. B.T.H.: Advisory boards for Pharmacyclics and Gilead; Research funding from Abbvie. M.M.: Honoraria for speaking engagements and research support from Janssen. S.O.: Consultant for Amgen, Celgene, and GSK; Advisory board for CLL Global Research Foundation; Research support from Acerta, TG Therapeutics, Regeneron, Gilead, Pharmacyclics, and ProNAi. J.P.-I.: Consultant for Janssen, Gilead, Pharmacyclics, Abbvie, and Celgene; Speaker Bureau for TEVA, Pharmacyclics, and Gilead. N.M.R.: Advisory boards of AbbVie and Gilead. All other authors report no conflicts of interest. NR 76 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2016 VL 22 IS 12 BP 2117 EP 2125 DI 10.1016/j.bbmt.2016.09.013 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA ED8CM UT WOS:000389099600003 PM 27660167 ER PT J AU Shah, NN Loeb, DM Khuu, H Stroncek, D Ariyo, T Raffeld, M Delbrook, C Mackall, CL Wayne, AS Fry, TJ AF Shah, Nirali N. Loeb, David M. Khuu, Hahn Stroncek, David Ariyo, Tolu Raffeld, Mark Delbrook, Cindy Mackall, Crystal L. Wayne, Alan S. Fry, Terry J. TI Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Wilms' tumor 1 (WT1); Dendritic cell vaccine; Post-transplantation relapse; Leukemia ID ACUTE MYELOID-LEUKEMIA; WT1 PEPTIDE VACCINATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; 2ND INTERNATIONAL WORKSHOP; GENE WT1; CANCER-IMMUNOTHERAPY; LEUKOCYTE INFUSIONS; ANTITUMOR IMMUNITY; HIGH-RISK; TRANSPLANTATION AB Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft versus-host disease (GVHD). The Wilms' tumor 1 (WTI) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WTI peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n =3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n=1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WTI peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Shah, Nirali N.; Ariyo, Tolu; Delbrook, Cindy; Mackall, Crystal L.; Wayne, Alan S.; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Loeb, David M.] Johns Hopkins Univ, Pediat Oncol, Baltimore, MD USA. [Khuu, Hahn; Stroncek, David] NCI, Dept Transfus Med, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Raffeld, Mark] Univ Southern Calif, Heck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Wayne, Alan S.] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90027 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute FX We gratefully acknowledge the study participants and their families, referring medical care teams, and the faculty and staff of the National Institutes of Health. This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. NR 30 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2016 VL 22 IS 12 BP 2149 EP 2154 DI 10.1016/j.bbmt.2016.08.028 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA ED8CM UT WOS:000389099600007 PM 27634018 ER PT J AU Gadalla, SM Wang, T Dagnall, C Haagenson, M Spellman, SR Hicks, B Jones, K Katki, HA Lee, SJ Savage, SA AF Gadalla, Shahinaz M. Wang, Tao Dagnall, Casey Haagenson, Michael Spellman, Stephen R. Hicks, Belynda Jones, Kristine Katki, Hormuzd A. Lee, Stephanie J. Savage, Sharon A. TI Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Aplastic anemia; Telomere length; Survival; Hematopoietic cell transplantation; Donor selection ID BONE-MARROW; PERIPHERAL-BLOOD; CHILDREN; STABILITY; JAPAN; TIME; PCR; SCT AB We previously showed an association between donor leukocyte relative telomere length (RTL) and posthematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages <40 years. Here, we tested the generalizability of the prior findings in an independent validation cohort and by recipient age and stem cell source in the combined discovery and validation cohorts. We used monoplex quantitative real-time PCR to measure RTL in: (1) a new SAA validation cohort of 428 patients (age range,2 to 77 years) with available pretransplantation donor blood samples in the Center for International Blood and Marrow Transplant Research repository, and (2) 278 patients from the original cohort who had sufficient DNA to repeat RTL testing. We used Cox proportional hazard models to calculate hazard ratios (HRs), and 95% confidence intervals (CIs) across categories of donor RTL. Data from the validation cohort showed no association between donor RTL and patient survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients <40 years, the HR comparing longest with shortest and middle RTL tertiles = .75; 95% CI,.44 to 1.30 versus HR = 1.05; 95% CI, .59 to 1.89 for patients >= 40 years, P interaction = .37. In bone marrow recipients, the HR = .68; 95% CI, .72 to 1.10 versus HR = 1.29; 95% CI, .64 to 2.62 for peripheral blood stem cell grafts; P interaction = .88. Analyses using data from the 2 cohorts showed a statistically significant survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Gadalla, Shahinaz M.; Katki, Hormuzd A.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wang, Tao; Lee, Stephanie J.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Wang, Tao] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Dagnall, Casey; Hicks, Belynda; Jones, Kristine] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dagnall, Casey; Hicks, Belynda; Jones, Kristine] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Haagenson, Michael; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. RP Gadalla, SM (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E-534, Rockville, MD 20850 USA. EM gadallas@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; U.S. Public Health Service from the National Cancer Institute [U24-CA76518]; National Heart Lung and Blood Institute; National Institute of Allergy and Infectious Diseases, Heath Resources, and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028] FX The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute; by a U.S. Public Health Service grant (U24-CA76518) from the National Cancer Institute, the National Heart Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases, Heath Resources, and Services Administration (HHSH234200637015C); and by 2 grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research. NR 28 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2016 VL 22 IS 12 BP 2276 EP 2282 DI 10.1016/j.bbmt.2016.09.012 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA ED8CM UT WOS:000389099600026 PM 27641680 ER PT J AU Wilcox, A Silverman, D Friesen, M Locke, S Russ, D Hyun, N Colt, J Figueroa, J Rothman, N Moore, L Koutros, S AF Wilcox, Amber N. Silverman, Debra T. Friesen, Melissa C. Locke, Sarah J. Russ, Daniel E. Hyun, Noorie Colt, Joanne S. Figueroa, Jonine D. Rothman, Nathaniel Moore, Lee E. Koutros, Stella TI Smoking status, usual adult occupation, and risk of recurrent urothelial bladder carcinoma: data from The Cancer Genome Atlas (TCGA) Project SO CANCER CAUSES & CONTROL LA English DT Article DE Bladder cancer; Recurrence; Occupation; Smoking status; Diesel exhaust ID RADICAL CYSTECTOMY; OUTCOMES; EXPOSURE; EXHAUST; MEN; P53 AB Tobacco smoking and occupational exposures are the leading risk factors for developing urothelial bladder carcinoma (UBC), yet little is known about the contribution of these two factors to risk of UBC recurrence. We evaluated whether smoking status and usual adult occupation are associated with time to UBC recurrence for 406 patients with muscle-invasive bladder cancer submitted to The Cancer Genome Atlas (TCGA) project. Kaplan-Meier and Cox proportional hazard methods were used to assess the association between smoking status, employment in a high-risk occupation for bladder cancer, occupational diesel exhaust exposure, and 2010 Standard Occupational Classification group and time to UBC recurrence. Data on time to recurrence were available for 358 patients over a median follow-up time of 15 months. Of these, 133 (37.2%) experienced a recurrence. Current smokers who smoked for more than 40 pack-years had an increased risk of recurrence compared to never smokers (HR 2.1, 95% CI 1.1, 4.1). Additionally, employment in a high-risk occupation was associated with a shorter time to recurrence (log-rank p = 0.005). We found an increased risk of recurrence for those employed in occupations with probable diesel exhaust exposure (HR 1.8, 95% CI 1.1, 3.0) and for those employed in production occupations (HR 2.0, 95% CI 1.1, 3.6). These findings suggest smoking status impacts risk of UBC recurrence, although several previous studies provided equivocal evidence regarding this association. In addition to the known causal relationship between occupational exposure and bladder cancer risk, our study suggests that occupation may also be related to increased risk of recurrence. C1 [Wilcox, Amber N.; Silverman, Debra T.; Friesen, Melissa C.; Locke, Sarah J.; Hyun, Noorie; Colt, Joanne S.; Rothman, Nathaniel; Moore, Lee E.; Koutros, Stella] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 9609 Med Ctr Dr, Rockville, MD USA. [Russ, Daniel E.] NIH, Div Computat Biosci, Dept Hlth & Human Serv, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. RP Koutros, S (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 9609 Med Ctr Dr, Rockville, MD USA. EM koutross@mail.nih.gov RI Friesen, Melissa/A-5362-2009 FU National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics [Z01CP010119] FX This work was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics (Z01CP010119). NR 19 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2016 VL 27 IS 12 BP 1429 EP 1435 DI 10.1007/s10552-016-0821-7 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA ED1EM UT WOS:000388587400003 PM 27804056 ER PT J AU Chen, XY Chen, RM Chen, ZY Chen, JP Shung, KK Zhou, QF AF Chen, Xiaoyang Chen, Ruimin Chen, Zeyu Chen, Jiping Shung, K. Kirk Zhou, Qifa TI Transparent lead lanthanum zirconate titanate (PLZT) ceramic fibers for high-frequency ultrasonic transducer applications SO CERAMICS INTERNATIONAL LA English DT Article DE PLZT fiber; Composites; Extrusion; Biomedical applications ID INTRAVASCULAR ULTRASOUND; THICKNESS-MODE; COMPOSITES; ELEMENT AB This paper presents fabrication of transparent lanthanum zirconate titanate (PLZT) fibers using extrusion technique. The diameter of the sintered PLZT fiber is about 400-mu m, and the fibers exhibit very good transparency. Measured dielectric constant, remnant polarization and coercive field of PLZT fiber were found to be 2340, 22.5-mu C/cm(2), and 9.8-kV/cm, respectively. The transparent piezoelectric materials may exhibit great potential for Photoacoustic (PA) imaging and hybrid intravascular imaging combining OCT and ultrasound imaging by using the transparent fiber as the path of light propagation and ultrasonic transducer material. In our study, these transparent PLZT fibers were designed to fabricate two types of high-frequency ultrasonic transducers: small aperture single PLZT fiber/epoxy composite and large aperture 1-3 PLZT fiber/epoxy composite ultrasonic transducers. Besides, a 20-mu m tungsten wire phantom and the cornea of the porcine eye were also imaged with the 1-3 PLZT fiber/epoxy composite ultrasonic transducer to demonstrate its imaging capability. (C) 2016 Elsevier Ltd and Techna Group S.r.l. All rights reserved. C1 [Chen, Xiaoyang] Sichuan Univ, Coll Mat Sci & Engn, Chengdu 610064, Peoples R China. [Chen, Ruimin; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Chen, Ruimin; Chen, Zeyu; Shung, K. Kirk; Zhou, Qifa] Univ Southern Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Chen, Jiping] Penn State Univ, Mat Res Inst, University Pk, PA 16802 USA. RP Zhou, QF (reprint author), Univ Southern Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA.; Zhou, QF (reprint author), Univ Southern Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu FU National Institutes of Health [P41-EB002182]; China Scholarship Council of China (CSC) FX This work was supported by the National Institutes of Health (Grant No. P41-EB002182) and the China Scholarship Council of China (CSC). NR 29 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0272-8842 EI 1873-3956 J9 CERAM INT JI Ceram. Int. PD DEC PY 2016 VL 42 IS 16 BP 18554 EP 18559 DI 10.1016/j.ceramint.2016.08.195 PG 6 WC Materials Science, Ceramics SC Materials Science GA ED0OV UT WOS:000388542700079 ER PT J AU Newmeyer, MN Swortwood, MJ Barnes, AJ Abulseoud, OA Scheidweiler, KB Huestis, MA AF Newmeyer, Matthew N. Swortwood, Madeleine J. Barnes, Allan J. Abulseoud, Osama A. Scheidweiler, Karl B. Huestis, Marilyn A. TI Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake SO CLINICAL CHEMISTRY LA English DT Article ID PLASMA; INGESTION; DELTA(9)-TETRAHYDROCANNABINOL; METABOLITE; MARIJUANA; TETRAHYDROCANNABINOL; DISPOSITION; EXCRETION; MARKER; THC AB BACKGROUND: There is increasing interest in markers of recent cannabis use because following frequent cannabis intake, Delta(9)-tetrahydrocannabinol (THC) may be detected in blood for up to 30 days. The minor cannabinoids cannabidiol, cannabinol (CBN), and THC-glucuronide were previously detected for <= 2.1 h in frequent and occasional smokers' blood after cannabis smoking. Cannabigerol (CBG), Delta(9)-tetrahydrocannabivarin (THCV), and 11-nor-9carboxy- THCV might also be recent use markers, but their blood pharmacokinetics have not been investigated. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. METHODS: We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 (occasional) and 72 (frequent) hours after controlled smoked, vaporized, and oral cannabis administration. RESULTS: Few differences were observed between smoked and vaporized blood cannabinoid pharmacokinetics, while significantly greater 11-nor-9-carboxy-THC (THCCOOH) and THCCOOH-glucuronide concentrations occurred following oral cannabis. CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. Implementation of a combined THC >= 5 mu g/L plus THCCOOH/11-hydroxy-THC ratio <20 cutoff produced detection windows <8 h after all routes for frequent smokers; no occasional smoker was positive 1.5 h or 12 h following inhaled or oral cannabis, respectively. CONCLUSIONS: Vaporization and smoking provide comparable cannabinoid delivery. CBG and CBN are recent-use cannabis markers after cannabis inhalation, but their absence does not exclude recent use. Multiple, complimentary criteria should be implemented in conjunction with impairment observations to improve interpretation of cannabinoid tests. (C) 2016 American Association for Clinical Chemistry C1 [Newmeyer, Matthew N.; Swortwood, Madeleine J.; Barnes, Allan J.; Abulseoud, Osama A.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab, Clin Pharmacol & Therapeut Res Branch, IRP,NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM kscheidweiler@intra.nida.nih.gov OI Newmeyer, Matthew/0000-0002-0653-1553 FU Intramural Research Program, National Institute on Drug Abuse, NIH FX M.N. Newmeyer, The Intramural Research Program, National Institute on Drug Abuse, NIH, to institution; M.Huestis, The Intramural Research Program, National Institute on Drug Abuse, NIH, to institution. NR 28 TC 3 Z9 3 U1 13 U2 13 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 DEC PY 2016 VL 62 IS 12 BP 1579 EP 1592 DI 10.1373/clinchem.2016.263475 PG 14 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ED5XN UT WOS:000388926800008 PM 27899456 ER PT J AU Mennigen, JA Zhang, DP AF Mennigen, Jan A. Zhang, Dapeng TI MicroTrout: A comprehensive, genome-wide miRNA target prediction framework for rainbow trout, Oncorhynchus mykiss SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS LA English DT Article ID MEDIATED REPRESSION; MICRORNAS; EXPRESSION; IDENTIFICATION; ZEBRAFISH; EVOLUTION; DIFFERENTIATION; PROLIFERATION; CONSEQUENCES; TRANSLATION AB Rainbow trout represent an important teleost research model and aquaculture species. As such, rainbow trout are employed in diverse areas of biological research, including basic biological disciplines such as comparative physiology, toxicology, and, since rainbow trout have undergone both teleost- and salmonid-specific rounds of genome duplication, molecular evolution. In recent years, microRNAs (miRNAs, small non-protein coding RNAs) have emerged as important posttranscriptional regulators of gene expression in animals. Given the increasingly recognized importance of miRNAs as an additional layer in the regulation of gene expression and hence biological function, recent efforts using RNA- and genome sequencing approaches have resulted in the creation of several resources for the construction of a comprehensive repertoire of rainbow trout miRNAs and isomiRs (variant miRNA sequences that all appear to derive from the same gene but vary in sequence due to post-transcriptional processing). Importantly, through the recent publication of the rainbow trout genome (Berthelot et al., 2014), mRNA 3'UTR information has become available, allowing for the first time the genome-wide prediction of miRNA-target RNA relationships in this species. We here report the creation of the microtrout database, a comprehensive resource for rainbow trout miRNA and annotated 3'UTRs. The comprehensive database was used to implement an algorithm to predict genome-wide rainbow trout-specific miRNA-mRNA target relationships, generating an improved predictive framework over previously published approaches. This work will serve as a useful framework and sequence resource to experimentally address the role of miRNAs in several research areas using the rainbow trout model, examples of which are discussed. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mennigen, Jan A.] Univ Ottawa, Dept Biol, 20 Marie Curie, Ottawa, ON K1N 6N5, Canada. [Zhang, Dapeng] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Mennigen, JA (reprint author), Univ Ottawa, Dept Biol, 20 Marie Curie, Ottawa, ON K1N 6N5, Canada. EM jan.mennigen@uottawa.ca NR 47 TC 2 Z9 2 U1 6 U2 6 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 DEC PY 2016 VL 20 BP 19 EP 26 DI 10.1016/j.cbd.2016.07.002 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA ED8BS UT WOS:000389097500003 PM 27494513 ER PT J AU Calkins, MJ Vartanian, V Owen, N Kirkali, G Jaruga, P Dizdaroglu, M McCullough, AK Lloyd, RS AF Calkins, Marcus J. Vartanian, Vladimir Owen, Nichole Kirkali, Guldal Jaruga, Pawel Dizdaroglu, Miral McCullough, Amanda K. Lloyd, R. Stephen TI Enhanced sensitivity of Neill-/- mice to chronic UVB exposure SO DNA REPAIR LA English DT Article DE DNA base excision repair; DNA glycosylases; UV-induced inflammation; Oxidatively-induced DNA base damage ID CYCLOBUTANE PYRIMIDINE DIMER; INDUCED OXIDATIVE DAMAGE; LEMLI-OPITZ-SYNDROME; CIS-THYMINE GLYCOL; HIGH-FAT DIET; ULTRAVIOLET-RADIATION; HUMAN SKIN; MURINE EPIDERMIS; IN-VIVO; MASS-SPECTROMETRY AB Oxidative stress and reactive oxygen species (ROS)-induced DNA base damage are thought to be central mediators of UV -induced carcinogenesis and skin aging. However, increased steady-state levels of ROS-induced DNA base damage have not been reported after chronic UV exposure. Accumulation of ROS-induced DNA base damage is governed by rates of lesion formation and repair. Repair is generally performed by Base Excision Repair(BER), which is initiated by DNA glycosylases, such as 8-oxoguanine glycosylase and Nei-Endonuclease VIII-Like 1 (NEIL1). In the current study, UV light (UVB) was used to elicit protracted low-level ROS challenge in wild-type (WT) and Neill -/- mouse skin. Relative to WT controls, Neill -/-mice showed an increased sensitivity to tissue destruction from the chronic UVB exposure, and corresponding enhanced chronic inflammatory responses as measured by cytokine message levels and profiling, as well as neutrophil infiltration. Additionally, levels of several ROS-induced DNA lesions were measured including 4,6-diamino-5-formamidopyrimidine (FapyAde), 2,6-diamino-4-hydroxy-5formamidopyrimidine (FapyGua), 8-hydroxyguanine (8-OH-Gua), 5,6-dihydroxyuracil (5,6-diOH-Ura) and thymine glycol (ThyGly). In WT mice, chronic UVB exposure led to increased steady-state levels of FapyGua, FapyAde, and ThyGly with no significant increases in 8-OH-Gua or 5,6-di0H-Ura. Interestingly, the lesions that accumulated were all substrates of NEIL1 Collectively, these data suggest that NEIL1-initiated repair of a subset of ROS-induced DNA base lesions may be insufficient to prevent the initiation of inflammatory pathways during chronic UV exposure in mouse skin. (c) 2016 Elsevier B.V. All rights reserved. C1 [Calkins, Marcus J.; Vartanian, Vladimir; Owen, Nichole; McCullough, Amanda K.; Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97239 USA. [Kirkali, Guldal; Jaruga, Pawel; Dizdaroglu, Miral] NIST, Biomol Measurement Div, Gaithersburg, MD 20899 USA. [McCullough, Amanda K.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. [Calkins, Marcus J.] Natl Cheng Kung Univ, Inst Clin Med, Tainan, Taiwan. [Kirkali, Guldal] NCI, NIH, Bethesda, MD 20841 USA. RP Lloyd, RS (reprint author), 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM lloydst@ohsu.edu FU NIH [R01 DK075974]; Training Program in the Molecular Basis of Skin/Mucosa Pathobiology [T32-CA106195] FX This work was partially supported by NIH R01 DK075974 (RSL) and the Training Program in the Molecular Basis of Skin/Mucosa Pathobiology (T32-CA106195) supported MJC. Certain commercial equipment or materials are identified in this paper in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. NR 46 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD DEC PY 2016 VL 48 BP 43 EP 50 DI 10.1016/j.dnarep.2016.10.010 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA ED7ZN UT WOS:000389091400005 PM 27818081 ER PT J AU Vitiello, B Ordonez, AE AF Vitiello, Benedetto Ordonez, Anna E. TI Pharmacological treatment of children and adolescents with depression SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE Antidepressants; children and adolescents; depressive disorder; efficacy; safety ID SEROTONIN REUPTAKE INHIBITORS; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIALS; DOUBLE-BLIND EFFICACY; QUALITY-OF-LIFE; ANTIDEPRESSANT TREATMENT; CLINICAL-TRIALS; PEDIATRIC DEPRESSION; MAJOR DEPRESSION; MENTAL-DISORDERS AB Introduction: Despite an increasing number of studies, there is debate whether antidepressants have a favorable benefit/risk balance in depressed youth.Areas covered: A systematic search identified 23 systematic reviews and meta-analyses published between 2010-2016. More than 30 controlled clinical trials were conducted in adolescents, but only a few in pre-pubertal patients. About one-third of the trials were severely statistically underpowered. Most studies failed to detect differences from placebo, but a few found fluoxetine effective. Although no suicide occurred in these studies, antidepressants increased suicidality risk (including suicidal ideation and behavior) versus placebo (OR=2.39). Only two placebo-controlled trials with acceptable statistical power were publicly funded: both showed efficacy of fluoxetine, and one found a higher incidence of suicidality (OR=3.7, 95% C.I. 1.00-13.7).Expert opinion: In youth, antidepressants have, on average, a small therapeutic effect. The high placebo response is exacerbated by the large number of sites in many industry-funded studies. There is evidence that fluoxetine leads to greater and faster improvement than placebo or psychotherapy in adolescents. Considering both the high response to non-specific interventions and safety concerns, antidepressants should be used cautiously in youth, and limited to patients with moderate-to-severe depression for whom psychosocial interventions are either ineffective or not feasible. C1 [Vitiello, Benedetto] NIMH, Treatment & Prevent Intervent Res Branch, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Ordonez, Anna E.] NIMH, Off Clin Res, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, MSC 9633,6001 Execut Blvd Rm 7147, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov NR 47 TC 0 Z9 0 U1 13 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD DEC PY 2016 VL 17 IS 17 BP 2273 EP 2279 DI 10.1080/14656566.2016.1244530 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED3LP UT WOS:000388750900004 PM 27690663 ER PT J AU Mayorova, TD Tian, S Cai, W Semmens, DC Odekunle, EA Zandawala, M Badi, Y Rowe, ML Egertova, M Elphick, MR AF Mayorova, Tatiana D. Tian, Shi Cai, Weigang Semmens, Dean C. Odekunle, Esther A. Zandawala, Meet Badi, Yusef Rowe, Matthew L. Egertova, Michaela Elphick, Maurice R. TI Localization of Neuropeptide Gene Expression in Larvae of an Echinoderm, the Starfish Asterias rubens SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE neuropeptide precursor; mRNA in situ hybridization; larval nervous system; bipinnaria; brachiolaria; attachment complex; Echinodermata ID URCHIN STRONGYLOCENTROTUS-PURPURATUS; NERVOUS-SYSTEM; SEA-STAR; BRACHIOLARIA LARVAE; HYDRACTINIA-ECHINATA; SALMFAMIDE NEUROPEPTIDE; DENDRASTER-EXCENTRICUS; RFAMIDE NEUROPEPTIDES; NEURAL ARCHITECTURE; ILYANASSA-OBSOLETA AB Neuropeptides are an ancient class of neuronal signaling molecules that regulate a variety of physiological and behavioral processes in animals. The life cycle of many animals includes a larval stage(s) that precedes metamorphic transition to a reproductively active adult stage but, with the exception of Drosophila melanogaster and other insects, research on neuropeptide signaling has hitherto largely focused on adult animals. However, recent advances in genome/transcriptome sequencing have facilitated investigation of neuropeptide expression/function in the larvae of protostomian (e.g., the annelid Platynereis durnerilii) and deuterostomian (e.g., the urochordate Ciona intestinalis) invertebrates. Accordingly, here we report the first multi-gene investigation of larval neuropeptide precursor expression in a species belonging to the phylum Echinodermata the starfish Asterias rubens. Whole-mount mRNA in situ hybridization was used to visualize in bipinnaria and brachiolaria stage larvae the expression of eight neuropeptide precursors: L-type SALMFamide (Si), F-type SALMFamide (S2), vasopressin/oxytocin-type, NGFFYamide, thyrotropin-releasing hormone-type, gonadotropin-releasing hormone-type, calcitonin-type and corticotropin-releasing hormone-type. Expression of only three of the precursors (Si, S2, NGFFYamide) was observed in bipinnaria larvae but by the brachiolaria stage expression of all eight precursors was detected. An evolutionarily conserved feature of larval nervous systems is the apical organ and in starfish larvae this comprises the bilaterally symmetrical lateral ganglia, but only the Si and S2 precursors were found to be expressed in these ganglia. A prominent feature of brachiolaria larvae is the attachment complex, comprising the brachia and adhesive disk, which mediates larval attachment to a substratum prior to metamorphosis. Interestingly, all of the neuropeptide precursors examined here are expressed in the attachment complex, with distinctive patterns of expression suggesting potential roles for neuropeptides in the attachment process. Lastly, expression of several neuropeptide precursors is associated with ciliary bands, suggesting potential roles for the neuropeptides derived from these precursors in control of larval locomotion and/or feeding. In conclusion, our findings provide novel perspectives on the evolution and development of neuropeptide signaling systems and neuroanatomical insights into neuropeptide function in echinoderm larvae. C1 [Mayorova, Tatiana D.; Tian, Shi; Cai, Weigang; Semmens, Dean C.; Odekunle, Esther A.; Zandawala, Meet; Badi, Yusef; Rowe, Matthew L.; Egertova, Michaela; Elphick, Maurice R.] Queen Mary Univ London, Sch Biol & Chem Sci, Dept Oranismal Biol, London, England. [Mayorova, Tatiana D.] Russian Acad Sci, Koltzov Inst Dev Biol, Dev Neurobiol Lab, Moscow, Russia. [Mayorova, Tatiana D.] NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Elphick, MR (reprint author), Queen Mary Univ London, Sch Biol & Chem Sci, Dept Oranismal Biol, London, England. EM m.relphick@qmul.ac.uk OI Zandawala, Meet/0000-0001-6498-2208 FU European Molecular Biology Organization fellowship [ASTF 168-2014]; Russian Foundation for Basic Research [15-04-04298]; BBSRC [BB/M001644/1]; Leverhulme Trust [RGP-2013-351]; China Scholarship Council; Society for Experimental Biology FX This study was supported by a European Molecular Biology Organization fellowship awarded to TM (ASTF 168-2014), Russian Foundation for Basic Research (grant 15-04-04298 awarded to TM), BBSRC (grant BB/M001644/1), the Leverhulme Trust (grant RGP-2013-351), the China Scholarship Council and the Society for Experimental Biology. NR 80 TC 0 Z9 0 U1 9 U2 9 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD DEC 1 PY 2016 VL 10 AR 553 DI 10.3389/fnins.2016.00553 PG 18 WC Neurosciences SC Neurosciences & Neurology GA ED7TT UT WOS:000389075000001 PM 27990106 ER PT J AU Polizzotto, MN Uldrick, TS Wyvill, KM Aleman, K Peer, CJ Bevans, M Sereti, I Maldarelli, F Whitby, D Marshall, V Goncalves, PH Khetani, V Figg, WD Steinberg, SM Zeldis, JB Yarchoan, R AF Polizzotto, Mark N. Uldrick, Thomas S. Wyvill, Kathleen M. Aleman, Karen Peer, Cody J. Bevans, Margaret Sereti, Irini Maldarelli, Frank Whitby, Denise Marshall, Vickie Goncalves, Priscila H. Khetani, Vikram Figg, William D. Steinberg, Seth M. Zeldis, Jerome B. Yarchoan, Robert TI Pomalidomide for Symptomatic Kaposi's Sarcoma in People With and Without HIV Infection: A Phase I/II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; MULTIPLE-MYELOMA; LENALIDOMIDE; TRIAL; HUMAN-HERPESVIRUS-8; CHEMOTHERAPY; PACLITAXEL; RESPONSES; CEREBLON; DISEASE AB Purpose Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma-associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resource-limited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. Methods The primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5mg once per day for 21 days per 28-day cycle, with a de-escalated level of 3mg if not tolerable, and aspirin 81 mg once per day thromboprophylaxis. HIV-infected patients required controlled viremia with either persistent KS despite 3 months of antiretroviral therapy (ART) or progressive KS despite 2 months of ART. Evaluations included tumor response and health-related quality of life (HRQL). Results Twenty-two patients were treated; 15 (68%) were HIV infected, 17 (77%) had advanced (T1) disease, and 19 (86%) previous KS therapy excluding ART. All were treated with 5 mg because no dose-limiting toxicities occurred. Over 156 cycles, the grade 3/4 adverse events possibly attributable to therapy were neutropenia (23 cycles, 10 patients), infection (1 cycle), and edema (1 cycle). Sixteen patients responded (73%; 95% Cl, 50% to 89%): nine of 15 HIV-infected patients (60%; 95% Cl, 32% to 84%) and all seven HIV-uninfected patients (100%; 95% Cl, 59% to 100%). Median time to response was 4 weeks (range, 4 to 36 weeks). HRQL showed no impairment during therapy and improved satisfaction with appearance at end therapy (P = .03). Significant increases in CD4(+) and CD8(+) cells were seen in patients with and without HIV, together with a transient increase in Kaposi's sarcoma-associated herpesvirus viral load at week 4 (P = .05). Conclusion Pomalidomide is well tolerated and active in KS regardless of HIV status. Responses were rapid, with improved self-reported outcomes, and occurred in advanced and heavily pretreated disease. Correlative studies support, at least in part, an immunologic mechanism of activity. (C) 2016 by American Society of Clinical Oncology C1 [Polizzotto, Mark N.; Uldrick, Thomas S.; Wyvill, Kathleen M.; Aleman, Karen; Peer, Cody J.; Maldarelli, Frank; Goncalves, Priscila H.; Figg, William D.; Steinberg, Seth M.; Yarchoan, Robert] NCI, Bethesda, MD 20892 USA. [Bevans, Margaret] NIH, Bethesda, MD USA. [Sereti, Irini] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Whitby, Denise; Marshall, Vickie] Frederick Natl Canc Lab Canc Res, Frederick, MD USA. [Khetani, Vikram; Zeldis, Jerome B.] Celgene Corp, Summit, NJ USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM robert.yarchoan@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; National Cancer Institute; Celgene Corporation; National Cancer Institute [HHSN261200800001E]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and by a Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Celgene Corporation. It was further supported by the National Cancer Institute, under Contract No. HHSN261200800001E (V.M. and D.W.) and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (I.S.). NR 30 TC 1 Z9 1 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 DEC 1 PY 2016 VL 34 IS 34 BP 4125 EP + DI 10.1200/JCO.2016.69.3812 PG 9 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900012 PM 27863194 ER PT J AU Hassan, R Thomas, A Alewine, C Le, DT Jaffee, EM Pastan, I AF Hassan, Raffit Thomas, Anish Alewine, Christine Le, Dung T. Jaffee, Elizabeth M. Pastan, Ira TI Mesothelin Immunotherapy for Cancer: Ready for Prime Time? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PANCREATIC DUCTAL ADENOCARCINOMA; PROLONGED PATIENT SURVIVAL; TRIPLE-NEGATIVE BREAST; MONOCLONAL-ANTIBODY K1; EXTRAHEPATIC BILE-DUCT; PHASE-I TRIAL; OVARIAN-CANCER; RECOMBINANT IMMUNOTOXIN; EXPRESSING MESOTHELIN; PLEURAL MESOTHELIOMA AB Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer. (C) 2016 by American Society of Clinical Oncology C1 [Hassan, Raffit; Thomas, Anish; Alewine, Christine; Pastan, Ira] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Le, Dung T.; Jaffee, Elizabeth M.] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. RP Hassan, R (reprint author), NCI, Thorac & GI Oncol Branch, Bldg 10CRC,Rm 4-5330, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research; NCI [1K23CA163672] FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research, and in part by Grant No. 1K23CA163672 from NCI (D.T.L.). NR 87 TC 2 Z9 2 U1 8 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4171 EP + DI 10.1200/JCO.2016.68.3672 PG 10 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900017 PM 27863199 ER PT J AU Bjorklund, P Pacak, K Crona, J AF Bjorklund, P. Pacak, K. Crona, J. TI Precision medicine in pheochromocytoma and paraganglioma: current and future concepts SO JOURNAL OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT Symposium on New Genetics with Impact on Treatment of Endocrine Tumour Disease CY JUN 04-05, 2015 CL Uppsala, SWEDEN DE cancer metabolism; neuroendocrine tumours; paraganglioma; personalized medicine; pheochromocytoma; precision medicine ID ENDOCRINE NEOPLASIA TYPE-2; VONHIPPEL-LINDAU-DISEASE; PANCREATIC NEUROENDOCRINE TUMORS; AUTOSOMAL-DOMINANT PARAGANGLIOMA; POSITRON-EMISSION-TOMOGRAPHY; OF-FUNCTION MUTATIONS; GERM-LINE MUTATIONS; SUCCINATE-DEHYDROGENASE; GENE-MUTATIONS; MALIGNANT PHEOCHROMOCYTOMAS AB Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions. C1 [Bjorklund, P.; Crona, J.] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. [Pacak, K.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol Program Reprod & Adult E, Bethesda, MD USA. RP Crona, J (reprint author), Uppsala Univ, Expt Surg Grp, Akademiska Sjukhuset,Ing 70,FOA2, S-75185 Uppsala, Sweden. EM Joakim.crona@surgsci.uu.se NR 148 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-6820 EI 1365-2796 J9 J INTERN MED JI J. Intern. Med. PD DEC PY 2016 VL 286 IS 6 BP 559 EP 573 DI 10.1111/joim.12507 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA ED0ZN UT WOS:000388573300004 ER PT J AU Valantine, H AF Valantine, Hannah TI NIH's Essential 21st-Century Research Challenge: Enhancing Scientific Workforce Diversity SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID SCIENCE C1 [Valantine, Hannah] NIH, Sci Workforce Divers, Bldg 10, Bethesda, MD 20892 USA. RP Valantine, H (reprint author), NIH, Off Director, Sci Workforce Divers, 1 Ctr Dr,Rm 316, Bethesda, MD 20892 USA. EM hannah.valantine@nih.gov NR 18 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 DEC PY 2016 VL 136 IS 12 BP 2327 EP 2329 DI 10.1016/j.jid.2016.07.042 PG 3 WC Dermatology SC Dermatology GA ED2KP UT WOS:000388673500007 PM 27884286 ER PT J AU Jo, JH Deming, C Kennedy, EA Conlan, S Polley, EC Ng, WL Segre, JA Kong, HH AF Jo, Jay-Hyun Deming, Clay Kennedy, Elizabeth A. Conlan, Sean Polley, Eric C. Ng, Weng-Lan Segre, Julia A. Kong, Heidi H. CA NISC Comparative Sequencing Progra TI Diverse Human Skin Fungal Communities in Children Converge in Adulthood SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; HEALTHY-SUBJECTS; MICROBIOTA; AGE; PREVALENCE; DISEASES; GENDER; GENE AB Understanding the skin mycobiome (fungal communities) is important because both commensal and pathogenic fungi can drive cutaneous disease depending on host status and body sites, including the scalp, feet, and groin. Interestingly, age may also affect skin fungal infections as certain dermatophytoses (i.e., tinea capitis) are more frequent in children than adults. We previously described the skin mycobiomes in healthy adults, showing lipophilic fungi Malassezia predominate in most skin sites. Because children have less sebaceous skin before puberty, we compared the fungal communities of primary clinical samples from healthy children and adults, based on sequencing of a fungal phylogenetic marker. Although Malassezia predominated on the trunk, head, and arm skin of adults (age 18-39), children (age <14) had more diverse fungal communities, for example, Eurotiomycetes, which includes common dermatophytes. Species-level classification showed that Malassezia globosa predominated in children. Collectively, our findings indicate that prepubertal skin is colonized by diverse fungi, whereas adult skin is predominantly obligatory lipophilic Malassezia, suggesting that fungal communities on skin profoundly shift during puberty. Mycobiome shifts during puberty are likely due to alterations in sebaceous gland activation and sebum composition. This study provides a foundational framework for studies investigating interactions between fungi, skin, and pediatric dermatophytosis. C1 [Jo, Jay-Hyun; Kennedy, Elizabeth A.; Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Deming, Clay; Conlan, Sean; Ng, Weng-Lan; Segre, Julia A.] NHGRI, Microbial Genom Sect, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Polley, Eric C.] NCI, Biometr Res Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Polley, Eric C.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN 55905 USA. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA.; Segre, JA (reprint author), NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov; konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU NIH NCI/CCR; NHGRI; Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [HI15C1095]; National Institutes of Health [1UH2AR057504-01, 4UH3AR057504-02] FX We thank Mark C. Udey, Keisuke Nagao, and Carmen Contreras-Sesvold for their helpful discussions; and Sheila Phang and Amynah Pradhan for their underlying efforts. This work was supported by NIH NCI/CCR and NHGRI Intramural Research Program and a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI15C1095; J-HJ). Sequencing was funded by grants from the National Institutes of Health (1UH2AR057504-01 and 4UH3AR057504-02). This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 40 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2016 VL 136 IS 12 BP 2356 EP 2363 DI 10.1016/j.jid.2016.05.130 PG 8 WC Dermatology SC Dermatology GA ED2KP UT WOS:000388673500014 PM 27476723 ER PT J AU Shi, JX Zhou, WY Zhu, B Hyland, PL Bennett, H Xiao, YZ Zhang, XJ Burke, LS Song, L Hsu, CH Yan, CH Chen, QR Meerzaman, D Dagnall, CL Burdette, L Hicks, B Freedman, ND Chanock, SJ Yeager, M Tucker, MA Goldstein, AM Yang, XR AF Shi, Jianxin Zhou, Weiyin Zhu, Bin Hyland, Paula L. Bennett, Hunter Xiao, Yanzi Zhang, Xijun Burke, Laura S. Song, Lei Hsu, Chih Hao Yan, Chunhua Chen, Qingrong Meerzaman, Daoud Dagnall, Casey L. Burdette, Laurie Hicks, Belynda Freedman, Neal D. Chanock, Stephen J. Yeager, Meredith Tucker, Margaret A. Goldstein, Alisa M. Yang, Xiaohong R. TI Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PANCREATIC-CANCER; CDKN2A MUTATIONS; PRONE FAMILIES; MC1R VARIANTS; RISK; ASSOCIATION; GENES; DUPLICATION; EXPRESSION; GENOMEL AB Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanomaprone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma. C1 [Shi, Jianxin; Zhu, Bin; Hyland, Paula L.; Bennett, Hunter; Xiao, Yanzi; Burke, Laura S.; Song, Lei; Freedman, Neal D.; Chanock, Stephen J.; Tucker, Margaret A.; Goldstein, Alisa M.; Yang, Xiaohong R.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Zhou, Weiyin; Zhang, Xijun; Dagnall, Casey L.; Burdette, Laurie; Hicks, Belynda; Yeager, Meredith] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Leidos Biomed Res, Frederick, MD USA. [Burke, Laura S.] Stat Collaborat Inc, Washington, DC USA. [Hsu, Chih Hao; Yan, Chunhua; Chen, Qingrong; Meerzaman, Daoud] NCI, Computat Genom Res Grp, Ctr Biomed Informat & Informat Technol, Bethesda, MD 20892 USA. RP Yang, XR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM royang@mail.nih.gov OI Dagnall, Casey/0000-0001-7334-4718 FU NIH, NCI, DCEG FX We are indebted to the participating families, whose generosity and cooperation have made this study possible. We thank Roche Nimblegen, Oxford Gene Technology, and Biodiscovery for their molecular and informatics services. We thank investigators from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), Cancer Prevention Study-II (CPS-II, American Cancer Society), Linxian Nutrition Intervention Trial (NITC), The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and Shanxi Upper Gastrointestinal Cancer Genetics Study (SHNX), for allowing us to use control GWAS data. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, Mary Fraser, and Barbara Rogers. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG. NR 27 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 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2016 VL 136 IS 12 BP 2436 EP 2443 DI 10.1016/j.jid.2016.07.023 PG 8 WC Dermatology SC Dermatology GA ED2KP UT WOS:000388673500023 PM 27476724 ER PT J AU Vanbellingen, T Wapp, M Stegmayer, K Bertschi, M Abela, E Kubel, S Nyffeler, T Muri, R Walther, S Nef, T Hallett, M Bohlhalter, S AF Vanbellingen, Tim Wapp, Manuela Stegmayer, Katharina Bertschi, Manuel Abela, Eugenio Kubel, Stefanie Nyffeler, Thomas Muri, Rene Walther, Sebastian Nef, Tobias Hallett, Mark Bohlhalter, Stephan TI Theta burst stimulation over premotor cortex in Parkinson's disease: an explorative study on manual dexterity SO JOURNAL OF NEURAL TRANSMISSION LA English DT Article DE Manual dexterity; Premotor cortex; Limb kinetic apraxia; Parkinson's disease; Coin rotation ID TRANSCRANIAL MAGNETIC STIMULATION; LIMB-KINETIC APRAXIA; HUMAN MOTOR CORTEX; FINGER DEXTERITY; EXCITABILITY AB Dorsal pre-motor cortex (PMd) is thought to play a role in fine motor control. The aim of the present study was to investigate whether inhibitory or excitatory stimulation of PMd would have an impact on manual dexterity in Parkinson's disease (PD). Fifteen patients with PD participated in this study. High resolution structural MRI was used for neuro-navigated TBS. Participants were targeted with one train of TBS in three experimental sessions: sham stimulation over vertex, continuous TBS (cTBS) over PMd and intermittent TBS (iTBS) over PMd, respectively. Dexterity was measured by a coin rotation task (CRT), which is a valid measure to detect limb kinetic apraxia (LKA). Neither cTBS or iTBS significantly interfered with CRT. Post hoc sub-analysis in a group of PD patients (n = 5) with stronger baseline impairment, indicating LKA, revealed further deterioration of dexterous performance for the cTBS condition (p = 0.04). This sham controlled pilot study demonstrates that TBS over PMd does not significantly interfere with dexterity in PD. However, patients with dexterous impairment qualifying for LKA may be more susceptible to TBS. C1 [Vanbellingen, Tim; Kubel, Stefanie; Nyffeler, Thomas; Bohlhalter, Stephan] Luzerner Kantonsspital, Neurol & Neurorehabil Ctr, Luzern, Switzerland. [Vanbellingen, Tim; Bertschi, Manuel; Nyffeler, Thomas; Muri, Rene; Bohlhalter, Stephan] Univ Hosp Bern, Inselspital, Percept & Eye Movement Lab, Dept Neurol, Bern, Switzerland. [Vanbellingen, Tim; Bertschi, Manuel; Nyffeler, Thomas; Muri, Rene; Bohlhalter, Stephan] Univ Hosp Bern, Inselspital, Percept & Eye Movement Lab, Dept Clin Res, Bern, Switzerland. [Vanbellingen, Tim; Nyffeler, Thomas; Muri, Rene; Nef, Tobias] Univ Bern, ARTORG Ctr Biomed Engn Res, Bern, Switzerland. [Wapp, Manuela; Abela, Eugenio] Univ Hosp Bern, Inselspital, Inst Diagnost & Intervent Neuroradiol, SCAN, Bern, Switzerland. [Stegmayer, Katharina; Walther, Sebastian] Univ Hosp Psychiat, Bern, Switzerland. [Nef, Tobias] Univ Bern, Gerontechnol & Rehabil Grp, Bern, Switzerland. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Bohlhalter, S (reprint author), Luzerner Kantonsspital, Neurol & Neurorehabil Ctr, Luzern, Switzerland.; Bohlhalter, S (reprint author), Univ Hosp Bern, Inselspital, Percept & Eye Movement Lab, Dept Neurol, Bern, Switzerland.; Bohlhalter, S (reprint author), Univ Hosp Bern, Inselspital, Percept & Eye Movement Lab, Dept Clin Res, Bern, Switzerland. EM stephan.bohlhalter@luks.ch RI Stegmayer, Katharina/A-6117-2017; Walther, Sebastian /E-3486-2010 OI Walther, Sebastian /0000-0003-4026-3561 FU Swiss National Science Foundation [320030_129668/1] FX We are grateful for the skilled editing by Prof. Dr. Einar Wilder-Smith. This study was supported by the Swiss National Science Foundation, Grant No. 320030_129668/1. NR 37 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 EI 1435-1463 J9 J NEURAL TRANSM JI J. Neural Transm. PD DEC PY 2016 VL 123 IS 12 BP 1387 EP 1393 DI 10.1007/s00702-016-1614-6 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ED1SX UT WOS:000388626300004 PM 27619658 ER PT J AU Stein, MB Ursano, RJ Campbell-Sills, L Colpe, LJ Fullerton, CS Heeringa, SG Nock, MK Sampson, NA Schoenbaum, M Sun, XY Jain, S Kessler, RC AF Stein, Murray B. Ursano, Robert J. Campbell-Sills, Laura Colpe, Lisa J. Fullerton, Carol S. Heeringa, Steven G. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Sun, Xiaoying Jain, Sonia Kessler, Ronald C. CA Army STARRS Collaborators TI Prognostic Indicators of Persistent Post-Concussive Symptoms after Deployment-Related Mild Traumatic Brain Injury: A Prospective Longitudinal Study in US Army Soldiers SO JOURNAL OF NEUROTRAUMA LA English DT Article DE concussion; deployment; mental health; military; stress; traumatic brain injury ID POSTTRAUMATIC-STRESS-DISORDER; MILITARY PERSONNEL; FORCES PERSONNEL; ASSESS RISK; TRACK-TBI; POSTCONCUSSION; PREDICTORS; RESILIENCE; POLYTRAUMA; MANAGEMENT AB Mild traumatic brain injury (mTBI), or concussion, is prevalent in the military. The course of recovery can be highly variable. This study investigates whether deployment-acquired mTBI is associated with subsequent presence and severity of post-concussive symptoms (PCS) and identifies predictors of persistent PCS among US Army personnel who sustained mTBI while deployed to Afghanistan. We used data from a prospective longitudinal survey of soldiers assessed 1-2 months before a 10-month deployment to Afghanistan (T0), on redeployment to the United States (T1), approximately 3 months later (T2), and approximately 9 months later (T3). Outcomes of interest were PCS at T2 and T3. Predictors considered were: sociodemographic factors, number of previous deployments, pre-deployment mental health and TBI history, and mTBI and other military-related stress during the index deployment. The study sample comprised 4518 soldiers, 822 (18.2%) of whom experienced mTBI during the index deployment. After adjusting for demographic, clinical, and deployment-related factors, deployment-acquired mTBI was associated with nearly triple the risk of reporting any PCS and with increased severity of PCS when symptoms were present. Among those who sustained mTBI, severity of PCS at follow-up was associated with history of pre-deployment TBI(s), pre-deployment psychological distress, more severe deployment stress, and loss of consciousness or lapse of memory (versus being "dazed'' only) as a result of deployment-acquired mTBI. In summary, we found that sustaining mTBI increases risk for persistent PCS. Previous TBI(s), pre-deployment psychological distress, severe deployment stress, and loss of consciousness or lapse of memory resulting from mTBI(s) are prognostic indicators of persistent PCS after an index mTBI. These observations may have actionable implications for prevention of chronic sequelae of mTBI in the military and other settings. C1 [Stein, Murray B.; Campbell-Sills, Laura] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.; Sun, Xiaoying; Jain, Sonia] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Ursano, Robert J.; Fullerton, Carol S.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Rockville, MD 20857 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. [Sampson, Nancy A.; Kessler, Ronald C.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. RP Stein, MB (reprint author), Univ Calif San Diego, 9500 Gilman Dr,Mailcode 0855, La Jolla, CA 92093 USA. EM mstein@ucsd.edu FU Department of the Army; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981] FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Veterans Administration, Department of the Army, or the Department of Defense. NR 33 TC 0 Z9 0 U1 6 U2 6 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 DEC 1 PY 2016 VL 33 IS 23 BP 2125 EP 2132 DI 10.1089/neu.2015.4320 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA ED2JG UT WOS:000388669800008 PM 26905672 ER PT J AU Lin, C Bradshaw, T Perk, T Harmon, S Eickhoff, J Jallow, N Choyke, PL Dahut, WL Larson, S Humm, JL Perlman, S Apolo, AB Morris, MJ Liu, G Jeraj, R AF Lin, Christie Bradshaw, Tyler Perk, Timothy Harmon, Stephanie Eickhoff, Jens Jallow, Ngoneh Choyke, Peter L. Dahut, William L. Larson, Steven Humm, John Laurence Perlman, Scott Apolo, Andrea B. Morris, Michael J. Liu, Glenn Jeraj, Robert TI Repeatability of Quantitative F-18-NaF PET: A Multicenter Study SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE sodium fluoride; PET; repeatability; metastatic prostate cancer; multicenter clinical trial ID F-18-FLUORIDE PET/CT; BONE METASTASES; PROSTATE-CANCER; F-18-SODIUM FLUORIDE; STATISTICAL-METHODS; MALIGNANT-TUMORS; LUNG-CANCER; REPRODUCIBILITY; AGREEMENT; SPECT AB F-18-NaF, a PET radiotracer of bone turnover, has shown potential as an imaging biomarker for assessing the response of bone metastases to therapy. This study aimed to evaluate the repeatability of F-18-NaF PET-derived SUV imaging metrics in individual bone lesions from patients in a multicenter study. Methods: Thirty-five castration-resistant prostate cancer patients with multiple metastases underwent 2 whole-body (test-retest) F-18-NaF PET/CT scans 3 +/- 2 d apart from 1 of 3 imaging sites. A total of 411 bone lesions larger than 1.5 cm(3) were automatically segmented using an SUV threshold of 15 g/mL. Two levels of analysis were performed: lesion-level, in which measures were extracted from individual-lesion regions of interest (ROI), and patient-level, in which all lesions within a patient were grouped into a patient ROI for analysis. Uptake was quantified with SUVmax, SUVmean, and SUVtotal. Test-retest repeatability was assessed using Bland Altman analysis, intraclass correlation coefficient (ICC), coefficient of variation, critical percentage difference, and repeatability coefficient. The 95% limit of agreement (LOA) of the ratio between test and retest measurements was calculated. Results: At the lesion level, the coefficient of variation for SUVmax, SUVmean, and SUVtotal was 14.1%, 6.6%, and 25.5%, respectively. At the patient level, it was slightly smaller: 12.0%, 5.3%, and 18.5%, respectively. ICC was excellent (>0.95) for all SUV metrics. Lesion-level 95% LOA for SUVmax SUVmean, and SUVtotal was (0.76, 1.32), (0.88, 1.14), and (0.63, 1.71), respectively. Patient-level 95% LOA was slightly narrower, at (0.79, 1.26), (0.89, 1.10), and (0.70, 1.44), respectively. We observed significant differences in the variance and sample mean of lesion-level and patient-level measurements between imaging sites. Conclusion: The repeatability of SUVmax, SUVmean, and SUVtotal for F-18-NaF PET/CT was similar between lesion-arid patient-level ROIs. We found significant differences in lesion-level and patient-level distributions between sites. These results can be used to establish F-18-NaF PET-based criteria for assessing treatment response at the lesion and patient levels. F-18-NaF PET demonstrates repeatability levels useful for clinically quantifying the response of bone lesions to therapy. C1 [Lin, Christie; Perk, Timothy; Harmon, Stephanie; Liu, Glenn; Jeraj, Robert] Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USA. [Bradshaw, Tyler; Perlman, Scott] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Eickhoff, Jens] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Jallow, Ngoneh] Emory Univ, Dept Radiol & Imaging Sci, Atlanta, GA 30322 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Dahut, William L.; Apolo, Andrea B.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Larson, Steven; Humm, John Laurence] Mem Sloan Kettering Canc Ctr, Dept Radiol, Mol Imaging & Therapy Serv, 1275 York Ave, New York, NY 10021 USA. [Perlman, Scott; Liu, Glenn; Jeraj, Robert] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Morris, Michael J.] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, 1275 York Ave, New York, NY 10021 USA. RP Jeraj, R (reprint author), Wisconsin Inst Med Res, Dept Med Phys, 1111 Highland Ave,Room 7003, Madison, WI 53705 USA. EM rjeraj@wisc.edu FU Prostate Cancer Foundation (PCF) through the PCF Creativity Award; PCF Mazzone Challenge Award FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This study was supported by the Prostate Cancer Foundation (PCF) through the PCF Creativity Award and the PCF Mazzone Challenge Award to Drs. Liu and Jeraj and was conducted within the Prostate Cancer Clinical Trials Consortium (PCCTC). No other potential conflict of interest relevant to this article was reported. NR 31 TC 1 Z9 1 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD DEC PY 2016 VL 57 IS 12 BP 1872 EP 1879 DI 10.2967/jnumed.116.177295 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8FG UT WOS:000389106800012 PM 27445292 ER PT J AU Shrestha, SS Liow, JS Jenko, K Ikawa, M Zoghbi, SS Innis, RB AF Shrestha, Stal S. Liow, Jeih-San Jenko, Kimberly Ikawa, Masamichi Zoghbi, Sami S. Innis, Robert B. TI The 5-HT1A Receptor PET Radioligand C-11-CUMI-101 Has Significant Binding to alpha(1)-Adrenoceptors in Human Cerebellum, Limiting Its Use as a Reference Region SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE autoradiography; 5-HT1A receptor; CUMI-101; cerebellum; alpha(1)-adrenoceptor; cross-reactivity ID BRAIN; DISEASE; LIGAND AB Prazosin, a potent and selective ai-adrenoceptor antagonist, displaces 25% of C-11-CUMI-101 ([O-methyl-C-11]2-(4-(4-(2-methoxy-phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione) binding in monkey cerebellum. We sought to estimate the percentage contamination of C-11-CUMI-101 binding to al-adrenoceptors in human cerebellum under in vivo conditions. In vitro receptor-binding techniques were used to measure alpha(1)-adrenoceptor density and the affinity of CUMI-101 for these receptors in human, monkey, and rat cerebellum. Methods: Binding potential (maximum number of binding sites x affinity [(1/dissociation constant]) was determined using in vitro homogenate binding assays in human, monkey, and rat cerebellum. H-3-prazosin was used to determine the maximum number of binding sites, as well as the dissociation constant of H-3-prazosin and the inhibition constant of CUMI-101. Results: alpha(1)-adrenoceptor density and the affinity of CUMI-101 for these receptors were similar across species. Cerebellar binding potentials were 3.7 for humans, 2.3 for monkeys, and 3.4 for rats. Conclusion: Reasoning by analogy, 25% of C-11-CUMI-101 uptake in human cerebellum reflects binding to alpha(1)-adrenoceptors, suggesting that the cerebellum is of limited usefulness as a reference tissue for quantification in human studies. C1 [Shrestha, Stal S.; Liow, Jeih-San; Jenko, Kimberly; Ikawa, Masamichi; Zoghbi, Sami S.; Innis, Robert B.] NIMH, Mol Imaging Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Shrestha, SS (reprint author), NIH, 10 Ctr Dr,B1D43, Bethesda, MD 20892 USA. EM stal.shrestha@nih.gov FU Intramural Research Program of the National Institute of Mental Health (NIH) [ZIAMH002795] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This study was funded by the Intramural Research Program of the National Institute of Mental Health (NIH project ZIAMH002795). No other potential conflict of interest relevant to this article was reported. NR 11 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD DEC PY 2016 VL 57 IS 12 BP 1945 EP 1948 DI 10.2967/jnumed.116.174151 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8FG UT WOS:000389106800023 PM 27587705 ER PT J AU Deroose, CM Hindie, E Kebebew, E Goichot, B Pacak, K Taieb, D Imperiale, A AF Deroose, Christophe M. Hindie, Elif Kebebew, Electron Goichot, Bernard Pacak, Karel Taieb, David Imperiale, Alessio TI Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE gastroenteropancreatic neuroendocrine tumors (GEP NETs); PET/CT; Ga-68-somatostatin analogues; F-18-FDOPA; F-18-FDG ID CONSENSUS GUIDELINES UPDATE; EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY; MEDIATED RADIONUCLIDE THERAPY; GA-68-DOTATATE PET/CT; GASTROINTESTINAL-TRACT; RADIATION-DOSIMETRY; ENDOCRINE TUMORS; RECEPTOR PET/CT; UNKNOWN ORIGIN; F-18-DOPA PET AB Through diagnostic imaging and peptide receptor radionuclide therapy, nuclear medicine has eamed a major role in gastroenteropancreatic neuroendocrine tumors (GEP NETs). GEP NETs are diagnosed fortuitously or on the basis of symptoms or hormonal syndrome. The functional tumor characteristics shown by radionuclide imaging allow for more accurate staging and treatment selection. Tumor grade helps determine which tracer should be selected. In the past, (111)ln-pentetreotide has been successful in well-differentiated (G1 and G2) tumors. However, PET/CT imaging with novel somatostatin analogs (e.g., Ga-68-DOTATOC, Ga-68-DOTATATE, Ga-68-DOTANOC, and Cu-64-DOTATATE) now offers improved sensitivity. F-18-fluorodihydroxyphenylalanine (F-18-FDOPA) is another interesting radiopharmaceutical. F-18-FDOPA sensitivity is influenced by a tumor's capacity to take up, decarboxylate, and store amine precursors. F-18-FDOPA sensitivities are highest in ileal NETs and may also be helpful in insulinomas. A high uptake of F-18-FDG with a low uptake of somatostatin analog usually indicates poorly differentiated tumors (G3). Starting from these principles, this article discusses theranostic approaches to GEP NETs, taking into account both primary and metastatic lesions. C1 [Deroose, Christophe M.] Univ Hosp Leuven, Nucl Med, Leuven, Belgium. [Hindie, Elif] Univ Bordeaux, Haut Leveque Hosp, Nucl Med, Bordeaux, France. [Hindie, Elif] Univ Bordeaux, LabEx TRAIL, Bordeaux, France. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Goichot, Bernard] Strasbourg Univ Hosp, Internal Med, Strasbourg, France. [Pacak, Karel] Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, Nucl Med, Marseille, France. [Taieb, David] European Ctr Res Med Imaging, Marseille, France. [Taieb, David] INSERM, UMR1068, Marseille, France. [Imperiale, Alessio] Strasbourg Univ Hosp, Biophys & Nucl Med, Strasbourg, France. [Imperiale, Alessio] Univ Strasbourg, CNRS, ICube, Strasbourg, France. [Imperiale, Alessio] Univ Strasbourg, Fac Med, FMTS, Strasbourg, France. RP Imperiale, A (reprint author), Hautepierre Univ Hosp, Biophys & Nucl Med, 1 Ave Moliere, F-67098 Strasbourg 09, France. EM alessio.imperiale@chru-strasbourg.fr NR 59 TC 3 Z9 3 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD DEC PY 2016 VL 57 IS 12 BP 1949 EP 1956 DI 10.2967/jnumed.116.179234 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8FG UT WOS:000389106800024 PM 27811124 ER PT J AU Rieves, D Jacobs, P AF Rieves, Dwaine Jacobs, Paula TI The Use of Published Clinical Study Reports to Support US Food and Drug Administration Approval of Imaging Agents SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE FDA; clinical trial reports; drug approval; imaging agents ID TRIALS AB Pharmaceutical companies typically perform prospective, multicenter phase 3 clinical studies to support approval of a new imaging agent by the U.S. Food and Drug Administration (FDA). In uncommon situations, the FDA has approved imaging agents based solely, or in large part, on the clinical study experience described in published reports, including reports of exploratory (i.e., phase 1 or 2) studies performed at a single clinical site. We performed a survey of published reports to assess the potential of the reported information to support FDA approval of a commonly cited investigational imaging agent. Our survey revealed critical data limitations in most publications, all of which reported exploratory clinical studies. Here we summarize the precedent for FDA approval of imaging agents using effectiveness data from publications, FDA guidance, and our experience in reviewing publications. We also present a key-data checklist for investigators to consider in the design, conduct, and reporting of exploratory clinical studies for publication. We encourage editors and peer reviewers to consider requiring these key data when reviewing these reports for publication. C1 [Rieves, Dwaine; Jacobs, Paula] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. RP Rieves, D (reprint author), 1907 New Hampshire Ave NW, Washington, DC 20009 USA. EM dcrieves@msn.com NR 16 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD DEC PY 2016 VL 57 IS 12 BP 2022 EP 2026 DI 10.2967/jnumed.116.178814 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8FG UT WOS:000389106800035 PM 27445294 ER PT J AU Sarangapani, PS Weaver, J Parupudi, A Besong, TMD Adams, GG Harding, SE Manikwar, P Castellanos, MM Bishop, SM Pathak, JA AF Sarangapani, Prasad S. Weaver, Justin Parupudi, Arun Besong, Tabot M. D. Adams, Gary G. Harding, Stephen E. Manikwar, Prakash Castellanos, Maria M. Bishop, Steven M. Pathak, Jai A. TI Both Reversible Self-Association and Structural Changes Underpin Molecular Viscoelasticity of mAb Solutions SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE viscosity; protein structure; mAb; light scattering (dynamic); calorimetry (DSC); rheology; analytical ultra-centrifugation; diffusion; protein formulation; protein aggregation ID MONOCLONAL-ANTIBODY SOLUTIONS; PROTEIN AGGREGATION KINETICS; 2ND VIRIAL-COEFFICIENT; CONCENTRATION-DEPENDENCE; ANALYTICAL ULTRACENTRIFUGATION; INTERACTION PARAMETER; THERAPEUTIC PROTEINS; VISCOSITY BEHAVIOR; GLOBULAR-PROTEINS; LIGHT-SCATTERING AB The role of antibody structure (conformation) in solution rheology is probed. It is demonstrated here that pH-dependent changes in the tertiary structure of 2 mAb solutions lead to viscoelasticity and not merely a shear viscosity (eta) increase. Steady shear flow curves on mAb solutions are reported over broad pH (3.0 <= pH <= 8.7) and concentration (2 mg/mL <= c <= 120 mg/mL) ranges to comprehensively characterize their rheology. Results are interpreted using size exclusion chromatography, differential scanning calorimetry, analytical ultracentrifugation, near-UV circular dichroism, and dynamic light scattering. Changes in tertiary structure with concentration lead to elastic yield stress and increased solution viscosity in solution of "mAb1." These findings are supported by dynamic light scattering and differential scanning calorimetry, which show increased hydrodynamic radius of mAb1 at low pH and a reduced melting temperature T-m, respectively. Conversely, another molecule at 120 mg/mL solution concentration is a strong viscoelastic gel due to perturbed tertiary structure (seen in circular dichroism) at pH 3.0, but the same molecule responds as a viscous liquid due to reversible self-association at pH 7.4 (verified by analytical ultracentrifugation). Both protein-protein interactions and structural perturbations govern pH-dependent viscoelasticity of mAb solutions. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved. C1 [Sarangapani, Prasad S.; Manikwar, Prakash; Bishop, Steven M.; Pathak, Jai A.] Medimmune Inc, Formulat Sci Dept, One MedImmune Way, Gaithersburg, MD 20878 USA. [Weaver, Justin] Medimmune Inc, Proc & Purificat Sci Dept, One MedImmune Way, Gaithersburg, MD 20878 USA. [Parupudi, Arun] Medimmune Inc, Analyt Biotechnol Dept, One MedImmune Way, Gaithersburg, MD 20878 USA. [Besong, Tabot M. D.; Adams, Gary G.; Harding, Stephen E.] Univ Nottingham, Sch Biosci, Natl Ctr Macromol Hydrodynam, Coll Rd,Sutton Bonnington Campus, Loughborough LE12 5RD, Leics, England. [Castellanos, Maria M.] Penn State Univ, Mat Sci & Engn Dept, University Pk, PA 16802 USA. [Sarangapani, Prasad S.] Regeneron Pharmaceut, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. [Weaver, Justin] Alexion Pharmaceut, 100 Coll St, New Haven, CT 06510 USA. [Castellanos, Maria M.] Univ Maryland NIST, Inst Biotechnol & Biosci Res, 9600 Gudelsky Dr, Rockville, MD 20850 USA. [Besong, Tabot M. D.] 4700 King Abdullah Univ Sci & Technol, Funct Nanomat Lab, Thuwal 239556900, Saudi Arabia. [Besong, Tabot M. D.] NIAID, Vaccine Prod Program, Vaccine Res Ctr, NIH, 9 West Watkins Mill Rd, Gaithersburg, MD 20878 USA. RP Pathak, JA (reprint author), Medimmune Inc, Formulat Sci Dept, One MedImmune Way, Gaithersburg, MD 20878 USA. EM jai.pathak@nih.gov NR 69 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD DEC PY 2016 VL 105 IS 12 BP 3496 EP 3506 DI 10.1016/j.xphs.2016.08.020 PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA ED7FO UT WOS:000389027800005 PM 27793346 ER PT J AU Perszyk, RE DiRaddo, JO Strong, KL Low, CM Ogden, KK Khatri, A Vargish, GA Pelkey, KA Tricoire, L Liotta, DC Smith, Y McBain, CJ Traynelis, SF AF Perszyk, Riley E. DiRaddo, John O. Strong, Katie L. Low, Chian-Ming Ogden, Kevin K. Khatri, Alpa Vargish, Geoffrey A. Pelkey, Kenneth A. Tricoire, Ludovic Liotta, Dennis C. Smith, Yoland McBain, Chris J. Traynelis, Stephen F. TI GluN2D-Containing N-methyl-D-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity SO MOLECULAR PHARMACOLOGY LA English DT Article ID GLUN1/GLUN2D NMDA RECEPTORS; MAJOR DEPRESSIVE DISORDER; SUBUNIT MESSENGER-RNA; PROOF-OF-CONCEPT; POSTNATAL-DEVELOPMENT; DEPENDENT PLASTICITY; PYRAMIDAL NEURONS; RAT; EXPRESSION; CELLS AB N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d-/- mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (1)-CIQ potentiation and was not accelerated in slices from Grin2d-/- mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing. C1 [Perszyk, Riley E.; DiRaddo, John O.; Ogden, Kevin K.; Khatri, Alpa; Traynelis, Stephen F.] Emory Univ, Dept Pharmacol, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. [DiRaddo, John O.; Strong, Katie L.; Liotta, Dennis C.] Emory Univ, Dept Chem, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. [Smith, Yoland] Emory Univ, Dept Neurol, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. [Smith, Yoland] Emory Univ, Yerkes Natl Primate Res Ctr, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. [Smith, Yoland] Emory Univ, Morris K Udall Ctr Excellence Parkinsons Dis Res, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. [Low, Chian-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore. [Low, Chian-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anaesthesiol, Singapore, Singapore. [Vargish, Geoffrey A.; Pelkey, Kenneth A.; Tricoire, Ludovic; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD USA. RP Traynelis, SF (reprint author), Emory Univ, Sch Med, Dept Pharma, Rollins Res Bldg,1510 Clifton Rd, Atlanta, GA 30322 USA. EM strayne@emory.edu FU National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]; Pfizer; Janssen Research and Development; NeurOp Inc. FX The authors thank Phoung Le and Jing Zhang for outstanding technical assistance; Susan Jenkins and Jean-Francois Pare for help with immunostaining; and the National Institute of Mental Health's Psychoactive Drug Screening Program, contract no. HHSN-271-2013-00017-C (NIMH PDSP), for Ki determinations and receptor binding profiles. The NIMH PDSP is directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD. Dennis Liotta, Katie Strong, and Stephen Traynelis are inventors on Emory-owned IP. Dennis Liotta is a member of the Board of Directors, and Stephen Traynelis is a paid consultant for NeurOp Inc., a company developing NMDA receptor modulators. Stephen Traynelis is a paid consultant for Pfizer and Janssen Research and Development. The authors also thank Sharon Swanger for critical comments on the manuscript. NR 57 TC 0 Z9 0 U1 9 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC 1 PY 2016 VL 90 IS 6 BP 689 EP 702 DI 10.1124/mol.116.105130 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED3CQ UT WOS:000388727300001 PM 27625038 ER PT J AU Sato, S Huang, XP Kroeze, WK Roth, BL AF Sato, Seiji Huang, Xi-Ping Kroeze, Wesley K. Roth, Bryan L. TI Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MOLECULAR-MECHANISM; GLUCOSE-HOMEOSTASIS; PANCREATIC-ISLETS; SENSING RECEPTOR; DRUG TARGETS; MOUSE; IDENTIFICATION; PROSTATE; GHRELIN AB In this study, we identified two previously described kinase inhibitors-3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinomethyl) imidazo[1,2-b] pyridazin-6-amine (LY2784544) and 1H-benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl) phenyl] methyl]-6-(4-morpholinyl)(GSK2636771)-as novel GPR39 agonists by unbiased small-molecule-based screening using a beta-arrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared their signaling patterns with a previously described "GPR39-selective" agonist N-[3-chloro-4-[[[2-(methylamino)-6-(2-pyridinyl)-4-pyrimidinyl] amino] methyl] phenyl] methanesulfonamide (GPR39-C3) at both canonical and noncanonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by concentrations of zinc reported to be physiologic. LY2784544 and GS2636771 at GPR39 in the presence of zinc were generally as potent or more potent than their reported activities against kinases in whole-cell assays. These findings reveal an unexpected role of zinc as an allosteric potentiator of small-molecule-induced activation of GPR39 and expand the list of potential kinase off-targets to include understudied G protein-coupled receptors. C1 [Sato, Seiji; Huang, Xi-Ping; Kroeze, Wesley K.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC USA. RP Roth, BL (reprint author), Genet Med Bldg,Room 4072,120 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu FU National Institutes of Health [U01-MH104974] FX This work was supported by the National Institutes of Health [Grant U01-MH104974]. NR 60 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC 1 PY 2016 VL 90 IS 6 BP 726 EP 737 DI 10.1124/mol.116.106112 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED3CQ UT WOS:000388727300004 PM 27754899 ER PT J AU Sayers, BC Germolec, DR Walker, NJ Shipkowski, KA Stout, MD Cesta, MF Roycroft, JH White, KL Baker, GL Dill, JA Smith, MJ AF Sayers, Brian C. Germolec, Dori R. Walker, Nigel J. Shipkowski, Kelly A. Stout, Matthew D. Cesta, Mark F. Roycroft, Joseph H. White, Kimber L. Baker, Gregory L. Dill, Jeffrey A. Smith, Matthew J. TI Respiratory toxicity and immunotoxicity evaluations of microparticle and nanoparticle C60 fullerene aggregates in mice and rats following nose-only inhalation for 13 weeks SO NANOTOXICOLOGY LA English DT Article DE Buckminsterfullerene; immunotoxicity; inhalation; nanoparticles; pulmonary inflammation ID FEMALE B6C3F1 MICE; INCREASED PULMONARY TOXICITY; SCAVENGER RECEPTOR CD163; HUMAN MONOCYTES; MACROPHAGE SUBPOPULATIONS; MONONUCLEAR PHAGOCYTES; ULTRAFINE PARTICLES; LUNG INFLAMMATION; CARBON NANOTUBES; ALPHA-SUBUNIT AB C60 fullerene (C60), or buckminsterfullerene, is a spherical arrangement of 60 carbon atoms, having a diameter of approximately 1nm, and is produced naturally as a by-product of combustion. Due to its small size, C60 has attracted much attention for use in a variety of applications; however, insufficient information is available regarding its toxicological effects. The effects on respiratory toxicity and immunotoxicity of C60 aggregates (50nm [nano-C60] and 1m [micro-C60] diameter) were examined in B6C3F1/N mice and Wistar Han rats after nose-only inhalation for 13 weeks. Exposure concentrations were selected to allow for data evaluations using both mass-based and particle surface area-based exposure metrics. Nano-C60 exposure levels selected were 0.5 and 2mg/m(3) (0.033 and 0.112 m(2)/m(3)), while micro-C60 exposures were 2, 15 and 30mg/m(3) (0.011, 0.084 and 0.167 m(2)/m(3)). There were no systemic effects on innate, cell-mediated, or humoral immune function. Pulmonary inflammatory responses (histiocytic infiltration, macrophage pigmentation, chronic inflammation) were concentration-dependent and corresponded to increases in monocyte chemoattractant protein (MCP)-1 (rats) and macrophage inflammatory protein (MIP)-1 (mice) in bronchoalveolar lavage (BAL) fluid. Lung overload may have contributed to the pulmonary inflammatory responses observed following nano-C60 exposure at 2mg/m(3) and micro-C60 exposure at 30mg/m(3). Phenotype shifts in cells recovered from the BAL were also observed in all C60-exposed rats, regardless of the level of exposure. Overall, more severe pulmonary effects were observed for nano-C60 than for micro-C60 for mass-based exposure comparisons. However, for surface-area-based exposures, more severe pulmonary effects were observed for micro-C60 than for nano-C60, highlighting the importance of dosimetry when evaluating toxicity between nano- and microparticles. C1 [Sayers, Brian C.; Germolec, Dori R.; Walker, Nigel J.; Shipkowski, Kelly A.; Stout, Matthew D.; Cesta, Mark F.; Roycroft, Joseph H.] NIEHS, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [White, Kimber L.; Smith, Matthew J.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. [Baker, Gregory L.; Dill, Jeffrey A.] Battelle Toxicol Northwest, Richland, WA USA. [Smith, Matthew J.] Richard Bland Coll William & Mary, Petersburg, VA USA. RP Sayers, BC (reprint author), DuPont Haskell Global Centers, 1090 Elkton Rd, Newark, DE 19711 USA. EM Brian.C.Sayers@dupont.com RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); NTP [N01-ES-55538, N01-ES-5553] FX This work was supported [in part] by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) and by NTP Contracts N01-ES-55538 and N01-ES-5553. NR 56 TC 0 Z9 0 U1 9 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1743-5390 EI 1743-5404 J9 NANOTOXICOLOGY JI Nanotoxicology PD DEC PY 2016 VL 10 IS 10 BP 1458 EP 1468 DI 10.1080/17435390.2016.1235737 PG 11 WC Nanoscience & Nanotechnology; Toxicology SC Science & Technology - Other Topics; Toxicology GA ED3RU UT WOS:000388767000008 PM 27618498 ER PT J AU Bielekova, B AF Bielekova, Bibi TI PERSPECTIVE Who dares, wins SO NATURE LA English DT Editorial Material ID MULTIPLE-SCLEROSIS C1 [Bielekova, Bibi] US Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, Intramural Res Program, Bethesda, MD 20824 USA. RP Bielekova, B (reprint author), US Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, Intramural Res Program, Bethesda, MD 20824 USA. EM bibi.bielekova@nih.gov FU US National Institute of Neurological Disorders and Stroke NR 5 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 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 1 PY 2016 VL 540 IS 7631 BP S10 EP S10 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5UA UT WOS:000388916600005 PM 27902681 ER PT J AU Wilfert, AB Chao, KR Kaushal, M Jain, S Zollner, S Adams, DR Conrad, DF AF Wilfert, Amy B. Chao, Katherine R. Kaushal, Madhurima Jain, Sanjay Zollner, Sebastian Adams, David R. Conrad, Donald F. TI Genome-wide significance testing of variation from single case exomes SO NATURE GENETICS LA English DT Article ID SEQUENCE VARIANTS; GENETIC-VARIATION; HUMAN-DISEASE; MUTATION; ASSOCIATION; GUIDELINES; FRAMEWORK AB Standard techniques from genetic epidemiology are ill-suited to formally assess the significance of variants identified from a single case. We developed a statistical inference framework for identifying unusual functional variation from a single exome or genome, what we refer to as the 'n-of-one' problem. Using this approach we assessed our ability to identify the causal genotypes in over 5 million simulated cases of Mendelian disease, identifying 39% of disease genotypes as the most damaging unit in a typical exome background. We applied our approach to 129 n-of-one families from the Undiagnosed Diseases Program, nominating 60% of 30 disease genes determined to be diagnostic by a standard clinical workup. Our method can currently produce well-calibrated P values when applied to single genomes, can facilitate integration of multiple data types for n-of-one analyses, and, with further work, could become a widely used epidemiological method like linkage analysis or genome-wide association analysis. C1 [Wilfert, Amy B.; Conrad, Donald F.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Chao, Katherine R.; Adams, David R.] NIH, Undiagnosed Dis Program, Bldg 10, Bethesda, MD 20892 USA. [Kaushal, Madhurima; Jain, Sanjay] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Jain, Sanjay; Conrad, Donald F.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63130 USA. [Zollner, Sebastian] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Conrad, DF (reprint author), Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA.; Conrad, DF (reprint author), Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63130 USA. EM dconrad@genetics.wustl.edu OI Conrad, Donald/0000-0003-3828-8970 FU US National Institutes of Health [R01MH101810]; March of Dimes Foundation [6-FY14-430] FX We thank D. Wilson and M. Stephens for helpful comments, N. Huang for useful discussions and for providing updated versions of some annotations used in this work, K. Vigh-Conrad for assistance in preparing the figures, D. MacArthur, M. Lek and the members of the ExAC Consortium for generous prepublication sharing of their data, and M. Hoffmann and WU Kidney Translational Research Core (KTRC) for patient enrolment and Genome Technology Access Center (GTAC) for exome sequencing of CAKUT patients. Our work was supported by US National Institutes of Health grant R01MH101810 (to D.F.C.), March of Dimes Foundation grant #6-FY14-430 (to S.J.). NR 21 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 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD DEC PY 2016 VL 48 IS 12 BP 1455 EP 1461 DI 10.1038/ng.3697 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA ED7BQ UT WOS:000389011100005 PM 27776118 ER PT J AU Barban, N Jansen, R de Vlaming, R Vaez, A Mandemakers, JJ Tropf, FC Shen, X Wilson, JF Chasman, DI Nolte, IM Tragante, V van der Laan, SW Perry, JRB Kong, A Ahluwalia, TS Albrecht, E Yerges-Armstrong, L Atzmon, G Auro, K Ayers, K Bakshi, A Ben-Avraham, D Berger, K Bergman, A Bertram, L Bielak, LF Bjornsdottir, G Bonder, MJ Broer, L Bui, M Barbieri, C Cavadino, A Chavarro, JE Turman, C Concas, MP Cordell, HJ Davies, G Eibich, P Eriksson, N Esko, T Eriksson, J Falahi, F Felix, JF Fontana, MA Franke, L Gandin, I Gaskins, AJ Gieger, C Gunderson, EP Guo, XQ Hayward, C He, CY Hofer, E Huang, HY Joshi, PK Kanoni, S Karlsson, R Kiechl, S Kifley, A Kluttig, A Kraft, P Lagou, V Lecoeur, C Lahti, J Li-Gao, RF Lind, PA Liu, T Makalic, E Mamasoula, C Matteson, L Mbarek, H McArdle, PF McMahon, G Meddens, SFW Mihailov, E Miller, M Missmer, SA Monnereau, C van der Most, PJ Myhre, R Nalls, MA Nutile, T Kalafati, IP Porcu, E Prokopenko, I Rajan, KB Rich-Edwards, J Rietveld, CA Robino, A Rose, LM Rueedi, R Ryan, KA Saba, Y Schmidt, D Smith, JA Stolk, L Streeten, E Tonjes, A Thorleifsson, G Ulivi, S Wedenoja, J Wellmann, J Willeit, P Yao, J Yengo, L Zhao, JH Zhao, W Zhernakova, DV Amin, N Andrews, H Balkau, B Barzilai, N Bergmann, S Biino, G Bisgaard, H Bonnelykke, K Boomsma, DI Buring, JE Campbell, H Cappellani, S Ciullo, M Cox, SR Cucca, F Toniolo, D Davey-Smith, G Deary, IJ Dedoussis, G Deloukas, P van Duijn, CM de Geus, EJC Eriksson, JG Evans, DA Faul, JD Sala, CF Froguel, P Gasparini, P Girotto, G Grabe, HJ Greiser, KH Groenen, PJF de Haan, HG Haerting, J Harris, TB Heath, AC Heikkila, K Hofman, A Homuth, G Holliday, EG Hopper, J Hypponen, E Jacobsson, B Jaddoe', VWV Johannesson, M Kahonen, M Kajantie, E Kardia, SLR Keavney, B Kolcic, I Koponen, P Kovacs, P Kronenberg, F Kutalik, Z La Bianca, M Lachance, G Iacono, WG Lai, S Lehtimaki, T Liewald, DC Lindgren, CM Liu, YM Luben, R Lucht, M Luoto, R Magnus, P Magnusson, PKE Martin, NG McGue, M McQuillan, R Medland, SE Meisinger, C Mellstrom, D Metspalu, A Traglia, M Milani, L Mitchell, P Montgomery, GW Mook-Kanamori, D de Mutsert, R Nohr, EA Ohlsson, C Olsen, P Ong, KK Paternoster, L Pattie, A Penninx, BWJH Perola, M Peyser, PA Pirastu, M Polasek, O Power, C Kaprio, J Raffel, LJ Raikkonen, K Raitakari, O Ridker, PM Ring, SM Roll, K Rudan, I Ruggiero, D Rujescu, D Salomaa, V Schlessinger, D Schmidt, H Schmidt, R Schupf, N Smit, J Sorice, R Spector, TD Starr, JM Stockl, D Strauch, K Stumvoll, M Swertz, MA Thorsteinsdottir, U Thurik, AR Timpson, NJ Tung, JY Uitterlinden, AG Vaccargiu, S Viikari, J Vitart, V Volzke, H Vollenweider, P Vuckovic, D Waage, J Wagner, GG Wang, JJ Wareham, NJ Weir, DR Willemsen, G Willeit, J Wright, AF Zondervan, KT Stefansson, K Krueger, RF Lee, JJ Benjamin, DJ Cesarini, D Koellinger, PD den Hoed, M Snieder, H Mills, MC AF Barban, Nicola Jansen, Rick de Vlaming, Ronald Vaez, Ahmad Mandemakers, Jornt J. Tropf, Felix C. Shen, Xia Wilson, James F. Chasman, Daniel I. Nolte, Illa M. Tragante, Vinicius van der Laan, Sander W. Perry, John R. B. Kong, Augustine Ahluwalia, Tarunveer S. Albrecht, Eva Yerges-Armstrong, Laura Atzmon, Gil Auro, Kirsi Ayers, Kristin Bakshi, Andrew Ben-Avraham, Danny Berger, Klaus Bergman, Aviv Bertram, Lars Bielak, Lawrence F. Bjornsdottir, Gyda Bonder, Marc Jan Broer, Linda Bui, Minh Barbieri, Caterina Cavadino, Alana Chavarro, Jorge E. Turman, Constance Concas, Maria Pina Cordell, Heather J. Davies, Gail Eibich, Peter Eriksson, Nicholas Esko, Tonu Eriksson, Joel Falahi, Fahimeh Felix, Janine F. Fontana, Mark Alan Franke, Lude Gandin, Ilaria Gaskins, Audrey J. Gieger, Christian Gunderson, Erica P. Guo, Xiuqing Hayward, Caroline He, Chunyan Hofer, Edith Huang, Hongyan Joshi, Peter K. Kanoni, Stavroula Karlsson, Robert Kiechl, Stefan Kifley, Annette Kluttig, Alexander Kraft, Peter Lagou, Vasiliki Lecoeur, Cecile Lahti, Jari Li-Gao, Ruifang Lind, Penelope A. Liu, Tian Makalic, Enes Mamasoula, Crysovalanto Matteson, Lindsay Mbarek, Hamdi McArdle, Patrick F. McMahon, George Meddens, S. Fleur W. Mihailov, Evelin Miller, Mike Missmer, Stacey A. Monnereau, Claire van der Most, Peter J. Myhre, Ronny Nalls, Mike A. Nutile, Teresa Kalafati, Ioanna Panagiota Porcu, Eleonora Prokopenko, Inga Rajan, Kumar B. Rich-Edwards, Janet Rietveld, Cornelius A. Robino, Antonietta Rose, Lynda M. Rueedi, Rico Ryan, Kathleen-A Saba, Yasaman Schmidt, Daniel Smith, Jennifer A. Stolk, Lisette Streeten, Elizabeth Toenjes, Anke Thorleifsson, Gudmar Ulivi, Sheila Wedenoja, Juho Wellmann, Juergen Willeit, Peter Yao, Jie Yengo, Loic Zhao, Jing Hua Zhao, Wei Zhernakova, Dania V. Amin, Najaf Andrews, Howard Balkau, Beverley Barzilai, Nir Bergmann, Sven Biino, Ginevra Bisgaard, Hans Bonnelykke, Klaus Boomsma, Dorret I. Buring, Julie E. Campbell, Harry Cappellani, Stefania Ciullo, Marina Cox, Simon R. Cucca, Francesco Toniolo, Daniela Davey-Smith, George Deary, Ian J. Dedoussis, George Deloukas, Panos van Duijn, Cornelia M. de Geus, Eco J. C. Eriksson, Johan G. Evans, Denis A. Faul, Jessica D. Sala, Cinzia Felicita Froguel, Philippe Gasparini, Paolo Girotto, Giorgia Grabe, Hans-Joergen Greiser, Karin Halina Groenen, Patrick J. F. de Haan, Hugoline G. Haerting, Johannes Harris, Tamara B. Heath, Andrew C. Heikkila, Kauko Hofman, Albert Homuth, Georg Holliday, Elizabeth G. Hopper, John Hypponen, Elina Jacobsson, Bo Jaddoe', Vincent W. V. Johannesson, Magnus Kahonen, Mika Kajantie, Eero Kardia, Sharon L. R. Keavney, Bernard Kolcic, Ivana Koponen, Paivikki Kovacs, Peter Kronenberg, Florian Kutalik, Zoltan La Bianca, Martina Lachance, Genevieve Iacono, William G. Lai, Sandra Lehtimaki, Terho Liewald, David C. Lindgren, Cecilia M. Liu, Yongmei Luben, Robert Lucht, Michael Luoto, Riitta Magnus, Per Magnusson, Patrik K. E. Martin, Nicholas G. McGue, Matt McQuillan, Ruth Medland, Sarah E. Meisinger, Christa Mellstrom, Dan Metspalu, Andres Traglia, Michela Milani, Lili Mitchell, Paul Montgomery, Grant W. Mook-Kanamori, Dennis de Mutsert, Renee Nohr, Ellen A. Ohlsson, Claes Olsen, Porn Ong, Ken K. Paternoster, Lavinia Pattie, Alison Penninx, Brenda W. J. H. Perola, Markus Peyser, Patricia A. Pirastu, Mario Polasek, Ozren Power, Chris Kaprio, Jaakko Raffel, Leslie J. Raikkonen, Katri Raitakari, Olli Ridker, Paul M. Ring, Susan M. Roll, Kathryn Rudan, Igor Ruggiero, Daniela Rujescu, Dan Salomaa, Veikko Schlessinger, David Schmidt, Helena Schmidt, Reinhold Schupf, Nicole Smit, Johannes Sorice, Rossella Spector, Tim D. Starr, John M. Stockl, Doris Strauch, Konstantin Stumvoll, Michael Swertz, Morris A. Thorsteinsdottir, Unnur Thurik, A. Roy Timpson, Nicholas J. Tung, Joyce Y. Uitterlinden, Andre G. Vaccargiu, Simona Viikari, Jorma Vitart, Veronique Voelzke, Henry Vollenweider, Peter Vuckovic, Dragana Waage, Johannes Wagner, Gert G. Wang, Jie Jin Wareham, Nicholas J. Weir, David R. Willemsen, Gonneke Willeit, Johann Wright, Alan F. Zondervan, Krina T. Stefansson, Kari Krueger, Robert F. Lee, James J. Benjamin, Daniel J. Cesarini, David Koellinger, Philipp D. den Hoed, Marcel Snieder, Harold Mills, Melinda C. CA Bios Consortium LifeLines Cohort Study TI Genome-wide analysis identifies 12 loci influencing human reproductive behavior SO NATURE GENETICS LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; GENE PRIORITIZATION; QUALITY-CONTROL; HUMAN-DISEASES; G1 PHASE; ASSOCIATION; FERTILITY; MOUSE; PROTEIN; AGE AB The genetic architecture of human reproductive behavior age at first birth (AFB) and number of children ever born (NEB) has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits. C1 [Barban, Nicola; Tropf, Felix C.; Mills, Melinda C.] Univ Oxford, Dept Sociol, Oxford, England. [Barban, Nicola; Tropf, Felix C.; Mills, Melinda C.] Univ Oxford, Nuffield Coll, Oxford, England. [Jansen, Rick; Penninx, Brenda W. J. H.; Smit, Johannes] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [de Vlaming, Ronald; Rietveld, Cornelius A.; Thurik, A. 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F.] Erasmus Univ, Erasmus Sch Econ, Econometric Inst, Rotterdam, Netherlands. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Heath, Andrew C.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld, Australia. [Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Holliday, Elizabeth G.] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia. [Holliday, Elizabeth G.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Hypponen, Elina] Univ South Australia, Sansom Inst Hlth Res, Ctr Populat Hlth Res, Adelaide, SA, Australia. [Hypponen, Elina] Univ South Australia, Sch Hlth Sci, Adelaide, SA, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Jacobsson, Bo] Gothenburg Univ, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynecol, Gothenburg, Sweden. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, Stockholm, Sweden. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Tampere Univ Hosp, Tampere, Finland. [Kahonen, Mika] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Kajantie, Eero] Helsinki Univ Cent Hosp, Childrens Hosp, Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, Helsinki, Finland. [Kajantie, Eero] Oulu Univ Hosp, MRC Oulu, Dept Obstet & Gynecol, Oulu, Finland. [Kajantie, Eero] Univ Oulu, Oulu, Finland. [Keavney, Bernard] Univ Manchester, Inst Cardiovasc Sci, Manchester, Lancs, England. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Koponen, Paivikki] Natl Inst Hlth & Welf, Hlth Monitoring Unit, Helsinki, Finland. [Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, Leipzig, Germany. [Kronenberg, Florian] Med Univ Innsbruck, Div Genet Epidemiol, Innsbruck, Austria. [Kutalik, Zoltan] Lausanne Univ Hosp CHUV, Inst Social & Prevent Med, Lausanne, Switzerland. [Lachance, Genevieve; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere, Finland. [Lindgren, Cecilia M.] NIHR Oxford Biomed Res Ctr, Oxford, England. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Luben, Robert] Univ Cambridge, Strangeways Res Lab, Cambridge, England. [Luoto, Riitta] UKK Inst Hlth Promot, Tampere, Finland. [McGue, Matt] Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, Odense, Denmark. [McGue, Matt] Univ Southern Denmark, Inst Publ Hlth, Danish Twin Registry, Odense, Denmark. [Meisinger, Christa] Cent Hosp Augsburg, MONICA KORA Myocardial Infarct Registry, Augsburg, Germany. [Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia. [Montgomery, Grant W.] Univ Queensland, Mol Biosci, Brisbane, Qld, Australia. [Mook-Kanamori, Dennis] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Mook-Kanamori, Dennis] King Faisal Specialist Hosp & Res Ctr, Epidemiol Sect, Dept BESC, Riyadh, Saudi Arabia. [Nohr, Ellen A.] Univ Southern Denmark, Dept Clin Res, Res Unit Gynecol & Obstet, Odense, Denmark. [Olsen, Porn] Aarhus Univ, Dept Clin Epidemiol, Aarhus, Denmark. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Rujescu, Dan] Martin Luther Univ Halle Wittenberg, Dept Psychiat, Halle, Saale, Germany. [Schlessinger, David] NIA, Lab Genet, Baltimore, MD 21224 USA. [Schupf, Nicole; Stockl, Doris] Columbia Univ, Med Ctr, Dept Epidemiol, New York, NY USA. [Schupf, Nicole; Stockl, Doris] Columbia Univ, Dept Psychiat, Med Ctr, New York, NY USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Strauch, Konstantin] Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Thurik, A. Roy] Montpellier Business Sch, Montpellier, France. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma] Turku Univ Hosp, Div Med, Turku, Finland. [Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Vollenweider, Peter] Lausanne Univ Hosp CHUV, Dept Internal Med, Lausanne, Switzerland. [Wagner, Gert G.] Max Planck Inst Human Dev, German Socioecon Panel Study SOEP, Berlin, Germany. [Wagner, Gert G.] Berlin Univ Technol TUB, Berlin, Germany. [Zondervan, Krina T.] Univ Oxford, Wellcome Trust Ctr Human Genet, Genet & Genom Epidemiol Unit, Oxford, England. [Zondervan, Krina T.] Univ Oxford, Nuffield Dept Obstet & Gynaecol, Endometriosis CaRe Ctr, Oxford, England. [Benjamin, Daniel J.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Cesarini, David] NYU, Dept Econ, New York, NY 10003 USA. [Cesarini, David] Res Inst Ind Econ, Stockholm, Sweden. [den Hoed, Marcel] Uppsala Univ, Mol Epidemiol & Sci Life Lab, Dept Med Sci, Uppsala, Sweden. RP Barban, N; Mills, MC (reprint author), Univ Oxford, Dept Sociol, Oxford, England.; Snieder, H (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.; den Hoed, M (reprint author), Uppsala Univ, Mol Epidemiol & Sci Life Lab, Dept Med Sci, Uppsala, Sweden. EM nicola.barban@sociology.ox.ac.uk; marcel.den_hoed@medsci.uu.se; h.snieder@umcg.nl; melinda.mills@nuffield.ox.ac.uk RI Bertram, Lars/K-3889-2015; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Bisgaard, Hans/N-4761-2016; Davey Smith, George/A-7407-2013; Kronenberg, Florian/B-1736-2008; Johannesson, Magnus/E-9680-2011; Colaus, PsyColaus/K-6607-2013; Magnusson, Patrik/C-4458-2017; Yengo, Loic/D-2692-2017; Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; OI Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; de Geus, Eco/0000-0001-6022-2666; Hypponen, Elina/0000-0003-3670-9399; van der Laan, Sander W./0000-0001-6888-1404; Bertram, Lars/0000-0002-0108-124X; Wang, Jie Jin/0000-0001-9491-4898; Bisgaard, Hans/0000-0003-4131-7592; Davey Smith, George/0000-0002-1407-8314; Kronenberg, Florian/0000-0003-2229-1120; Johannesson, Magnus/0000-0001-8759-6393; Yengo, Loic/0000-0002-4272-9305; Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Jansen, Rick/0000-0002-3333-6737; Wedenoja, Juho/0000-0002-6155-0378; Bakshi, Andrew/0000-0001-5650-7036; Girotto, Giorgia/0000-0003-4507-6589; Bui, Minh/0000-0002-9099-6870; Barban, Nicola/0000-0002-4362-4652; Kaprio, Jaakko/0000-0002-3716-2455; Timpson, Nicholas/0000-0002-7141-9189; Smith, Jennifer/0000-0002-3575-5468; Bonder, Marc Jan/0000-0002-8431-3180 FU ERC Consolidator Grant SOCIOGENOME [615603]; Dutch Science Foundation (NWO) grant (VIDI grant) [452-10-012]; UK ESRC/NCRM SOCGEN grant [ES/N011856/1]; European Union [320116]; Wellcome Trust ISSF; John Fell Fund; Swedish Research Council [2015-03657, 421-2013-1061, 537-2014-371]; Swedish Heart-Lung Foundation [20140543]; US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'); National Institutes of Health Office of Behavioral and Social Science Research; Ragnar Soderberg Foundation [E9/11]; Jan Wallander and Tom Hedelius Foundation; ERC [647648 EdGe]; Pershing Square Fund of the Foundations of Human Behavior; NIA/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23, R01-AG042568-02] FX For full acknowledgments, see the Supplementary Note. Funding to lead this consortium was provided by grants awarded to M.C.M.: ERC Consolidator Grant SOCIOGENOME (615603), a Dutch Science Foundation (NWO) grant (VIDI grant 452-10-012), a UK ESRC/NCRM SOCGEN grant (ES/N011856/1), the European Union's FP7 Families And Societies project (320116), and the Wellcome Trust ISSF and John Fell Fund. M.d.H. was supported by grants from the Swedish Research Council (2015-03657) and the Swedish Heart-Lung Foundation (20140543). Research was carried out in collaboration with the Social Science Genetic Association Consortium (SSGAC), with funding from the US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'), a Supplementary grant from the National Institutes of Health Office of Behavioral and Social Science Research, the Ragnar Soderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), the Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to NBER and R01-AG042568-02 to the University of Southern California. X.S. was supported by a grant from the Swedish Research Council (537-2014-371). We thank X. Ding for research assistance, N. Pirastu, K. Coward and L. Layman for valuable comments, and the University of Oxford Advanced Research Computing (ARC) facility (http://dx.doi.org/10.5281/zenodo.22558). This research has been conducted using the UK Biobank Resource. NR 79 TC 1 Z9 1 U1 21 U2 21 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 DEC PY 2016 VL 48 IS 12 BP 1462 EP 1472 DI 10.1038/ng.3698 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA ED7BQ UT WOS:000389011100006 PM 27798627 ER PT J AU Lyons, JJ Yu, XM Hughes, JD Le, QT Jamil, A Bai, Y Ho, N Zhao, M Liu, YH O'Connell, MP Trivedi, NN Nelson, C DiMaggio, T Jones, N Matthews, H Lewis, KL Oler, AJ Carlson, RJ Arkwright, PD Hong, C Agama, S Wilson, TM Tucker, S Zhang, Y McElwee, JJ Pao, M Glover, SC Rothenberg, ME Hohman, RJ Stone, KD Caughey, GH Heller, T Metcalfe, DD Biesecker, LG Schwartz, LB Milner, JD AF Lyons, Jonathan J. Yu, Xiaomin Hughes, Jason D. Le, Quang T. Jamil, Ali Bai, Yun Ho, Nancy Zhao, Ming Liu, Yihui O'Connell, Michael P. Trivedi, Neil N. Nelson, Celeste DiMaggio, Thomas Jones, Nina Matthews, Helen Lewis, Katie L. Oler, Andrew J. Carlson, Ryan J. Arkwright, Peter D. Hong, Celine Agama, Sherene Wilson, Todd M. Tucker, Sofie Zhang, Yu McElwee, Joshua J. Pao, Maryland Glover, Sarah C. Rothenberg, Marc E. Hohman, Robert J. Stone, Kelly D. Caughey, George H. Heller, Theo Metcalfe, Dean D. Biesecker, Leslie G. Schwartz, Lawrence B. Milner, Joshua D. TI Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number SO NATURE GENETICS LA English DT Article ID JOINT HYPERMOBILITY SYNDROME; EPIDEMIOLOGY AB Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown(1,2). Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding alpha-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of alpha-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of alpha-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia. C1 [Lyons, Jonathan J.; Yu, Xiaomin; Jamil, Ali; Bai, Yun; Liu, Yihui; O'Connell, Michael P.; Nelson, Celeste; DiMaggio, Thomas; Carlson, Ryan J.; Agama, Sherene; Wilson, Todd M.; Tucker, Sofie; Stone, Kelly D.; Metcalfe, Dean D.; Milner, Joshua D.] NIAID, Lab Allerg Dis, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hughes, Jason D.; McElwee, Joshua J.] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Le, Quang T.; Schwartz, Lawrence B.] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. [Ho, Nancy; Heller, Theo] NIDDK, Liver Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Zhao, Ming; Hohman, Robert J.] NIAID, Res Technol Branch, US Natl Inst Hlth, Rockville, MD USA. [Trivedi, Neil N.; Caughey, George H.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA. [Trivedi, Neil N.; Caughey, George H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Trivedi, Neil N.; Caughey, George H.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Jones, Nina] SAIC Frederick Inc, Frederick Natl Lab Clin Res, Clin Res Directorate CMRP, Frederick, MD USA. [Matthews, Helen] NIAID, Immunol Lab, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. [Lewis, Katie L.; Hong, Celine; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Oler, Andrew J.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Inst Infect Immun & Resp Med, Manchester, Lancs, England. [Zhang, Yu] NIAID, Host Def Lab, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pao, Maryland] NIMH, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Glover, Sarah C.] Univ Florida, Div Gastroenterol Hepatol & Nutr, Gainesville, FL USA. [Rothenberg, Marc E.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45229 USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov OI Lyons, Jonathan/0000-0002-2346-8189 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH; NCI [HHSN261200800001E]; ARTrust/The Mastocytosis Society Research Award in Mastocytosis; Mast Cell Activation Syndrome; NIH [HL024136]; Intramural Research Program of the NHGRI FX We thank the patients, their families, and the numerous healthy volunteers who contributed to this research, as well as the clinical staff of the LAD, NIMH, NIDDK, and NHGRI for their efforts, in particular the Gastrointestinal and Psychiatry Consultation Liaison Services physicians, especially T. Alqassem, who participated in the care of these patients. We thank all the referring care providers, in particular A. Maitland and M. Carter for each referring several families for evaluation. We also acknowledge the collaborative spirit and efforts of the NIAMS and NIAID clinical genomics programs, specifically the investigators (M.J. Lenardo, H.S. Su, and R.T. Goldbach-Mansky) who shared clinical genomics data and study samples. We also thank M.J. Lenardo, W. Gahl, C. Akin, and J.-L. Casanova for their review of the manuscript. Lastly, we thank D. Abdulazeez of VCU for performing the tryptase immunoassays. This study was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. The involvement of N.J. was funded by NCI contract HHSN261200800001E. Funding was also provided in part by ARTrust/The Mastocytosis Society Research Award in Mastocytosis and/or Mast Cell Activation Syndrome (J.J.L.) and by NIH HL024136 (G.H.C.). L.G.B., C.H., and K.L.L. were supported by the Intramural Research Program of the NHGRI. NR 20 TC 2 Z9 2 U1 2 U2 2 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 DEC PY 2016 VL 48 IS 12 BP 1564 EP 1569 DI 10.1038/ng.3696 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ED7BQ UT WOS:000389011100018 PM 27749843 ER PT J AU Adams, HHH Hibar, DP Chouraki, V Stein, JL Nyquist, PA Renteria, ME Trompet, S Arias-Vasquez, A Seshadri, S Desrivieres, S Beecham, AH Jahanshad, N Wittfeld, K Van der Lee, SJ Abramovic, L Alhusaini, S Amin, N Andersson, M Arfanakis, K Aribisala, BS Armstrong, NJ Athanasiu, L Axelsson, T Beiser, A Bernard, M Bis, JC Blanken, LME Blanton, SH Bohlken, MM Boks, MP Bralten, J Brickman, AM Carmichael, O Chakravarty, MM Chauhan, G Chen, Q Ching, CRK Cuellar-Partida, G Den Braber, A Doan, NT Ehrlich, S Filippi, I Ge, T Giddaluru, S Goldman, AL Gottesman, RF Greven, CU Grimm, O Griswold, ME Guadalupe, T Hass, J Haukvik, UK Hilal, S Hofer, E Hoehn, D Holmes, AJ Hoogman, M Janowitz, D Jia, T Kasperaviciute, D Kim, S Klein, M Kraemer, B Lee, PH Liao, J Liewald, DCM Lopez, LM Luciano, M Macare, C Marquand, A Matarin, M Mather, KA Mattheisen, M Mazoyer, B Mckay, DR McWhirter, R Milaneschi, Y Mirza-Schreiber, N Muetzel, RL Maniega, SM Nho, K Nugent, AC Loohuis, LMO Oosterlaan, J Papmeyer, M Pappa, I Pirpamer, L Pudas, S Puetz, B Rajan, KB Ramasamy, A Richards, JS Risacher, SL Roiz-Santianez, R Rommelse, N Rose, EJ Royle, NA Rundek, T Samann, PG Satizabal, CL Schmaal, L Schork, AJ Shen, L Shin, J Shumskaya, E Smith, AV Sprooten, E Strike, LT Teumer, A Thomson, R Tordesillas-Gutierrez, D Toro, R Trabzuni, D Vaidya, D Van der Grond, J Van der Meer, D Van Donkelaar, MMJ Van Eijk, KR Van Erp, TGM Van Rooij, D Walton, E Westlye, LT Whelan, CD Windham, BG Winkler, AM Woldehawariat, G Wolf, C Wolfers, T Xu, B Yanek, LR Yang, JY Zijdenbos, A Zwiers, MP Agartz, I Aggarwal, NT Almasy, L Ames, D Amouyel, P Andreassen, OA Arepalli, S Assareh, AA Barral, S Bastin, ME Becker, DM Becker, JT Bennett, DA Blangero, J van Bokhoven, H Boomsma, DI Brodaty, H Brouwer, RM Brunner, HG Buckner, RL Buitelaar, JK Bulayeva, KB Cahn, W Calhoun, VD Cannon, DM Cavalleri, GL Chen, C Cheng, CY Cichon, S Cookson, MR Corvin, A Crespo-Facorro, B Curran, JE Czisch, M Dale, AM Davies, GE De Geus, EJC De Jager, PL de Zubicaray, GI Delanty, N Depondt, C DeStefano, AL Dillman, A Djurovic, S Donohoe, G Drevets, WC Duggirala, R Dyer, TD Erk, S Espeseth, T Evans, DA Fedko, I Fernandez, G Ferrucci, L Fisher, SE Fleischman, DA Ford, I Foroud, TM Fox, PT Francks, C Fukunaga, M Gibbs, JR Glahn, DC Gollub, RL Goring, HHH Grabe, HJ Green, RC Gruber, O Gudnason, V Guelfi, S Hansell, NK Hardy, J Hartman, CA Hashimoto, R Hegenscheid, K Heinz, A Le Hellard, S Hernandez, DG Heslenfeld, DJ Ho, BC Hoekstra, PJ Hoffmann, W Hofman, A Holsboer, F Homuth, G Hosten, N Hottenga, JJ Pol, HEH Ikeda, M Ikram, MK Jack, CR Jenldnson, M Johnson, R Jonsson, EG Jukema, JW Kahn, RS Kanai, R Kloszewska, I Knopman, DS Kochunov, P Kwok, JB Lawrie, SM Lemaitre, H Liu, XM Longo, DL Longstreth, WT Lopez, OL Lovestone, S Martinez, O Martinot, JL Mattay, VS McDonald, C McIntosh, AM McMahon, KL McMahon, FJ Mecocci, P Melle, I Meyer-Lindenberg, A Mohnke, S Montgomery, GW Morris, DW Mosley, TH Muhleisen, TW Muller-Myhsok, B Nalls, MA Nauck, M Nichols, TE Niessen, WJ Nothen, MM Nyberg, L Ohi, K Olvera, RL Ophoff, RA Pandolfo, M Paus, T Pausova, Z Penninx, BWJH Pike, GB Potkin, SG Psaty, BM Reppermund, S Rietschel, M Roffman, JL Romanczuk-Seiferth, N Rotter, JI Ryten, M Sacco, RL Sachdev, PS Saykin, AJ Schmidt, R Schofield, PR Sigurdsson, S Simmons, A Singleton, A Sisodiya, SM Smith, C Smoller, JW Soininen, H Srikanth, V Steen, VM Stott, DJ Sussmann, JE Thalamuthu, A Tiemeier, H Toga, AW Traynor, BJ Troncoso, J Turner, JA Tzourio, C Uitterlinden, AG Hernandez, MCV Van der Brug, M Van der Lugt, A Van der Wee, NJA Van Duijn, CM Van Haren, NEM Van't Ent, D Van Tol, MJ Vardarajan, BN Veltman, DJ Vernooij, MW Volzke, H Walter, H Wardlaw, JM Wassink, TH Weale, ME Weinberger, DR Weiner, MW Wen, W Westman, E White, T Wong, TY Wright, CB Zielke, HR Zonderman, AB Deary, IJ DeCarli, C Schmidt, H Martin, NG De Craen, AJM Wright, MJ Launer, LJ Schumann, G Fornage, M Franke, B Debette, S Medland, SE Ikram, MA Thompson, PM AF Adams, Hieab H. H. Hibar, Derrek P. Chouraki, Vincent Stein, Jason L. Nyquist, Paul A. Renteria, Miguel E. Trompet, Stella Arias-Vasquez, Alejandro Seshadri, Sudha Desrivieres, Sylvane Beecham, Ashley H. Jahanshad, Neda Wittfeld, Katharine Van der Lee, Sven J. Abramovic, Lucija Alhusaini, Saud Amin, Najaf Andersson, Micael Arfanakis, Konstantinos Aribisala, Benjamin S. Armstrong, Nicola J. Athanasiu, Lavinia Axelsson, Tomas Beiser, Alexa Bernard, Manon Bis, Joshua C. Blanken, Laura M. E. Blanton, Susan H. Bohlken, Marc M. Boks, Marco P. Bralten, Janita Brickman, Adam M. Carmichael, Owen Chakravarty, M. Mallar Chauhan, Ganesh Chen, Qiang Ching, Christopher R. K. Cuellar-Partida, Gabriel Den Braber, Anouk Doan, Nhat Trung Ehrlich, Stefan Filippi, Irina Ge, Tian Giddaluru, Sudheer Goldman, Aaron L. Gottesman, Rebecca F. Greven, Corina U. Grimm, Oliver Griswold, Michael E. Guadalupe, Tulio Hass, Johanna Haukvik, Unn K. Hilal, Saima Hofer, Edith Hoehn, David Holmes, Avram J. Hoogman, Martine Janowitz, Deborah Jia, Tianye Kasperaviciute, Dalia Kim, Sungeun Klein, Marieke Kraemer, Bernd Lee, Phil H. Liao, Jiemin Liewald, David C. M. Lopez, Lorna M. Luciano, Michelle Macare, Christine Marquand, Andre Matarin, Mar Mather, Karen A. Mattheisen, Manuel Mazoyer, Bernard Mckay, David R. McWhirter, Rebekah Milaneschi, Yuri Mirza-Schreiber, Nazanin Muetzel, Ryan L. Maniega, Susana Munoz Nho, Kwangsik Nugent, Allison C. Loohuis, Loes M. Olde Oosterlaan, Jaap Papmeyer, Martina Pappa, Irene Pirpamer, Lukas Pudas, Sara Puetz, Benno Rajan, Kumar B. Ramasamy, Adaikalavan Richards, Jennifer S. Risacher, Shannon L. Roiz-Santianez, Roberto Rommelse, Nanda Rose, Emma J. Royle, Natalie A. Rundek, Tatjana Saemann, Philipp G. Satizabal, Claudia L. Schmaal, Lianne Schork, Andrew J. Shen, Li Shin, Jean Shumskaya, Elena Smith, Albert V. Sprooten, Emma Strike, Lachlan T. Teumer, Alexander Thomson, Russell Tordesillas-Gutierrez, Diana Toro, Roberto Trabzuni, Daniah Vaidya, Dhananjay Van der Grond, Jeroen Van der Meer, Dennis Van Donkelaar, Marjolein M. J. Van Eijk, Kristel R. Van Erp, Theo G. M. Van Rooij, Daan Walton, Esther Westlye, Lars T. Whelan, Christopher D. Windham, Beverly G. Winkler, Anderson M. Woldehawariat, Girma Wolf, Christiane Wolfers, Thomas Xu, Bing Yanek, Lisa R. Yang, Jingyun Zijdenbos, Alex Zwiers, Marcel P. Agartz, Ingrid Aggarwal, Neelum T. Almasy, Laura Ames, David Amouyel, Philippe Andreassen, Ole A. Arepalli, Sampath Assareh, Amelia A. Barral, Sandra Bastin, Mark E. Becker, Diane M. Becker, James T. Bennett, David A. Blangero, John van Bokhoven, Hans Boomsma, Dorret I. Brodaty, Henry Brouwer, Rachel M. Brunner, Han G. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cahn, Wiepke Calhoun, Vince D. Cannon, Dara M. Cavalleri, Gianpiero L. Chen, Christopher Cheng, Ching -Yu Cichon, Sven Cookson, Mark R. Corvin, Aiden Crespo-Facorro, Benedicto Curran, Joanne E. Czisch, Michael Dale, Anders M. Davies, Gareth E. De Geus, Eco J. C. De Jager, Philip L. de Zubicaray, Greig I. Delanty, Norman Depondt, Chantal DeStefano, Anita L. Dillman, Allissa Djurovic, Srdjan Donohoe, Gary Drevets, Wayne C. Duggirala, Ravi Dyer, Thomas D. Erk, Susanne Espeseth, Thomas Evans, Denis A. Fedko, Iryna Fernandez, Guillen Ferrucci, Luigi Fisher, Simon E. Fleischman, Debra A. Ford, Ian Foroud, Tatiana M. Fox, Peter T. Francks, Clyde Fukunaga, Masaki Gibbs, J. Raphael Glahn, David C. Gollub, Randy L. Goring, Harald H. H. Grabe, Hans J. Green, Robert C. Gruber, Oliver Gudnason, Vilmundur Guelfi, Sebastian Hansell, Narelle K. Hardy, John Hartman, Catharina A. Hashimoto, Ryota Hegenscheid, Katrin Heinz, Andreas Le Hellard, Stephanie Hernandez, Dena G. Heslenfeld, Dirk J. Ho, Beng-Choon Hoekstra, Pieter J. Hoffmann, Wolfgang Hofman, Albert Holsboer, Florian Homuth, Georg Hosten, Norbert Hottenga, Jouke-Jan Pol, Hilleke E. Hulshoff Ikeda, Masashi Ikram, M. Kamran Jack, Clifford R., Jr. Jenldnson, Mark Johnson, Robert Jonsson, Erik G. Jukema, J. Wouter Kahn, Rene S. Kanai, Ryota Kloszewska, Iwona Knopman, David S. Kochunov, Peter Kwok, John B. Lawrie, Stephen M. Lemaitre, Herve Liu, Xinmin Longo, Dan L. Longstreth, W. T., Jr. Lopez, Oscar L. Lovestone, Simon Martinez, Oliver Martinot, Jean-Luc Mattay, Venkata S. McDonald, Colm McIntosh, Andrew M. McMahon, Katie L. McMahon, Francis J. Mecocci, Patrizia Melle, Ingrid Meyer-Lindenberg, Andreas Mohnke, Sebastian Montgomery, Grant W. Morris, Derek W. Mosley, Thomas H. Muhleisen, Thomas W. Mueller-Myhsok, Bertram Nalls, Michael A. Nauck, Matthias Nichols, Thomas E. Niessen, Wiro J. Noethen, Markus M. Nyberg, Lars Ohi, Kazutaka Olvera, Rene L. Ophoff, Roel A. Pandolfo, Massimo Paus, Tomas Pausova, Zdenka Penninx, Brenda W. J. H. Pike, G. Bruce Potkin, Steven G. Psaty, Bruce M. Reppermund, Simone Rietschel, Marcella Roffman, Joshua L. Romanczuk-Seiferth, Nina Rotter, Jerome I. Ryten, Mina Sacco, Ralph L. Sachdev, Perminder S. Saykin, Andrew J. Schmidt, Reinhold Schofield, Peter R. Sigurdsson, Sigurdur Simmons, Andy Singleton, Andrew Sisodiya, Sanjay M. Smith, Colin Smoller, Jordan W. Soininen, Hindu. Srikanth, Velandai Steen, Vidar M. Stott, David J. Sussmann, Jessika E. Thalamuthu, Anbupalam Tiemeier, Henning Toga, Arthur W. Traynor, Bryan J. Troncoso, Juan Turner, Jessica A. Tzourio, Christophe Uitterlinden, Andre G. Hernandez, Maria C. Valdes Van der Brug, Marcel Van der Lugt, Aad Van der Wee, Nic J. A. Van Duijn, Cornelia M. Van Haren, Neeltje E. M. Van't Ent, Dennis Van Tol, Marie Jose Vardarajan, Badri N. Veltman, Dick J. Vernooij, Meike W. Voelzke, Henry Walter, Henrik Wardlaw, Joanna M. Wassink, Thomas H. Weale, Michael E. Weinberger, Daniel R. Weiner, Michael W. Wen, Wei Westman, Eric White, Tonya Wong, Tien Y. Wright, Clinton B. Zielke, H. Ronald Zonderman, Alan B. Deary, Ian J. DeCarli, Charles Schmidt, Helena Martin, Nicholas G. De Craen, Anton J. M. Wright, Margaret J. Launer, Lenore J. Schumann, Gunter Fornage, Myriam Franke, Barbara Debette, Stephanie Medland, Sarah E. Ikram, M. Arfan Thompson, Paul M. CA Alzheimer's Dis Neuroimaging Initi EPIGEN IMAGEN SYS TI Novel genetic loci underlying human intracranial volume identified through genome-wide association SO NATURE NEUROSCIENCE LA English DT Article ID COMMON VARIANTS; 17Q21.31 MICRODELETION; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; HEAD CIRCUMFERENCE; BRAIN SIZE; IGF-I; METAANALYSIS; CONSORTIUM; GROWTH AB Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits. C1 [Adams, Hieab H. H.; Van der Lee, Sven J.; Amin, Najaf; Hofman, Albert; Ikram, M. Kamran; Tiemeier, Henning; Uitterlinden, Andre G.; Van Duijn, Cornelia M.; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Adams, Hieab H. H.; Niessen, Wiro J.; Van der Lugt, Aad; Vernooij, Meike W.; White, Tonya; Ikram, M. Arfan] Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands. [Hibar, Derrek P.; Stein, Jason L.; Jahanshad, Neda; Ching, Christopher R. K.; Whelan, Christopher D.; Thompson, Paul M.] Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA. [Chouraki, Vincent; Seshadri, Sudha; Beiser, Alexa; Satizabal, Claudia L.; Debette, Stephanie] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chouraki, Vincent; Amouyel, Philippe] Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France. [Chouraki, Vincent; Seshadri, Sudha; Beiser, Alexa; Satizabal, Claudia L.; DeStefano, Anita L.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Stein, Jason L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Stein, Jason L.] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC USA. [Nyquist, Paul A.] Johns Hopkins Univ, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, Baltimore, MD 21218 USA. [Renteria, Miguel E.; Cuellar-Partida, Gabriel; Strike, Lachlan T.; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Wolfers, Thomas; van Bokhoven, Hans; Brunner, Han G.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Rommelse, Nanda; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Greven, Corina U.; Richards, Jennifer S.; Van Rooij, Daan; Buitelaar, Jan K.; Fernandez, Guillen] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Marquand, Andre; Richards, Jennifer S.; Rommelse, Nanda; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Van Rooij, Daan; Wolfers, Thomas; Zwiers, Marcel P.; van Bokhoven, Hans; Brunner, Han G.; Buitelaar, Jan K.; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Franke, Barbara] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands. [Desrivieres, Sylvane; Jia, Tianye; Macare, Christine; Xu, Bing; Schumann, Gunter] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC SGDP Ctr, London, England. [Beecham, Ashley H.; Blanton, Susan H.] Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA. [Beecham, Ashley H.; Blanton, Susan H.; Sacco, Ralph L.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA. [Wittfeld, Katharine; Hoffmann, Wolfgang] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany. [Wittfeld, Katharine; Janowitz, Deborah; Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, Greifswald, Germany. [Abramovic, Lucija; Bohlken, Marc M.; Boks, Marco P.; Brouwer, Rachel M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Kahn, Rene S.; Ophoff, Roel A.; Van Haren, Neeltje E. M.] UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Alhusaini, Saud] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Alhusaini, Saud; Whelan, Christopher D.; Cavalleri, Gianpiero L.; Delanty, Norman] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Andersson, Micael; Pudas, Sara; Nyberg, Lars] Umea Univ, Dept Integrat Med Biol, Umea, Sweden. [Arfanakis, Konstantinos] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Arfanakis, Konstantinos; Yang, Jingyun; Aggarwal, Neelum T.; Bennett, David A.; Fleischman, Debra A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Arfanakis, Konstantinos] Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland. [Aribisala, Benjamin S.] Lagos State Univ, Dept Comp Sci, Lagos, Nigeria. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland. [Armstrong, Nicola J.; Mather, Karen A.; Assareh, Amelia A.; Brodaty, Henry; Reppermund, Simone; Sachdev, Perminder S.; Thalamuthu, Anbupalam; Wen, Wei] Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia. [Armstrong, Nicola J.] Murdoch Univ, Math & Stat, Perth, WA, Australia. [Athanasiu, Lavinia; Doan, Nhat Trung; Haukvik, Unn K.; Agartz, Ingrid; Andreassen, Ole A.; Jonsson, Erik G.; Melle, Ingrid] Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway. [Athanasiu, Lavinia; Westlye, Lars T.; Andreassen, Ole A.; Espeseth, Thomas; Melle, Ingrid] Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway. [Axelsson, Tomas] Uppsala Univ, Dept Med Sci Mol Med, Uppsala, Sweden. [Axelsson, Tomas] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bernard, Manon; Shin, Jean; Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada. 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[Chauhan, Ganesh] Univ Bordeaux, INSERM Unit U1219, Bordeaux, France. [Chen, Qiang; Goldman, Aaron L.; Mattay, Venkata S.; Weinberger, Daniel R.; Debette, Stephanie] Lieber Inst Brain Dev, Baltimore, MD USA. [Ching, Christopher R. K.] Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna; Hottenga, Jouke-Jan; Van't Ent, Dennis] Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna; Hottenga, Jouke-Jan; Van't Ent, Dennis] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Ehrlich, Stefan] Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany. [Ehrlich, Stefan; Holmes, Avram J.; Lee, Phil H.; Buckner, Randy L.; Gollub, Randy L.; Roffman, Joshua L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. 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[Giddaluru, Sudheer; DeStefano, Anita L.; Le Hellard, Stephanie; Steen, Vidar M.] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway. [Gottesman, Rebecca F.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Greven, Corina U.; Richards, Jennifer S.; Rommelse, Nanda; Buitelaar, Jan K.] Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands. [Greven, Corina U.] Kings Coll London, Med Res Council Social, Genet & Dev Psychiat Ctr, Inst Psychol Psychiat & Neurosci, London, England. [Grimm, Oliver; Meyer-Lindenberg, Andreas; Rietschel, Marcella] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Guadalupe, Tulio; Fisher, Simon E.; Francks, Clyde] Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands. [Guadalupe, Tulio] Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands. [Hass, Johanna; Walton, Esther] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany. [Haukvik, Unn K.; Agartz, Ingrid] Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway. [Hilal, Saima; Chen, Christopher; Ikram, M. Kamran] Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore. [Hilal, Saima; Chen, Christopher; Ikram, M. Kamran] Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore. [Hofer, Edith; Pirpamer, Lukas; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Hoehn, David; Mirza-Schreiber, Nazanin; Puetz, Benno; Saemann, Philipp G.; Czisch, Michael; Holsboer, Florian; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT USA. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] UCL, Inst Neurol, London, England. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] Epilepsy Soc, Gerrards Cross, Bucks, England. [Kasperaviciute, Dalia] Imperial Coll London, Dept Med, London, England. [Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA. [Kim, Sungeun; Nho, Kwangsik; Shen, Li; Foroud, Tatiana M.] Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA. [Kraemer, Bernd; Gruber, Oliver] Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany. [Lee, Phil H.] Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA. [Liao, Jiemin; Cheng, Ching -Yu; Ikram, M. Kamran; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; McIntosh, Andrew M.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland. [Marquand, Andre; Shumskaya, Elena; Zwiers, Marcel P.] Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark. [Mattheisen, Manuel] Aarhus Univ, iSEQ, Ctr Integrated Sequencing, Aarhus, Denmark. [Mazoyer, Bernard] UMR5296 Univ Bordeaux, CNRS, CEA, Bordeaux, France. [Mckay, David R.; Sprooten, Emma; Winkler, Anderson M.; Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Mckay, David R.; Sprooten, Emma; Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT USA. [McWhirter, Rebekah] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia. [Milaneschi, Yuri] VU Univ Med Ctr GGZ Geest, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri] VU Univ Med Ctr GGZ Geest, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Nugent, Allison C.; Woldehawariat, Girma; Cannon, Dara M.; Drevets, Wayne C.; Liu, Xinmin; McMahon, Francis J.] NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Loohuis, Loes M. Olde; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Oosterlaan, Jaap] Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands. [Papmeyer, Martina; Sprooten, Emma; Lawrie, Stephen M.; McIntosh, Andrew M.; Sussmann, Jessika E.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Papmeyer, Martina] Univ Bern, Univ Hosp Psychiat, Translat Res Ctr, Div Syst Neurosci Psychopathol, CH-3012 Bern, Switzerland. [Pappa, Irene] Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands. [Rajan, Kumar B.; Aggarwal, Neelum T.; Evans, Denis A.] Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA. [Ramasamy, Adaikalavan; Ryten, Mina; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, London, England. [Ramasamy, Adaikalavan] Univ Oxford, Jenner Inst Labs, Oxford, England. [Roiz-Santianez, Roberto; Crespo-Facorro, Benedicto] Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain. [Roiz-Santianez, Roberto; Tordesillas-Gutierrez, Diana; Crespo-Facorro, Benedicto] CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland. [Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA. [Schmaal, Lianne] Orygen, Melbourne, Vic, Australia. [Schmaal, Lianne] Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia. [Schmaal, Lianne; Penninx, Brenda W. J. H.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Schork, Andrew J.] Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, San Diego, CA 92103 USA. [Schork, Andrew J.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA. [Smith, Albert V.; Gudnason, Vilmundur; Sigurdsson, Sigurdur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sprooten, Emma] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Strike, Lachlan T.; Hansell, Narelle K.; Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Teumer, Alexander; Hoffmann, Wolfgang; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Thompson, Paul M.] Univ Western Sydney, Sch Comp Engn & Math, Parramatta, NSW, Australia. [Tordesillas-Gutierrez, Diana] Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain. [Toro, Roberto] Inst Pasteur, Paris, France. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia. [Vaidya, Dhananjay; Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA. [Van der Grond, Jeroen] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Van der Meer, Dennis; Van Rooij, Daan; Hartman, Catharina A.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Van Eijk, Kristel R.] UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Van Erp, Theo G. M.; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Westlye, Lars T.; Espeseth, Thomas] Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway. [Windham, Beverly G.; Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Winkler, Anderson M.; Jenldnson, Mark; Jonsson, Erik G.; Nichols, Thomas E.] Univ Oxford, FMRIB Ctr, Oxford, England. [Wolf, Christiane] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Yang, Jingyun; Aggarwal, Neelum T.; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Zijdenbos, Alex] Biospect Inc, Montreal, PQ, Canada. [Agartz, Ingrid] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA. [Almasy, Laura] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Almasy, Laura] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Ames, David] Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia. [Ames, David] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia. [Arepalli, Sampath; Cookson, Mark R.; Dillman, Allissa; Gibbs, J. Raphael; Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew; Traynor, Bryan J.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Becker, James T.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Becker, James T.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Becker, James T.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Brodaty, Henry] UNSW, Dementia Collaborat Res Ctr Assessment & Better, Sydney, NSW, Australia. [Brunner, Han G.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Buckner, Randy L.] Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA. [Bulayeva, Kazima B.; Wong, Tien Y.] Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince D.] LBERI, Albuquerque, NM USA. [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Cannon, Dara M.; McDonald, Colm; Muhleisen, Thomas W.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland. [Cheng, Ching -Yu; Ikram, M. Kamran] Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore. [Cheng, Ching -Yu; Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore. [Cichon, Sven] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Muhleisen, Thomas W.] Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany. [Dale, Anders M.] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA. [Davies, Gareth E.] Avera Inst Human Genet, Sioux Falls, SD USA. [Davies, Gareth E.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Gen, 75 Francis St, Boston, MA 02115 USA. [Davies, Gareth E.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Davies, Gareth E.] Harvard Med Sch, Boston, MA USA. [Davies, Gareth E.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [De Jager, Philip L.] Broad Inst, Cambridge, MA USA. [de Zubicaray, Greig I.] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia. [de Zubicaray, Greig I.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Delanty, Norman] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Depondt, Chantal; Pandolfo, Massimo] Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. [Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland. [Drevets, Wayne C.] Janssen Res & Dev LLC, Titusville, NJ USA. [Erk, Susanne; Heinz, Andreas; Mohnke, Sebastian; Romanczuk-Seiferth, Nina; Walter, Henrik] Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany. [Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Fleischman, Debra A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Fleischman, Debra A.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA. [Fox, Peter T.; Olvera, Rene L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fukunaga, Masaki] Natl Inst Physiol Sci, Div Cerebral Integrat, Aichi, Japan. [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Hashimoto, Ryota; Ohi, Kazutaka] Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan. [Hashimoto, Ryota] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan. [Hegenscheid, Katrin; Hosten, Norbert] Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Hernandez, Dena G.] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Heslenfeld, Dirk J.] Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands. [Ho, Beng-Choon] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Holsboer, Florian] HMNC Brain Hlth, Munich, Germany. [Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany. [Ikeda, Masashi] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi, Japan. [Jack, Clifford R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Johnson, Robert; Zielke, H. Ronald] Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA. [Kanai, Ryota] Univ Sussex, Sch Psychol, Brighton, E Sussex, England. [Kanai, Ryota] UCL, Inst Cognit Neurosci, London, England. [Kanai, Ryota] Araya Brain Imaging, Dept Neuroinformat, Tokyo, Japan. [Kloszewska, Iwona] Med Univ Lodz, Lodz, Poland. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Kochunov, Peter] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Kwok, John B.; Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW, Australia. [Kwok, John B.; Schofield, Peter R.] UNSW, Sch Med Sci, Sydney, NSW, Australia. [Liu, Xinmin] Columbia Univ, Med Ctr, New York, NY USA. [Longo, Dan L.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Lovestone, Simon] Univ Oxford, Dept Psychiat, Oxford, England. [Lovestone, Simon] Kings Coll London, NIHR Dementia Biomed Res Unit, London, England. [Martinez, Oliver; DeCarli, Charles] Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA. [Martinez, Oliver; DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [McMahon, Katie L.; Wright, Margaret J.] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia. [Mecocci, Patrizia] Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Mueller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Nauck, Matthias] German Ctr Cardiovasc Res DZHK eV, Partner Site Greifswald, Berlin, Germany. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry, W Midlands, England. [Nichols, Thomas E.] Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England. [Niessen, Wiro J.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Paus, Tomas] Child Mind Inst, New York, NY USA. [Pausova, Zdenka] Univ Toronto, Dept Phys, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Pike, G. Bruce] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Pike, G. Bruce] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. [Reppermund, Simone] UNSW Med, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Kensington, NSW, Australia. [Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Ilnst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat Harbor, Torrance, CA 90509 USA. [Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA. [Sachdev, Perminder S.] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia. [Simmons, Andy] Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England. [Simmons, Andy] Kings Coll London, Biomed Res Ctr Mental Hlth, London, England. [Simmons, Andy] Kings Coll London, Biomed Res Unit Dementia, London, England. [Smith, Colin] Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh, Midlothian, Scotland. [Soininen, Hindu.] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland. [Soininen, Hindu.] Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland. [Srikanth, Velandai] Peninsula Hlth & Monash Univ, Dept Med, Melbourne, Vic, Australia. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Toga, Arthur W.] Univ Southern Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA USA. [Troncoso, Juan] Johns Hopkins Univ, Brain Resource Ctr, Baltimore, MD USA. [Turner, Jessica A.] Georgia State Univ, Atlanta, GA 30303 USA. [Tzourio, Christophe] Univ Bordeaux, Institute Neurodegenerat Disorders, CEA, CNRS,UMR 5293, Bordeaux, France. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Van der Brug, Marcel] Genentech Inc, San Francisco, CA 94080 USA. [Van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands. [Van Tol, Marie Jose] Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, Groningen, Netherlands. [Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Weiner, Michael W.] Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA. [Westman, Eric] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [De Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA. [Debette, Stephanie] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France. [Ikram, M. Arfan] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Andersson, Micael; Pudas, Sara; Nyberg, Lars] Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden. RP Ikram, MA (reprint author), Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.; Ikram, MA (reprint author), Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.; Thompson, PM (reprint author), Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.; Ikram, MA (reprint author), Erasmus MC, Dept Neurol, Rotterdam, Netherlands. EM m.a.ikram@erasmusmc.nl; pthomp@usc.edu RI Tzourio, christophe/B-4015-2009; Simmons, Andrew/B-8848-2008; Hardy, John/C-2451-2009; Hansell, Narelle/A-4553-2016; Zwiers, Marcel/D-2968-2009; Franke, Barbara/D-4836-2009; Meyer-Lindenberg, Andreas/H-1076-2011; McMahon, Katie/C-6440-2009; Thomson, Russell/H-5653-2012; Fernandez, Guillen/B-3771-2009; Cuellar Partida, Gabriel/C-6686-2017; OI Tzourio, christophe/0000-0002-6517-2984; Simmons, Andrew/0000-0003-2306-5811; Hansell, Narelle/0000-0002-8229-9741; Zwiers, Marcel/0000-0001-5483-2935; Franke, Barbara/0000-0003-4375-6572; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; McMahon, Katie/0000-0002-6357-615X; Thomson, Russell/0000-0003-4949-4120; Fernandez, Guillen/0000-0002-5522-0604; Adams, Hieab/0000-0003-3687-2508; Rose, Emma/0000-0001-5365-4794; Zonderman, Alan B/0000-0002-6523-4778; Vaidya, Dhananjay/0000-0002-7164-1601; Beiser, Alexa/0000-0001-8551-7778; Westlye, Lars T./0000-0001-8644-956X; de Geus, Eco/0000-0001-6022-2666; Kanai, Ryota/0000-0002-0186-2687; McIntosh, Andrew/0000-0002-0198-4588; Cuellar Partida, Gabriel/0000-0001-7648-4097; Desrivieres, Sylvane/0000-0002-9120-7060; Cavalleri, Gianpiero/0000-0002-9802-0506; Pudas, Sara/0000-0001-9512-3289; Westman, Eric/0000-0002-3115-2977; Arfanakis, Konstantinos/0000-0001-9705-597X; Jonsson, Erik/0000-0001-8368-6332 FU National Heart, Lung and Blood Institute [HL105756]; National Institute on Aging [AG033193]; NIH Institute, NIBIB [U54 EB020403]; NIH Institute, NCI [U54 EB020403]; NIH [N01-AG-1-2100, 271201200022C, R01MH62873, K99MH102357, R01 HD050735, P30AG10161, RF1AG15819, R01AG17917, R01AG30146, R01AG40039, 5R01AG037212]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); ADNI (National Institutes of Health Grant) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; lzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; EU; Kuopio University Hospital; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C, R01D0042157-01A, MH081802, 1RC2 MH089951, 1RC2 MH089995]; component of the NIH and NIH Roadmap for Medical Research [UL1RR025005]; NIH R01 grant [NS087541]; Austrian Science Fund (FWF) [1904]; Medical University of Graz; Steiermarkische Krankenanstalten Gesellschaft; Knut and Alice Wallenberg (KAW) foundation; Torsten and Ragnar Soderbergs Foundation; HelseVest RHF [911554]; Brain Research Imaging Centre Edinburgh, a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration; National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award; Health Foundation Clinician Scientist Fellowship; European Community [602450, 278948, 602805, 643051]; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Hersenstichting Nederland; Netherlands Organization for Scientific Research (NWO); NWO Gravitation grant 'Language in Interaction'; ERC [268800-NEUROSCHEMA]; ENIGMA Consortium from the BD2K Initiative of a cross-NIH partnership [U54 EB020403]; Center for Brain Science Neuroinformatics Research Group; Athinoula A. Martinos Center for Biomedical Imaging; Center for Human Genetic Research; NIMH [K99 MH101367, R01-MH079799, K24MH094614, K01MH099232]; National Institute of Health [AG033193, AG011101, AG030146, AG008122, AG054076, AG049607, AG010129, NS017950, U01AG49505]; International Alzheimer's Association [NIRP-14-302587]; National Medical Research Council, Singapore [0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, CG/SERI/2010]; Biomedical Research Council, Singapore [09/1/35/19/616]; National Medical Research Council, Singapore (NMRC/CG/NUHS) [R-184-006-184-511]; Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/038/2013]; Wellcome Trust [084730, 082604/2/07/Z]; University College London (UCL)/University College London Hospitals (UCLH) NIHR Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) [114]; European Union Marie Curie Reintegration; UK NIHR [08-08-SCC]; Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) [CEL1300]; Big Lottery Fund; Wolfson Trust; Epilepsy Society; UK Department of Health's NIHR Biomedical Research Centres funding scheme; Science Foundation Ireland [08/RFP/GEN1538]; Netherlands Organization for Scientific Research NWO [MW904-61-193, 400-07-080, MagW 480-04-004, 51.02.060, 668.772]; European Research Council [ERC-230374]; High Potential Grant Utrecht University; NWO Brain and Cognition [433-09-220]; Neuroscience Campus Amsterdam; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, R01 HL105756]; National Institute on Aging (NIA) [R01AG023629, R01AG15928, R01AG20098, R01AG027002, R01AG05133, R01AG027058]; National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Brainwave-the Irish Epilepsy Association; Epilepsy Research UK [F1206]; European Commission [018947 (LSHG-CT-2006-01947), 223004]; European Community's Seventh Framework Programme (FP7) by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; Netherlands Organization for Scientific Research; Russian Foundation for Basic Research [NWO-RFBR 047.017.043]; Netherlands Brain Foundation [F2013(1)-28, 15F07[2]27]; National Heart, Lung and Blood Institute's Framingham Heart Study [HHSN2682015000011]; ZonMw [TOP 40-00812-98-11021, 916.13.054]; National Institute of Neurological Disorders and Stroke [R01NS062059]; National Heart, Lung, and Blood Institute [U01 HL72518, HL097698]; National Institutes of Health/National Center for Research Resources [M01-RR000052]; National Institute of Mental Health [MH0708143, MH078111, MH083824]; Research Facilities Improvement Program from the National Center for Research Resources, NIH [C06 RR13556, C06 RR017515]; Swedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Stockholm County Council; Karolinska Institutet; Knut and Alice Wallenberg Foundation; HUBIN project; Swedish Research Council; European Union [602450, LSHM-CT-2007-037286, 603016]; Innovative Medicine Initiative Project EU-AIMS [115300-2]; Medical Research Council Programme Grant "Developmental pathways into adolescent substance abuse" [93558]; NIHR-biomedical Research Center "Mental Health": Swedish Research Council FORMAS; German Federal Ministry for Education and Research BMBF (Forschungsnetz AERIAL) [eMED SysAlc 01ZX1311A, 1EV0711]; US National Institutes of Health (Axon); US National Institutes of Health (Testosterone); US National Institutes of Health (Mental Health during Adolescence); US National Institutes of Health [MH085772-01A1]; French MILDECA; Fondation pour la Recherche Medicale; Brain & Cognition Excellence Program of the Netherlands Organization for Scientific Research (NWO) [433-09-229]; Netherlands Organization for Scientific Research (NWO) [016.130.669]; Research into Ageing programme grant; Age UK-Disconnected Mind project; UK Medical Research Council (MRC); Scottish Funding Council through the SINAPSE Collaboration; Row Fogo Charitable Trust; UK Biotechnology and Biological Sciences Research Council (BBSRC) [MRC MR/K026992/1]; UK MRC; BBSRC [BB/F019394/1]; Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]; Netherlands Consortium for Healthy Ageing [050-060-810]; Department of Energy [DE-FG02-08ER64581]; German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) unde (NGFNplus) [01GS08144, 01GS08147, 01GS08148]; German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme [01ZX1314A, 01ZX1314C, 01ZX1314G]; Exzellenz-Stiftung of the Max Planck Society; Federal Ministry of Education and Research (BMBF) [FKZ 01GS0481]; Bergen Research Foundation; University of Bergen; Dr. Einar Martens Fund; K.G. Jebsen Foundation; Research Council of Norway; Netherlands Organization for Scientific Research [10-000-1002]; Center for Medical Systems Biology (CSMB, NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); VU University's Institutes for Health and Care Research (EMGO+); University Medical Center Groningen; Leiden University Medical Center; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; BiG Grid; Dutch e-Science Grid - NWO; NWO Large Investment Grant [1750102007010]; Radboud University Nijmegen Medical Center; University Medical Center Groningen and Accare; VU University Amsterdam; NIMH Intramural Research Program [ZIAMH002810, Z01MH002792, Z01MH002790]; Intramural Research Program of the NIH, National Institute on Aging; NHMRC/Australian Research Council Strategic Award [401162]; NHMRC [R01 HD050735, 1045325, 310667, 401184, 525453, 568940, 389875, 486682, 1009064, 1061457]; Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant; Australian Government - Dementia Collaborative Research Centre (DCRC), UNSW; Alzheimer's Australia Dementia Research Foundation; Japanese Ministry of Health, Labor and Welfare; Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI; Scientific Research on Innovative Areas (Comprehensive Brain Science Network); Brain Sciences Project of the Center for Novel Science Initiatives (CNSI); National Institutes of Natural Sciences (NINS); Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED; Instituto de Salud Carlos III [FIS00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639]; SENY Fundacio Research Grant [CI 2005-0308007]; Fundacion Marques de Valdecilla [API07/011]; Carlos III Health Institute [CA12/00312]; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Autism Speaks; Australian Research Council [FT0991634]; National Health and Medical Research Council (NHMRC), Australia [1103623, 619667]; Translational Genomics Research Institute; Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; 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; Dutch Technology Foundation STW, NWO; Ministry of Economic Affairs; European Research Council (ERC) under the European Union's Horizon research and innovation programme [678543]; Joint Programme - Neurodegenerative Disease Research working group on High-Dimensional Research in Alzheimer's Disease (ZonMW) [733051031]; Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences; Heart and Stroke Foundation of Quebec; Canadian Foundation for Innovation; Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto; German Federal Ministry of Education and Research; German Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania [01ZZ9603, 01ZZ0103, 01ZZ0403]; network 'Greifswald Approach to Individualized Medicine (GANI_MED)' - Federal Ministry of Education and Research [03IS2061A]; Federal Ministry of Education and Research [03ZIK012]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Australian National Health and Medical Research Council (NHMRC) Program [350833, 568969]; National Health and Medical Research Council of Australia (NHMRC) [403000, 491109, 606543]; Wicking Dementia Education and Research Centre; Heart Foundation Future Leader Fellowship [100089]; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Mutuelle Generale de l'Education Nationale (MGEN); Institut de la Longevite; Conseil Regionaux of Aquitaine; Conseil Regionaux of Bourgogne; Fondation de France; Ministry of Research INSEAM Programme "Cohortes et collections de donnees biologiques"; Fondation Leducq; Research Council of Norway [213837, 223273, 229129]; South-East Norway Health Authority [2013-123]; KG Jebsen Foundation; Netherlands Organization for Health Research and Development ZonMW [917.46.370, 908-02-123]; French National Foundation on Alzheimer's disease and related disorders; LABEX (laboratory of excellence program investment for the future) DISTALZ grant; Inserm; Institut Pasteur de Lille; University de Lille 2; Lille University Hospital; Medical Research Council [503480]; Alzheimer's Research UK [503176]; German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01G10102, 01G10711, 01G10420]; NIH/NIA grant [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]; NIA [AG081220]; AGES [N01-AG-12100]; Icelandic Heart Association; Erasmus University; Alzheimer's Association [ADGC-10-196728]; [NWO/SPI 56-464-14192]; [MH59490] FX CHARGE: Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung and Blood Institute grant HL105756 and for the neuroCHARGE phenotype working group through the National Institute on Aging grant AG033193.; ENIGMA: ENIGMA was supported in part by a Consortium grant (U54 EB020403 to PMT) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB and NCI.; Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik): This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.; Alzheimer's Disease Neuroimaging Initiative (ADNI): Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California.; ANM: AddNeuroMed was funded through the EU FP6 programme. HS: Academy of Finland, Research Council for Health, 258081, UEFBrain, University of Eastern Finland, VTR funding Kuopio University Hospital.; Atherosclerosis Risk In Communities Study (ARIC): The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F.; Austrian Stroke Prevention Study Family (ASPS-Fam): The ASPS-Fam is funded by the Austrian Science Fund (FWF) project 1904, the Medical University of Graz and the Steiermarkische Krankenanstalten Gesellschaft.; BETULA: This sample collection was supported by a Wallenberg Scholar grant from the Knut and Alice Wallenberg (KAW) foundation and a grant from Torsten and Ragnar Soderbergs Foundation to Lars Nyberg. S.l.H. was supported by a grant from HelseVest RHF (grant 911554).; Bipolar Family Study (BFS): The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh, a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration, for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A.M.M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship. The research leading to these results also receives funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements #602450 (IMAGEMEND) and ongoing support from the Wellcome Trust (Ref 104036/Z/14/Z).; Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (http://www.cognomics.nl), a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience Departments of the Radboud University Medical Center and the Max Planck Institute for Psycholinguistics in Nijmegen. The Board of the Cognomics Initiative consists of B. Franke, S. Fisher, G. Fernandez, P. Hagoort, H. Brunner, J. Buitelaar, H. van Bokhoven and D. Norris. The Cognomics Initiative has received supported from the participating departments and centers and from external grants, that is, the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organization for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant 'Language in Interaction', the European Community's Seventh Framework Programme (FP7/2007-.2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS), and no 602805 (Aggressotype), as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. We wish to thank all persons who kindly participated in the BIG research.; Brain Genomics Superstruct Project (GSP): Data were provided in part by the Brain Genomics Superstruct Project of Harvard University and the Massachusetts General Hospital, with support from the Center for Brain Science Neuroinformatics Research Group, the Athinoula A. Martinos Center for Biomedical Imaging, and the Center for Human Genetic Research. 20 individual investigators at Harvard and MGH generously contributed data to GSP. This work is supported by NIMH grants K99 MH101367 (P.H.L.), R01-MH079799 (J.W.S.), K24MH094614 (J.W.S.) and K01MH099232 (A.J.H.).; Brainscale and NTR-Adults: We would like to thank all twin participants from the Netherlands Twin Register. The NTR-adult and Brainscale studies were supported by the Netherlands Organization for Scientific Research NWO [MW904-61-193 (E.d.G. and D.B.), MaGW-nr: 400-07-080 (D. V't E.), MagW 480-04-004 (D.B.), (51.02.060 (H.H.), 668.772 (D.B. and H.H.); NWO/SPI 56-464-14192 (D.B.), the European Research Council (ERC-230374) (D.B.), High Potential Grant Utrecht University (H.H.), NWO Brain and Cognition 433-09-220 (H.H.) and the Neuroscience Campus Amsterdam.; Cardiovascular Health Study (CHS): This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, R01AG027002, R01AG05133, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; CHAP: This research was funded by grants from the National Institute of Health (AG011101 and AG030146) and the International Alzheimer's Association (NIRP-14-302587). DNA samples were collected during clinical evaluations and population interviews, and analyzed at the Broad Institute.; Epidemiology of Dementia in Singapore (EDIS): The Singapore Malay Eye Study (SiMES) and the Singapore Chinese Eye. Study (SCES) are funded by National Medical Research Council (grants 0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008 and CG/SERI/2010) and Biomedical Research Council (grants 09/1/35/19/616), Singapore. The Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services for genotyping. The Epidemiology of Dementia in Singapore study is supported by the National Medical Research Council, Singapore (NMRC/CG/NUHS/2010, grant no. R-184-006-184-511). M.K.I. received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013).; EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S.M.S.), University College London (UCL)/University College London Hospitals (UCLH) NIHR Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S.M.S.), the European Union Marie Curie Reintegration (to M. Matarin and S.M.S.), the UK NIHR (08-08-SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S.M.S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave-the Irish Epilepsy Association. M. Matarin is funded by Epilepsy Research UK (grant F1206).; Erasmus Rucphen Family study (ERF) The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. N. Amin is supported by the Netherlands Brain Foundation (project number F2013(1)-28). The ERF study genome-wide array data and phenotype data (age and gender) is archived in European Genome-Phenome Database (EGA). The study is archived in the DAC named Erasmus Rucphen Family Study with the accession code: EGAS00001001134. Researchers who wish to use other phenotypic data of the Erasmus Rucphen Family Study must seek approval from the management team of the Erasmus Rucphen Family study. They are advised to contact Cornelia van Duijn (c.vanduijn@erasmusmc.nl).; Framingham Heart Study (FHS): This work was supported by the dedication of the Framingham Study participants, the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. HHSN2682015000011), and by grants from the National Institute of Health (AG008122, AG054076, AG049607, AG033193, AG010129, NS017950, and U01AG49505).; Generation R: The Generation R Study is conducted by the Erasmus Medical Centre in close collaboration with the Municipal Health Service Rotterdam area, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR), Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam. Additional support for neuroimaging came from ZonMw TOP 40-00812-98-11021.; GeneSTAR: GeneSTAR was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS062059), the National Heart, Lung, and Blood Institute (U01 HL72518, HL097698) and the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. We would like to thank the participants and families of GeneSTAR and our dedicated staff for all their sacrifices.; GOBS: We acknowledge the ultimate source of our data, the Mexican American community of San Antonio and surrounding areas. Financial support for this study was provided by grants from the National Institute of Mental Health MH0708143 (D.C. Glahn), MH078111 (J. Blangero) and MH083824 (D.C. Glahn and J. Blangero). Theoretical development of SOLAR is supported by MH59490 (J. Blangero). This investigation was conducted, in part, in facilities constructed with support from Research Facilities Improvement Program grant numbers C06 RR13556 and C06 RR017515 from the National Center for Research Resources, NIH. Some of this work was performed at Texas Biomedical Research Institute, where J. Blangero began this investigator-initiated competitively publicly funded work.; HUBIN: This study was financed by the Swedish Research Council (K2007-62X-15077-04-1, K2008-62P-20597-01-3. K2010-62X-15078-07-2, K2012-61X-15078-09-3), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Knut and Alice Wallenberg Foundation, and the HUBIN project. Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala. The platform is part of Science for Life Laboratory at Uppsala University and supported as a national infrastructure by the Swedish Research Council.; IMAGEN: IMAGEN was supported by the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the FP7 projects IMAGEMEND (602450) and MATRICS (603016), and the Innovative Medicine Initiative Project EU-AIMS (115300-2), the Medical Research Council Programme Grant "Developmental pathways into adolescent substance abuse" (93558), as well as the NIHR-biomedical Research Center "Mental Health": Further support was provided by the Swedish Research Council FORMAS, and the German Federal Ministry for Education and Research BMBF (eMED SysAlc 01ZX1311A; Forschungsnetz AERIAL; 1EV0711) and the US National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; MH085772-01A1), and grants from the French MILDECA and from the Fondation pour la Recherche Medicale.; IMpACT: This study was funded by a grant from the Brain & Cognition Excellence Program of the Netherlands Organization for Scientific Research (NWO, grant 433-09-229) and in part by the Netherlands Brain Foundation (grant number, 15F07[2]27). B. Franke is supported by a Vici grant from the Netherlands Organization for Scientific Research (NWO; grant no 016.130.669). The research leading to these results also receives funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS), and no 602805 (Aggressotype) as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND). In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership.; LBC1936: We thank the LBC1936 participants and the members of the LBC1936 research team who collected and collated the phenotypic and genotypic data. This work was undertaken as part of the Cross Council and University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE; http://www.ccace.ed.ac.uk). This work was supported by a Research into Ageing programme grant (to I.J.D.) and the Age UK-funded Disconnected Mind project (http://www.disconnectedmind.ed.ac.uk; to I.J.D. and J.M.W.), with additional funding from the UK Medical Research Council (MRC; to I.J.D., J.M.W. and M.E.B.). J.M.W. is supported by the Scottish Funding Council through the SINAPSE Collaboration (http://www.sinapse.ac.uk). M.V.M. is supported by the Row Fogo Charitable Trust. CCACE (MRC MR/K026992/1) is funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the UK MRC. Genotyping was supported by a grant from the BBSRC (BB/F019394/1).The image acquisition and analysis was performed at the Brain Research Imaging Centre, University of Edinburgh (http://www.bric.ed.ac.uk).; Leiden Longevity Study (LLS): The Leiden Longevity Study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007) and the Netherlands Consortium for Healthy Ageing (grant number 050-060-810).; Mind Clinical Imaging Consortium (MCIC): Data used in the preparation of this work were obtained from the Mind Clinical Imaging Consortium database through the Mind Research Network (http://www.mrn.org). The MCIC project was supported by the Department of Energy under Award Number DE-FG02-08ER64581. MCIC is the result of efforts of co-investigators from University of Iowa, University of Minnesota, University of New Mexico, and Massachusetts General Hospital.; MooDS: The establishment of the MooDS sample was funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to M.M. Nothen and S. Cichon, grant 01GS08147 to J. Rietschel and A. Meyer-Lindenberg and grant 01GS08148 to A. Heinz), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A to M.M. Nothen, grant 01ZX1314C to H. Walter, grant 01ZX1314G to M. Rietschel).; MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) Case-Control study performed at the MPIP, and control subjects acquired at the Ludwig-Maximilians-University, Munich, Department of Psychiatry. We thank E. Meisenzahl and D. Rujescu for providing MRI and genetic data for inclusion into the MPIP Munich Morphometry sample. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter, R. Borschke and I. Eidner for image acquisition and data preparation. We thank D.P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the Recurrent Unipolar Depression Case-Control Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481.; NCNG: this sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr. Einar Martens Fund, the K.G. Jebsen Foundation, the Research Council of Norway, to S.L.H., V.M.S. and T.E.; NESDA: Funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO.; NeuroIMAGE: The NeuroIMAGE project was supported by NIH Grant R01MH62873 (to S.V. Faraone), NWO Large Investment Grant 1750102007010 (to J. Buitelaar), and by grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. The work contributing to this result also receives support from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS) and no 602805 (Aggressotype) as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND). In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership.; NIMH-IRP: Supported in part by the NIMH Intramural Research Program (ZIAMH002810; Z01MH002792; Z01MH002790).; North American Brain Expression Consortium (NABEC): This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.; Older Australian Twins Study (OATS): We would like to acknowledge and thank the OATS participants, their supporters and respective Research Teams. This work was supported by a number of sources. OATS is supported by the NHMRC/Australian Research Council Strategic Award 401162 and NHMRC Project Grant 1045325 to P. Sachdev and colleagues. OATS was facilitated through access to the Australian Twin Registry, a national research resource supported by the NHMRC Enabling Grant 310667, administered by the University of Melbourne. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by the NHMRC Grant 401184. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. Henry Brodaty is supported by the Australian Government funded Dementia Collaborative Research Centre (DCRC), UNSW. Nicola Armstrong was supported by the NHMRC Project Grant 525453 and Karen Mather is supported by an Alzheimer's Australia Dementia Research Foundation Postdoctoral Fellowship and the NHMRC Capacity Building Grant 568940.; Osaka: This study was supported, in part, by research grants from the Japanese Ministry of Health, Labor and Welfare; the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI and Scientific Research on Innovative Areas (Comprehensive Brain Science Network); and the Brain Sciences Project of the Center for Novel Science Initiatives (CNSI), the National Institutes of Natural Sciences (NINS), and the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED.; PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639, the SENY Fundacio Research Grant CI 2005-0308007, and the Fundacion Marques de Valdecilla API07/011. PAFIP wish to acknowledge WTCCC2 (Wellcome Trust Case Control Consortium 2) for DNA Genotyping, Valdecilla Biobank for providing the biological samples and associated data included in this study and Idival Neuroimaging Unit for its help in the technical execution of this work. D. Tordesillas-Gutierrez is funded by a contract from the Carlos III Health Institute (CA12/00312).; PROSPER: The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810).; QTIM: D.P.H., N.J., C.R.K.C. and P.M.T. are supported, in part, by NIH grants R01 NS080655, R01AG040060, R01 EB008432, R01 MH097268, U01 AG024904, R01 MH085667, R01 MH089722, P41 EB015922, and R01 MH094343. R.K.W. is supported by National Science Foundation (BCS-1229450). J.L.S. was supported by the NIMH (K99MH102357) and Autism Speaks. G.Z. is supported by a Future Fellowship (FT0991634) from the Australian Research Council. S.E.M. and G.W.M. are supported by a National Health and Medical Research Council (NHMRC), Australia, Fellowships (1103623, 619667). The QTIM study is supported by grants from NIH (R01 HD050735) and the NHMRC (389875, 486682, 1009064). We thank the twins and siblings for their participation, M. Grace and A. Eldridge for twin recruitment, A. Al Najjar and other radiographers for scanning, K. McAloney and D. Park for research support, and A. Henders and staff for DNA sample processing and preparation.; ROS and MAP: The clinical, genomic, and neuroimaging data for the Religious Orders Study and the Rush Memory and Aging Project was funded by NIH grants P30AG10161, RF1AG15819, R01AG17917, R01AG30146, R01AG40039, and the Translational Genomics Research Institute.; Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of 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 Organisation for Scientific Research (NWO) project nr. 050-060-810. 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. This research is supported by the Dutch Technology Foundation STW, which is part of the NWO, and which is partly funded by the Ministry of Economic Affairs. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 678543). Further support was obtained through the Joint Programme - Neurodegenerative Disease Research working group on High-Dimensional Research in Alzheimer's Disease (ZonMW grant number 733051031). MAI is supported by ZonMW grant number 916.13.054. H.H.H.A. is supported by the Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences.; Saguenay Youth Study (SYS): The Saguenay Youth Study project is funded by the Canadian Institutes of Health Research (T.P., Z.P.), Heart and Stroke Foundation of Quebec (Z.P.), and the Canadian Foundation for Innovation (Z.P.). T.P. is supported by the Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto.; SHIP and TREND: The SHIP data sets are part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg-West Pomerania (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member oft the Cache Campus Program of the InterSystems GmbH.; Sydney Memory and Ageing Study (Sydney MAS): We would like to thank the Sydney MAS participants, their supporters and respective research teams. Sydney MAS was supported by the Australian National Health and Medical Research Council (NHMRC) Program Grants 350833 and 568969 to P. Sachdev, H. Brodaty and G. Andrews. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by the NHMRC Grant 401184. H. Brodaty is supported by the Australian Government funded Dementia Collaborative Research Centre (DCRC), UNSW. N. Armstrong was supported by the NHMRC Project Grant 525453 and K. Mather is supported by an Alzheimer's Australia Dementia Research Foundation Postdoctoral Fellowship. Both S. Reppermund and K. Mather are supported by the NHMRC Capacity Building Grant 568940.; Tasmanian Study of Gait and Cognition (TASCOG): The Tasmanian Study of Gait and Cognition is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC; 403000, 491109, and 606543) and a grant from the Wicking Dementia Education and Research Centre, Hobart. V.S. is supported by a cofunded NHMRC Career Development Fellowship (1061457) and a Heart Foundation Future Leader Fellowship (ID 100089).; Three-City Dijon Study: The Three-City Study is conducted under a partnership agreement among the Institut National de la Sante et de la Recherche Medicale (INSEAM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The Three-City Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN), Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research INSEAM Programme "Cohortes et collections de donnees biologiques." Christophe Tzourio and Stephanie Debette are supported by a grant from the Fondation Leducq.; TOP: The study was supported by the Research Council of Norway (#213837, #223273, #229129), South-East Norway Health Authority (#2013-123) and KG Jebsen Foundation. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 602450 (IMAGEMEND).; UMCU: UMCU acknowledgment data: This work was supported by 917.46.370 (H.H.) and 908-02-123 (H.H.) from the Netherlands Organization for Health Research and Development ZonMW.; WHICAP: This study was supported by a grant from the NIH (5R01AG037212). CHARGE consortium: See ref. 40 for the general cognitive function GWAS, and ref. 29 for the white matter lesion GWAS.; IGAP: We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, University de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant no 503480), Alzheimer's Research UK (Grant no 503176), the Wellcome Trust (Grant no 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01G10102, 01G10711, 01G10420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728. NR 46 TC 0 Z9 0 U1 29 U2 29 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 DEC PY 2016 VL 19 IS 12 BP 1569 EP 1582 DI 10.1038/nn.4398 PG 14 WC Neurosciences SC Neurosciences & Neurology GA ED7BY UT WOS:000389011900016 PM 27694991 ER PT J AU Garfield, AS Shah, BP Burgess, CR Li, MM Li, C Steger, JS Madara, JC Campbell, JN Kroeger, D Scammell, TE Tannous, BA Myers, MG Andermann, ML Krashes, MJ Lowell, BB AF Garfield, Alastair S. Shah, Bhavik P. Burgess, Christian R. Li, Monica M. Li, Chia Steger, Jennifer S. Madara, Joseph C. Campbell, John N. Kroeger, Daniel Scammell, Thomas E. Tannous, Bakhos A. Myers, Martin G., Jr. Andermann, Mark L. Krashes, Michael J. Lowell, Bradford B. TI Dynamic GABAergic afferent modulation of AgRP neurons SO NATURE NEUROSCIENCE LA English DT Article ID BROWN ADIPOSE-TISSUE; DORSOMEDIAL HYPOTHALAMUS; FEEDING CIRCUITS; LEPTIN ACTION; NUCLEUS; HUNGER; PRESSURE; BEHAVIOR; OBESITY; POMC AB Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues before ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the preconsummatory modulation of ARC(AgRP) neurons. In a manner reciprocal to ARC(AgRP) neurons, ARC-projecting leptin receptor expressing GABAergic vDMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, leptin receptor-expressing GABAergic vDMH neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARC(AgRP) neuron activity and feeding behavior. C1 [Garfield, Alastair S.; Shah, Bhavik P.; Burgess, Christian R.; Li, Monica M.; Steger, Jennifer S.; Madara, Joseph C.; Campbell, John N.; Andermann, Mark L.; Lowell, Bradford B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Garfield, Alastair S.] Univ Edinburgh, Ctr Integrat Physiol, Hugh Robson Bldg, Edinburgh, Midlothian, Scotland. [Li, Chia; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Li, Chia; Krashes, Michael J.] NIDA, NIH, Baltimore, MD USA. [Kroeger, Daniel; Scammell, Thomas E.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. [Tannous, Bakhos A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Myers, Martin G., Jr.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Myers, Martin G., Jr.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Andermann, Mark L.; Lowell, Bradford B.] Harvard Med Sch, Program Neurosci, Boston, MA USA. [Garfield, Alastair S.; Shah, Bhavik P.] Pfizer, Cardiovasc & Metab Dis, Cambridge, MA 02139 USA. RP Garfield, AS (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA.; Garfield, AS (reprint author), Univ Edinburgh, Ctr Integrat Physiol, Hugh Robson Bldg, Edinburgh, Midlothian, Scotland.; Garfield, AS (reprint author), Pfizer, Cardiovasc & Metab Dis, Cambridge, MA 02139 USA. EM alastair.garfield@pfizer.com; manderma@bidmc.harvard.edu; michael.krashes@nih.gov; blowell@bidmc.harvard.edu FU University of Edinburgh Chancellor's Fellowship; National Institutes of Health [R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, P30 DK046200, R01 DK056731, P30 DK057521, F32 DK089710, DP2 DK105570-01, R01 DK109930]; McKnight Foundation; Klarman Family Foundation; Richard and Susan Smith Family Foundation; Pew Scholars Program in Biomedical Sciences; ADA Mentor-Based Fellowship; Davis Family Foundation; AHA postdoctoral fellowship [14POST20100011]; Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK075087, DK075088]; NIH/NINDS [P30NS045776] FX We thank B. Sabatini and K.W. Huang for assistance with in vivo fiber photometry. We thank Drs. V. Jayaraman, R.A. Kerr, D.S. Kim, L.L. Looger and K. Svoboda and the GENIE Project at Janelia Farm Research Campus, Howard Hughes Medical Institute, for distribution of GCaMP6. This work was supported by the University of Edinburgh Chancellor's Fellowship (A.S.G.); National Institutes of Health grants R01 DK096010 (B.B.L.), R01 DK089044 (B.B.L.), R01 DK071051 (B.B.L.), R01 DK075632 (B.B.L.), R37 DK053477 (B.B.L.), BNORC Transgenic Core P30 DK046200 (B.B.L.), R01 DK056731 (M.J.G.), BADERC Transgenic Core P30 DK057521 (B.B.L.), F32 DK089710 (M.J.K.), DP2 DK105570-01 (M.L.A.) and R01 DK109930 (M.L.A.); the McKnight Foundation (M.L.A.); the Klarman Family Foundation (M.L.A.); the Richard and Susan Smith Family Foundation (M.L.A.); the Pew Scholars Program in Biomedical Sciences (M.L.A.); ADA Mentor-Based Fellowship (B.P.S. and B.B.L.); Davis Family Foundation postdoctoral fellowship award (C.R.B.); and AHA postdoctoral fellowship 14POST20100011 (J.N.C.). This research was supported, in part, by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; DK075087, DK075088). The GH Viral vector core facility was funded by NIH/NINDS grant P30NS045776 (B.A.T.) for the preparation of the rabies virus. NR 29 TC 2 Z9 2 U1 5 U2 5 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 DEC PY 2016 VL 19 IS 12 BP 1628 EP 1635 DI 10.1038/nn.4392 PG 8 WC Neurosciences SC Neurosciences & Neurology GA ED7BY UT WOS:000389011900022 PM 27643429 ER PT J AU Adiseshaiah, PP Crist, RM Hook, SS McNeil, SE AF Adiseshaiah, Pavan P. Crist, Rachael M. Hook, Sara S. McNeil, Scott E. TI Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID ADVANCED SOLID TUMORS; PHASE-III TRIAL; HEDGEHOG SIGNALING PATHWAY; GEMCITABINE PLUS PLACEBO; DUCTAL ADENOCARCINOMA; NAB-PACLITAXEL; COLORECTAL-CANCER; CLINICAL-TRIALS; DRUG-DELIVERY; BLOOD-VESSELS AB Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancerrelated deaths. PDAC remains one of the most difficult-to-treat cancers, owing to its unique pathobiological features: a nearly impenetrable desmoplastic stroma, and hypovascular and hypoperfused tumour vessels render most treatment options largely ineffective. Progress in understanding the pathobiology and signalling pathways involved in disease progression is helping researchers to develop novel ways to fight PDAC, including improved nanotechnology-based drug-delivery platforms that have the potential to overcome the biological barriers of the disease that underlie persistent drug resistance. So-called 'nanomedicine' strategies have the potential to enable targeting of the Hedgehog-signalling pathway, the autophagy pathway, and specific RAS-mutant phenotypes, among other pathological processes of the disease. These novel therapies, alone or in combination with agents designed to disrupt the pathobiological barriers of the disease, could result in superior treatments, with increased efficacy and reduced off-target toxicities compared with the current standard-of-care regimens. By overcoming drug-delivery challenges, advances can be made in the treatment of PDAC, a disease for which limited improvement in overall survival has been achieved over the past several decades. We discuss the approaches to nanomedicine that have been pursued to date and those that are the focus of ongoing research, and outline their potential, as well as the key challenges that must be overcome. C1 [Adiseshaiah, Pavan P.; Crist, Rachael M.; McNeil, Scott E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick, MD 21702 USA. [Hook, Sara S.] NCI, Off Director, NIH, Bethesda, MD 20892 USA. RP Adiseshaiah, PP (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick, MD 21702 USA. EM pavan.adiseshaiah@fnlcr.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012; Crist, Rachael/K-7603-2012 FU Frederick National Laboratory for Cancer Research, US NIH [HHSN261200800001E] FX The authors thank Dr Stephan T. Stern and Dr Jennifer H. Grossman for their critical review of the manuscript, and Allen Kane of Leidos Biomedical Research for assistance with graphic illustrations. The work of P.P.A., R.M.C., and S.E.M. has been funded, in whole or in part, by Federal funds from the Frederick National Laboratory for Cancer Research, US NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 175 TC 1 Z9 1 U1 34 U2 34 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 DEC PY 2016 VL 13 IS 12 BP 750 EP 765 DI 10.1038/nrclinonc.2016.119 PG 16 WC Oncology SC Oncology GA ED5YG UT WOS:000388929200008 PM 27531700 ER PT J AU Hesse, BW Greenberg, AJ Rutten, LJF AF Hesse, Bradford W. Greenberg, Alexandra J. Rutten, Lila J. Finney TI The role of Internet resources in clinical oncology: promises and challenges SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID NATIONAL TRENDS SURVEY; HEALTH INFORMATION-SEEKING; CONNECTED HEALTH; CANCER; CARE; COMMUNICATION; SCIENCE; ACCESS; TELEDERMATOLOGY; ATTITUDES AB The Internet is a valuable tool that continues to revolutionize many aspects of our lives; however, the ability to disseminate diverse data across populations and nations presents both opportunities and challenges. Online resources are increasingly used in health care, providing wider access to information for patients, researchers, and clinicians. At the turn of the millennium, the National Cancer Institute (NCI) predicted that Internet-based technologies would create a revolution in communication for oncology professionals and patients with cancer. Herein, findings from the NCI's Health Information National Trends Survey are reviewed to give insight into how Internet trends related to oncology patients are evolving. Future trends are discussed, including examples of 'connected health' in oncology; the spread of mobile and ubiquitous access points to Internet-hosted information; the diffusion of devices, sensors, and apps; the spread of personal data sharing; and an evolution in how networks can support person-centred and family-centred care. C1 [Hesse, Bradford W.; Greenberg, Alexandra J.] NCI, HCIRB, BRP, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Rutten, Lila J. Finney] Mayo Clin, Robert D & Patricia E Kern Ctr Sci Hlth Care Deli, Rochester, MN 55905 USA. RP Hesse, BW (reprint author), NCI, HCIRB, BRP, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov FU NIH National Cancer Institute; Cancer Prevention Fellowship at the National Cancer Institute FX The work of B.W.H., A.J.G., and L.J.F.R. is supported by the NIH National Cancer Institute. A.J.G. was supported by the Cancer Prevention Fellowship at the National Cancer Institute. NR 103 TC 1 Z9 1 U1 9 U2 9 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 DEC PY 2016 VL 13 IS 12 BP 767 EP 776 DI 10.1038/nrclinonc.2016.78 PG 10 WC Oncology SC Oncology GA ED5YG UT WOS:000388929200009 PM 27273045 ER PT J AU Lenardo, MJ AF Lenardo, Michael J. TI Focus on Research Clinical Genomics - Molecular Pathogenesis Revealed SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lenardo, Michael J.] NIAID, Clin Genom Program, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Lenardo, MJ (reprint author), NIAID, Clin Genom Program, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 2 U2 2 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 DEC 1 PY 2016 VL 375 IS 22 BP 2117 EP 2119 DI 10.1056/NEJMp1611419 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA ED7GN UT WOS:000389030400003 PM 27959769 ER PT J AU Baeten, JM Palanee-Phillips, T Brown, ER Schwartz, K Soto-Torres, LE Govender, V Mgodi, NM Kiweewa, FM Nair, G Mhlanga, F Siva, S Bekker, LG Jeenarain, N Gaffoor, Z Martinson, F Makanani, B Pather, A Naidoo, L Husnik, M Richardson, BA Parikh, UM Mellors, JW Marzinke, MA Hendrix, CW van der Straten, A Ramjee, G Chirenje, ZM Nakabiito, C Taha, TE Jones, J Mayo, A Scheckter, R Berthiaume, J Livant, E Jacobson, C Ndase, P White, R Patterson, K Germuga, D Galaska, B Bunge, K Singh, D Szydlo, DW Montgomery, ET Mensch, BS Torjesen, K Grossman, CI Chakhtoura, N Nel, A Rosenberg, Z McGowan, I Hillier, S AF Baeten, J. M. Palanee-Phillips, T. Brown, E. R. Schwartz, K. Soto-Torres, L. E. Govender, V. Mgodi, N. M. Kiweewa, F. Matovu Nair, G. Mhlanga, F. Siva, S. Bekker, L. -G. Jeenarain, N. Gaffoor, Z. Martinson, F. Makanani, B. Pather, A. Naidoo, L. Husnik, M. Richardson, B. A. Parikh, U. M. Mellors, J. W. Marzinke, M. A. Hendrix, C. W. van der Straten, A. Ramjee, G. Chirenje, Z. M. Nakabiito, C. Taha, T. E. Jones, J. Mayo, A. Scheckter, R. Berthiaume, J. Livant, E. Jacobson, C. Ndase, P. White, R. Patterson, K. Germuga, D. Galaska, B. Bunge, K. Singh, D. Szydlo, D. W. Montgomery, E. T. Mensch, B. S. Torjesen, K. Grossman, C. I. Chakhtoura, N. Nel, A. Rosenberg, Z. McGowan, I. Hillier, S. CA MTN-020-ASPIRE Study Team TI Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PREEXPOSURE PROPHYLAXIS; ANTIRETROVIRAL PROPHYLAXIS; CLINICAL-TRIALS; AFRICAN WOMEN; DOUBLE-BLIND; INFECTION; TENOFOVIR; THAILAND; SAFETY; MEN AB BACKGROUND Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 personyears, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [ CI], 1 to 46; P = 0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P = 0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P < 0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P = 0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096.) C1 [Baeten, J. M.; Richardson, B. A.; Ndase, P.] Univ Washington, Dept Global Hlth, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Baeten, J. M.] Univ Washington, Dept Med, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Baeten, J. M.; Husnik, M.] Univ Washington, Dept Epidemiol, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Brown, E. R.; Richardson, B. A.] Univ Washington, Dept Biostat, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Brown, E. R.; Husnik, M.; Richardson, B. A.; Berthiaume, J.; Patterson, K.; Szydlo, D. W.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Palanee-Phillips, T.] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Govender, V.; Siva, S.; Jeenarain, N.; Gaffoor, Z.; Pather, A.; Naidoo, L.; Ramjee, G.] South African Med Res Council, HIV Prevent Res Unit, Durban, South Africa. [Nair, G.] Ctr AIDS Programme Res South Africa, Durban, South Africa. [Bekker, L. -G.] Univ Cape Town, Desmond Tutu HIV Ctr, Cape Town, South Africa. [Schwartz, K.; Mayo, A.; Scheckter, R.; White, R.; Torjesen, K.] FHI 360, Durham, NC USA. [Soto-Torres, L. E.; Germuga, D.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Grossman, C. I.] NIMH, NIH, Bethesda, MD 20892 USA. [Chakhtoura, N.] Eunice Kennedy Shiver Natl Inst Child Hlth & Huma, NIH, Bethesda, MD USA. [Marzinke, M. A.; Hendrix, C. W.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Taha, T. E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Nel, A.; Rosenberg, Z.] Int Partnership Microbicides, Silver Spring, MD USA. [Mgodi, N. M.; Mhlanga, F.; Chirenje, Z. M.] Univ Zimbabwe Univ Calif San Francisco Collaborat, Harare, Zimbabwe. [Kiweewa, F. Matovu; Nakabiito, C.] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Martinson, F.] Univ North Carolina Project, Lilongwe, Malawi. [Makanani, B.; Taha, T. E.] Queen Elizabeth Cent Hosp, Malawi Coll Med Johns Hopkins Univ Res Project, Blantyre, Malawi. [Parikh, U. M.; Mellors, J. W.; McGowan, I.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Bunge, K.; Hillier, S.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Jones, J.; Livant, E.; Jacobson, C.; Galaska, B.; Singh, D.] Magee Womens Res Inst, Pittsburgh, PA USA. [van der Straten, A.; Montgomery, E. T.] RTI Int, Womens Global Hlth Imperat, San Francisco, CA USA. [van der Straten, A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Mensch, B. S.] Populat Council, 1230 York Ave, New York, NY 10021 USA. RP Baeten, JM (reprint author), Univ Washington, Dept Global Hlth, Int Clin Res Ctr, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. EM jbaeten@uw.edu FU National Institute of Allergy and Infectious Diseases [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health FX Supported by grants (UM1AI068633, UM1AI068615, and UM1AI106707) from the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health. NR 33 TC 17 Z9 17 U1 2 U2 2 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 DEC 1 PY 2016 VL 375 IS 22 BP 2121 EP 2132 DI 10.1056/NEJMoa1506110 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA ED7GN UT WOS:000389030400004 PM 26900902 ER PT J AU Hourigan, CS Haferlach, T Hokland, P AF Hourigan, Christopher S. Haferlach, Torsten Hokland, Peter TI Cord-Blood Transplantation in Patients with Minimal Residual Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HEMATOPOIETIC-CELL TRANSPLANTATION; COMPLETE REMISSION C1 [Hourigan, Christopher S.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Haferlach, Torsten] Munich Leukemia Lab, Munich, Germany. [Hokland, Peter] Aarhus Univ Hosp, Aarhus, Denmark. RP Hourigan, CS (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM hourigan@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 1 PY 2016 VL 375 IS 22 BP 2204 EP 2204 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA ED7GN UT WOS:000389030400024 PM 27959750 ER PT J AU Walkley, SU Davidson, CD Jacoby, J Marella, PD Ottinger, EA Austin, CP Porter, FD Vite, CH Ory, DS AF Walkley, Steven U. Davidson, Cristin D. Jacoby, Jonathan Marella, Philip D. Ottinger, Elizabeth A. Austin, Christopher P. Porter, Forbes D. Vite, Charles H. Ory, Daniel S. TI Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Cyclodextrin; Collaborative science; Drug pipeline; Lysosomal disease; Miglustat; Niemann-Pick C; Patient advocacy; Rare disease; Therapy development; Translational medicine ID CHOLESTEROL HOMEOSTASIS; NEURONAL CHOLESTEROL; MURINE MODEL; MOUSE; 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN; PROGRESSION; STORAGE; NPC1; ESTERIFICATION; GANGLIOSIDES AB Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the "SOAR" mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders. C1 [Walkley, Steven U.; Davidson, Cristin D.] Albert Einstein Coll Med, Rose F Kennedy Intellectual & Dev Disabil Res Ctr, Dominick P Purpura Dept Neurosci, 1410 Pelham Pkwy South, Bronx, NY 10461 USA. [Jacoby, Jonathan] Hide & Seek Fdn Lysosomal Dis Res, 6475 East Pacific Coast Highway,Suite 466, Long Beach, CA 90803 USA. [Marella, Philip D.] Danas Angels Res Trust, 15 East Putnam Ave,117, Greenwich, CT 06830 USA. [Ottinger, Elizabeth A.] NIH, Div PreClin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20817 USA. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Translat Med, NIH, DHHS, Rm 5-2571,10CRC,10 Ctr Dr, Bethesda, MD 20892 USA. [Vite, Charles H.] Univ Penn, Sch Vet Med, Dept Clin Sci, 3800 Spruce St, Philadelphia, PA 19104 USA. [Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, Box 8086,660 S Euclid Ave, St Louis, MO 63110 USA. RP Walkley, SU (reprint author), Albert Einstein Coll Med, Rose F Kennedy Intellectual & Dev Disabil Res Ctr, Dominick P Purpura Dept Neurosci, 1410 Pelham Pkwy South, Bronx, NY 10461 USA. EM Steve.Walkley@einstein.yu.edu RI Davidson, Cristin/F-4889-2017 OI Davidson, Cristin/0000-0002-5508-8113 FU Dana's Angel's Research Trust; Hide & Seek Foundation for Lysosomal Disease Research; Hadley Hope; Race for Adam; Fight NPC; Andrews Firefly Fund FX We are grateful to the families who sponsor SOAR-NPC and collaborate with the scientific research team in this endeavor: Dana's Angel's Research Trust (Marella family), the Hide & Seek Foundation for Lysosomal Disease Research, Hadley Hope (Hadley family), Race for Adam (Recke family), Fight NPC (Chan family), and Andrews Firefly Fund (Andrews family). The important roles that these funding groups play in the operation of the SOAR-NPC Collaborative are outlined in the article. Two individuals (JJ, PDM) associated with these groups also participated in writing this article. NR 36 TC 0 Z9 0 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD DEC 1 PY 2016 VL 11 AR 161 DI 10.1186/s13023-016-0540-x PG 11 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA ED7AW UT WOS:000389009100001 PM 27903269 ER PT J AU Moss, JL Reiter, PL Truong, YK Rimer, BK Brewer, NT AF Moss, Jennifer L. Reiter, Paul L. Truong, Young K. Rimer, Barbara K. Brewer, Noel T. TI School Entry Requirements and Coverage of Nontargeted Adolescent Vaccines SO PEDIATRICS LA English DT Article ID HUMAN-PAPILLOMAVIRUS; HPV VACCINATION; UNITED-STATES; IMMUNIZATION REQUIREMENTS; NONMEDICAL EXEMPTIONS; IMPACT; RATES; RECOMMENDATIONS; SCHOOLCHILDREN; MANDATES AB BACKGROUND: Low human papillomavirus (HPV) vaccination coverage is an urgent public health problem requiring action. To identify policy remedies to suboptimal HPV vaccination, we assessed the relationship between states' school entry requirements and adolescent vaccination. METHODS: We gathered data on states' school entry requirements for adolescent vaccination (tetanus, diphtheria, and pertussis [Tdap] booster; meningococcal; and HPV) from 2007 to 2012 from Immunization Action Coalition. The National Immunization Survey-Teen provided medical record-verified vaccination data for 99 921 adolescents. We calculated coverage (among 13- to 17-year-olds) for individual vaccinations and concomitant vaccination. HPV vaccination outcomes were among female adolescents. Analyses used weighted longitudinal multivariable models. RESULTS: States with requirements for Tdap booster and meningococcal vaccination had 22 and 24 percentage point increases in coverage for these vaccines, respectively, compared with other states (both P < .05). States with HPV vaccination requirements had < 1 percentage point increase in coverage for this vaccine (P < .05). Tdap booster and meningococcal vaccination requirements, respectively, were associated with 8 and 4 percentage point spillover increases for HPV vaccination coverage (both P < .05) and with increases for concomitant vaccination (all P < .05). CONCLUSIONS: Ensuring all states have meningococcal vaccination requirements could improve the nation's HPV vaccination coverage, given that many states already require Tdap booster but not meningococcal vaccination for school entry. Vaccination programs and clinicians should capitalize on changes in adolescent vaccination, including concomitant vaccination, that may arise after states adopt vaccination requirements. Additional studies are needed on the effects of HPV vaccination requirements and opt-out provisions. C1 [Moss, Jennifer L.; Rimer, Barbara K.; Brewer, Noel T.] Univ N Carolina, Dept Hlth Behav, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Truong, Young K.] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Rimer, Barbara K.; Brewer, Noel T.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Reiter, Paul L.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. RP Moss, JL (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E514,MSC 9765, Bethesda, MD 20892 USA. EM jennifer.moss@nih.gov FU National Institutes of Health [F31 CA189411]; National Institutes of Health (NIH); [NSF-DMS-1106962] FX Supported by National Institutes of Health grant F31 CA189411 (principal investigator: Jennifer L. Moss). Dr Truong was supported by NSF-DMS-1106962. Funded by the National Institutes of Health (NIH). NR 38 TC 1 Z9 1 U1 3 U2 3 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 DEC PY 2016 VL 138 IS 6 AR e20161414 DI 10.1542/peds.2016-1414 PG 10 WC Pediatrics SC Pediatrics GA ED5WX UT WOS:000388924800027 ER PT J AU McCafferty, CL Sergeev, YV AF McCafferty, Caitlyn L. Sergeev, Yuri V. TI In silico Mapping of Protein Unfolding Mutations for Inherited Disease SO SCIENTIFIC REPORTS LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; AMINO-ACID VARIANTS; RHODOPSIN GENE; OCULAR FINDINGS; PERSONALIZED MEDICINE; DISULFIDE-ISOMERASE; MISSENSE MUTATIONS; POLYPEPTIDE-CHAIN; STABILITY CHANGES; MECHANISMS AB The effect of disease-causing missense mutations on protein folding is difficult to evaluate. To understand this relationship, we developed the unfolding mutation screen (UMS) for in silico evaluation of the severity of genetic perturbations at the atomic level of protein structure. The program takes into account the protein-unfolding curve and generates propensities using calculated free energy changes for every possible missense mutation at once. These results are presented in a series of unfolding heat maps and a colored protein 3D structure to show the residues critical to the protein folding and are available for quick reference. UMS was tested with 16 crystal structures to evaluate the unfolding for 1391 mutations from the ProTherm database. Our results showed that the computational accuracy of the unfolding calculations was similar to the accuracy of previously published free energy changes but provided a better scale. Our residue identity control helps to improve protein homology models. The unfolding predictions for proteins involved in age-related macular degeneration, retinitis pigmentosa, and Leber's congenital amaurosis matched well with data from previous studies. These results suggest that UMS could be a useful tool in the analysis of genotype-to-phenotype associations and next-generation sequencing data for inherited diseases. C1 [McCafferty, Caitlyn L.; Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Sergeev, YV (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM sergeevy@nei.nih.gov NR 64 TC 1 Z9 1 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 1 PY 2016 VL 6 AR 37298 DI 10.1038/srep37298 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6UR UT WOS:000388992600001 PM 27905547 ER PT J AU Schuemie, MJ Trifiro, G Coloma, PM Ryan, PB Madigan, D AF Schuemie, Martijn J. Trifiro, Gianluca Coloma, Preciosa M. Ryan, Patrick B. Madigan, David TI Detecting adverse drug reactions following long-term exposure in longitudinal observational data: The exposure-adjusted self-controlled case series SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE adverse drug reactions; methods analysis; self-controlled case series; claims databases; receiver operator characteristics curve ID LEVODOPA-INDUCED DYSKINESIA; ORAL-CONTRACEPTIVES; PARKINSONS-DISEASE; RISK; CANCER; COHORT; EPIDEMIOLOGY; MODEL; INHIBITORS; DEPENDENCE AB Most approaches used in postmarketing drug safety monitoring, including spontaneous reporting and statistical risk identification using electronic health care records, are primarily suited to pick up only acute adverse drug effects. With the availability of increasingly larger electronic health record and administrative claims databases comes the opportunity to monitor for potential adverse effects that occur only after prolonged exposure to a drug, but analysis methods are lacking. We propose an adaptation of the self-controlled case series design that uses the notion of accumulated exposure to capture long-term effects of drugs and evaluate extensions to correct for age and recurrent events. Several variations of the approach are tested on simulated data and two large insurance claims databases. To evaluate performance a set of positive and negative control drug-event pairs was created by medical experts based on drug product labels and review of the literature. Performance on the real data was measured using the area under the receiver operator characteristics curve. The best performing method achieved an area under the receiver operator characteristics curve of 0.86 in the largest database using a spline model, adjustment for age, and ignoring recurrent events, but it appears this performance can only be achieved with very large data sets. C1 [Schuemie, Martijn J.; Trifiro, Gianluca; Coloma, Preciosa M.] Erasmus Univ, Med Ctr Rotterdam, Dept Med Informat, POB 2040, NL-3000 CA Rotterdam, Netherlands. [Schuemie, Martijn J.; Ryan, Patrick B.; Madigan, David] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. [Trifiro, Gianluca] Univ Messina, Dept Clin & Expt Med, Messina, Italy. [Ryan, Patrick B.] Janssen Res & Dev LLC, Titusville, FL USA. [Madigan, David] Columbia Univ, Dept Stat, New York, NY USA. RP Schuemie, MJ (reprint author), Erasmus Univ, Med Ctr Rotterdam, Dept Med Informat, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM m.schuemie@erasmusmc.nl FU Observational Medical Outcomes Partnership, Foundation for 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 has been funded by a grant from the Observational Medical Outcomes Partnership, Foundation for the National Institutes of Health. NR 39 TC 2 Z9 2 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD DEC PY 2016 VL 25 IS 6 BP 2577 EP 2592 DI 10.1177/0962280214527531 PG 16 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA ED1SR UT WOS:000388625700012 PM 24685766 ER PT J AU van den Heuvel, MI Thomason, ME AF van den Heuvel, Marion I. Thomason, Moriah E. TI Functional Connectivity of the Human Brain in Utero SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID PRENATAL ALCOHOL EXPOSURE; RESTING-STATE NETWORKS; MAGNETIC-RESONANCE; HUMAN FETAL; WHITE-MATTER; HEMODYNAMIC-RESPONSES; SPATIOTEMPORAL ATLAS; PRETERM INFANTS; DEFAULT-MODE; FOLLOW-UP AB The brain is subject to dramatic developmental processes during the prenatal period. Nevertheless, information about the development of functional brain networks during gestation is scarce. Until recently it has not been possible to probe function in the living human fetal brain. Advances in functional MRI have changed the paradigm, making it possible to measure spontaneous activity in the fetal brain and to cross-correlate functional signals to attain information about neural connectional architecture across human gestation. We summarize the earliest MRI studies of fetal neural functional connectivity and highlight unique challenges and limitations inherent in the technique. In addition, we discuss future directions to unlock the potential of fetal brain functional MRI research. C1 [van den Heuvel, Marion I.; Thomason, Moriah E.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [van den Heuvel, Marion I.; Thomason, Moriah E.] NICHHD, Perinatol Res Branch, NICHD, NIH,DHHS, Detroit, MI 48201 USA. [Thomason, Moriah E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. RP Thomason, ME (reprint author), Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA.; Thomason, ME (reprint author), NICHHD, Perinatol Res Branch, NICHD, NIH,DHHS, Detroit, MI 48201 USA.; Thomason, ME (reprint author), Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. EM moriah@wayne.edu FU National Institutes of Health [MH110793, ES026022]; NARSAD Young Investigator Award; NIH [HHSN 275201300006C] FX This project was supported by awards to M.E.T. from the National Institutes of Health, MH110793 and ES026022, and by a NARSAD Young Investigator Award. This project was also supported in part by NIH contract HHSN 275201300006C. The authors also thank participant families who generously shared their time. NR 71 TC 1 Z9 1 U1 9 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD DEC PY 2016 VL 20 IS 12 BP 931 EP 939 DI 10.1016/j.tics.2016.10.001 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA ED8FE UT WOS:000389106600007 PM 27825537 ER PT J AU Hand, TW Vujkovic-Cvijin, I Ridaura, VK Belkaid, Y AF Hand, Timothy W. Vujkovic-Cvijin, Ivan Ridaura, Vanessa K. Belkaid, Yasmine TI Linking the Microoiota, Chronic Disease, anc the Immune System SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID INFLAMMATORY-BOWEL-DISEASE; NEGLECTED TROPICAL DISEASES; RANDOMIZED CONTROLLED-TRIAL; CHRONIC HIV-INFECTION; T-CELL RESPONSES; GUT MICROBIOTA; INTESTINAL MICROBIOTA; COMMENSAL BACTERIA; ADIPOSE-TISSUE; BEIGE FAT AB Chronic inflammatory diseases (CIDs) are the most important causes of mortality in the world today and are on the rise. We now know that immune-driven inflammation is critical in the etiology of these diseases, though the environmental triggers and cellular mechanisms that lead to their development are still mysterious. Many CIDs are associated with significant shifts in the microbiota toward inflammatory configurations, which can affect the host both by inducing local and systemic inflammation and by alterations in microbiota-derived metabolites. This review discusses recent findings suggesting that shifts in the microbiota may contribute to chronic disease via effects on the immune system. C1 [Hand, Timothy W.] Univ Pittsburgh, Richard King Mellon Inst Pediat Res, Childrens Hosp Pittsburgh, UPMC, Pittsburgh, PA 15224 USA. [Vujkovic-Cvijin, Ivan; Ridaura, Vanessa K.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Microbiome Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Hand, TW (reprint author), Univ Pittsburgh, Richard King Mellon Inst Pediat Res, Childrens Hosp Pittsburgh, UPMC, Pittsburgh, PA 15224 USA. EM timothy.hand@chp.edu FU NIAID [K22 AI108719]; NIH intramural program FX The authors would like to apologize that due to length requirements not all work in this burgeoning field could be discussed and properly cited. This work was supported by NIAID K22 AI108719 (T.W.H.) and the NIH intramural program (V.K.R, I.V-C., and Y.B,). The authors would like to thank K. Gopalakrishna and J. Tometich for critical reading of the manuscript. NR 131 TC 1 Z9 1 U1 7 U2 7 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 DEC PY 2016 VL 27 IS 12 BP 831 EP 843 DI 10.1016/jtem.2016.08.003 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED8DO UT WOS:000389102400001 PM 27623245 ER PT J AU Kumar, NP Moideen, K Sivakumar, S Menon, PA Viswanathan, V Kornfeld, H Babu, S AF Kumar, Nathella Pavan Moideen, Kadar Sivakumar, Shanmugam Menon, Pradeep A. Viswanathan, Vijay Kornfeld, Hardy Babu, Subash TI Modulation of dendritic cell and monocyte subsets in tuberculosis diabetes co-morbidity upon standard tuberculosis treatment SO TUBERCULOSIS LA English DT Article ID MELLITUS AB Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis (PTB), with development of DM pandemic in countries where tuberculosis (TB) is also endemic. However, the effect of anti-TB treatment on the changes in dentritic cell (DC) and monocyte subset phenotype in TB-DM co-morbidity is not well understood. In this study, we characterized the frequency of DC and monocyte subsets in individuals with PTB with (PTB-DM) or without coincident diabetes mellitus (PTB-NDM) before, during and after completion of anti-TB treatment. PTB-DM is characterized by diminished frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes at baseline and 2 months of anti-TB treatment but not following 6 months of treatment completion in comparison to PTB-NDM. DC and monocyte subsets exhibit significant but borderline correlation with fasting. blood glucose and glycated hemoglobin levels. Finally, while minor changes in the DC and monocyte compartment were observed at 2 months of treatment, significantly increased frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes were observed at the successful completion of anti-TB treatment. Our data show that coincident diabetes alters the frequencies of innate subset distribution of DC and monocytes in TB-DM co-morbidity and suggests that most of these changes are reversible following anti-TB therapy. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kumar, Nathella Pavan; Moideen, Kadar; Babu, Subash] Natl Inst Hlth, Int Ctr Excellence Res, NIRT, Madras, Tamil Nadu, India. [Viswanathan, Vijay] Prof M Viswanathan Diabet Res Ctr, Madras, Tamil Nadu, India. [Sivakumar, Shanmugam; Menon, Pradeep A.] Natl Inst Res TB, Madras, Tamil Nadu, India. [Kornfeld, Hardy] Univ Massachusetts, Sch Med, Worcester, MA USA. [Babu, Subash] NIAID, LPD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kumar, NP (reprint author), NIH NIRT ICER, Natl Inst Res TB, Madras, Tamil Nadu, India. EM pavankumarn@nirt.res.in FU Indian Department of Biotechnology; Indian Council of Medical Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Division of Intramural Research, NIAID, NIH; CRDF Global [USB1-31149-XX-13] 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, R. Anuradha, Prabha Chandran, Yukthi Bothra and Gokul Raj of the NIH-ICER for technical assistance. This work was jointly sponsored by the Indian Department of Biotechnology; the Indian Council of Medical Research; and the National Institute of 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 22 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD DEC PY 2016 VL 101 BP 191 EP 200 DI 10.1016/j.tube.2016.10.004 PG 10 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA ED8DT UT WOS:000389102900028 PM 27865391 ER PT J AU Varble, AJ Ried, CD Hammond, WJ Marquis, KA Woodruff, MC Ferran, MC AF Varble, Andrew J. Ried, Christopher D. Hammond, Warren J. Marquis, Kaitlin A. Woodruff, Matthew C. Ferran, Maureen C. TI The vesicular stomatitis virus matrix protein inhibits NF-kappa B activation in mouse L929 cells SO VIROLOGY LA English DT Article DE Vesicular stomatitis virus; VSV; L929 cells; Matrix protein; M51 mutation; NF-kappa B (NF-kappa B); Interferon; IKK inhibitor; Canonical pathway ID HOST GENE-EXPRESSION; TRANSCRIPTION FACTOR; IN-VIVO; INDUCTION; RNA; APOPTOSIS; ABILITY; AUTOPHAGY; TRANSPORT; MUTANTS AB A previous study found that NF-kappa B activation is delayed in L929 cells infected with wild-type (wt) strains of VSV, while activation occurred earlier in cells infected with mutant strain T1026R1 (RI) that encodes a mutation in the cytotoxic matrix (M) protein. The integrity of the other R1 proteins is unknown; therefore our goal was to identify the viral component responsible for preventing NF-kappa B activation in L929 cells. We found that the M protein inhibits viral-mediated activation of NF-kappa B in the context of viral infection and when expressed alone via transfection, and that the M51R mutation in M abrogates this function. Addition of an l kappa B kinase (IKK) inhibitor blocked NF-kappa B activation and interferon-beta mRNA expression in cells infected with viruses encoding the M51R mutation in M. These results indicate that the VSV M protein inhibits activation of NF-kappa B by targeting an event upstream of IKK in the canonical pathway. (C) 2016 Elsevier Inc. All rights reserved. C1 [Varble, Andrew J.; Ried, Christopher D.; Hammond, Warren J.; Marquis, Kaitlin A.; Woodruff, Matthew C.; Ferran, Maureen C.] Rochester Inst Technol, Thomas Gosnell Sch Life Sci, 153 Lomb Mem Dr, Rochester, NY 14623 USA. [Varble, Andrew J.] Rockefeller Univ, 1230 York Ave, New York, NY 10021 USA. [Ried, Christopher D.] Essex Technol Grp, La Vergne, TN USA. [Hammond, Warren J.] Warren Hammond Entertainment, Boulder, CO USA. [Marquis, Kaitlin A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Woodruff, Matthew C.] Emory Univ, Atlanta, GA 30322 USA. RP Ferran, MC (reprint author), Rochester Inst Technol, Thomas Gosnell Sch Life Sci, 153 Lomb Mem Dr, Rochester, NY 14623 USA. EM mcfsbi@rit.edu FU NIH/NIAID grant [R15 AIO58969] FX We thank Douglas Lyles for generously providing the recombinant virus strains. We thank Sanjay Maggirwar for his invaluable scientific input and generous use of reagents and equipment. We also thank Jonelle Mattiacio, Joanna Shisler, Hyla Sweet, and Brian Ward for their support and insightful comments on the manuscript. We thank the Rochester Institute of Technology (RIT) College of Science (COS) for helping to support this work and the COS Summer Undergraduate Research Program and the RIT Honors Program for supporting many of the undergraduates who contributed to this work. This research was supported by the NIH/NIAID grant R15 AIO58969 (M. F.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 35 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 499 BP 99 EP 104 DI 10.1016/j.virol.2016.09.009 PG 6 WC Virology SC Virology GA EC3YI UT WOS:000388062600011 PM 27643886 ER PT J AU Boi, S Rosenke, K Hansen, E Hendrick, D Malik, F Evans, LH AF Boi, Stefano Rosenke, Kyle Hansen, Ethan Hendrick, Duncan Malik, Frank Evans, Leonard H. TI Endogenous retroviruses mobilized during friend murine leukemia virus infection SO VIROLOGY LA English DT Article DE Retroviruses; Mouse; Pseudotyping; Endogenous; Proviruses ID LONG TERMINAL REPEAT; FOCUS-FORMING VIRUSES; LUPUS-PRONE MICE; OLIGONUCLEOTIDE PROBES; POLYTROPIC RETROVIRUS; HETERODUPLEX ANALYSIS; THYMIC LYMPHOMAS; UP-REGULATION; MOLONEY-MULV; PROVIRAL DNA AB We have demonstrated in a mouse model that infection with a retrovirus can lead not only to the generation of recombinants between exogenous and endogenous gammaretrovirus, but also to the mobilization of endogenous proviruses by pseudotyping entire polytropic proviral transcripts and facilitating their infectious spread to new cells. However, the frequency of this occurrence, the kinetics, and the identity of mobilized endogenous proviruses was unclear. Here we find that these mobilized transcripts are detected after only one day of infection. They predominate over recombinant polytropic viruses early in infection, persist throughout the course of disease and are comprised of multiple different polytropic proviruses. Other endogenous retroviral elements such as intracisternal A particles (IAPs) were not detected. The integration of the endogenous transcripts into new cells could result in loss of transcriptional control and elevated expression which may facilitate pathogenesis, perhaps by contributing to the generation of polytropic recombinant viruses. Published by Elsevier Inc. C1 [Boi, Stefano; Rosenke, Kyle; Hansen, Ethan; Hendrick, Duncan; Malik, Frank; Evans, Leonard H.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Evans, LH (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM levans@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. The authors wish to thank K. Hasenkrug, S. Priola, and K. Peterson for helpful discussions. NR 64 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 0042-6822 J9 VIROLOGY JI Virology PD DEC PY 2016 VL 499 BP 136 EP 143 DI 10.1016/j.virol.2016.07.009 PG 8 WC Virology SC Virology GA EC3YI UT WOS:000388062600015 PM 27657834 ER PT J AU Saligan, LN Lukkahatai, N Holder, G Walitt, B Machado-Vieira, R AF Saligan, L. N. Lukkahatai, N. Holder, G. Walitt, B. Machado-Vieira, R. TI Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE fatigue; depression; brain-derived neurotrophic factor; radiation; prostate neoplasm ID SYNAPTIC-TRANSMISSION; FUNCTIONAL ASSESSMENT; UP-REGULATION; BDNF; PERFORMANCE; DEPRESSION; DISORDERS; SYSTEM; SCALE; RELEVANCE AB Objectives. Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. Methods. Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. Results. FACT-F scores of 47 subjects decreased from baseline (43.95 +/- 1.3) to mid-EBRT (38.36 +/- 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (r(s) = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). Conclusions. Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue. C1 [Saligan, L. N.; Lukkahatai, N.; Holder, G.; Walitt, B.] NINR, NIH, Bethesda, MD 20892 USA. [Lukkahatai, N.] Univ Nevada, Sch Nursing, Las Vegas, NV USA. [Machado-Vieira, R.] NIMH, NIH, Bethesda, MD USA. RP Saligan, LN (reprint author), NINR, NIH, Bethesda, MD 20892 USA.; Saligan, LN (reprint author), 3 Ctr Dr,B3-5E14, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov FU Division of Intramural Research of the National Institute of Nursing Research of the National Institutes of Health, Bethesda, Maryland FX This study was supported by the Division of Intramural Research of the National Institute of Nursing Research of the National Institutes of Health, Bethesda, Maryland. NR 48 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD DEC PY 2016 VL 17 IS 8 BP 608 EP 614 DI 10.3109/15622975.2015.1012227 PG 7 WC Psychiatry SC Psychiatry GA ED1YR UT WOS:000388641300005 PM 25815565 ER PT J AU Das, D Velez, JI Acosta, MT Muenke, M Arcos-Burgos, M Easteal, S AF Das, Debjani Velez, Jorge I. Acosta, Maria T. Muenke, Maximilian Arcos-Burgos, Mauricio Easteal, Simon TI Retrospective assessment of childhood ADHD symptoms for diagnosis in adults: validity of a short 8-item version of the Wender-Utah Rating Scale SO ADHD-ATTENTION DEFICIT AND HYPERACTIVITY DISORDERS LA English DT Article DE Adult ADHD; WURS; CAARS; ROC; Sensitivity; Specificity ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; LATE-ONSET; SUBTHRESHOLD DIAGNOSES; ROC ANALYSIS; RELIABILITY; PREVALENCE; CURVES; WURS AB The Wender-Utah Rating Scale (WURS) is a widely used self-report instrument for retrospective assessment of childhood ADHD. However, many WURS items are not specific to ADHD. Here, we investigated the effect of excluding these items on the performance of the WURS in predicting adult ADHD based on previous diagnosis and current clinically significant symptoms. The study was conducted on a sample of adults (n = 1014; 48 % male) participating in a family-based investigation of ADHD. Participants completed the 61-item WURS questionnaire and the 66-item Conners Adult ADHD Rating Scale. Receiver operating characteristic (ROC) curves were used to compare the performance of the eight-item WURS (WURS-8) and the longer WURS-25 in predicting previous ADHD diagnosis and current clinically significant ADHD symptoms. WURS-8 and WURS-25 have approximately the same power to predict adult ADHD, based on either previous diagnosis or current symptoms (area under the ROC curves > 0.8). WURS-8 performs at least as well as the longer WURS-25 in predicting adult ADHD. This 8-item questionnaire is thus a valid instrument and is especially useful for screening for ADHD in large epidemiological samples. C1 [Das, Debjani; Velez, Jorge I.; Arcos-Burgos, Mauricio; Easteal, Simon] Australian Natl Univ, John Curtin Sch Med Res, Bldg 131,Garran Rd, Canberra, ACT 2601, Australia. [Velez, Jorge I.; Arcos-Burgos, Mauricio] Univ Antioquia, Neuroscience Res Grp, Medellin, Colombia. [Velez, Jorge I.] Univ Norte, Dept Ind Engn, Barranquilla, Colombia. [Acosta, Maria T.] Jennifer & Daniel Gilbert Neurofibromatosis Inst, Washington, DC USA. [Acosta, Maria T.] Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Washington, DC USA. [Acosta, Maria T.; Muenke, Maximilian; Arcos-Burgos, Mauricio] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. RP Das, D (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Bldg 131,Garran Rd, Canberra, ACT 2601, Australia. EM debjani.das@anu.edu.au NR 45 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1866-6116 EI 1866-6647 J9 ADHD-ATTEND DEFICIT JI ADHD-Attend. Deficit Hyperact. Disord. PD DEC PY 2016 VL 8 IS 4 BP 215 EP 223 DI 10.1007/s12402-016-0202-9 PG 9 WC Psychiatry SC Psychiatry GA EC1ER UT WOS:000387847200006 PM 27510231 ER PT J AU Valkanas, E Schaffer, K Dunham, C Maduro, V du Souich, C Rupps, R Adams, DR Baradaran-Heravi, A Flynn, E Malicdan, MC Gahl, WA Toro, C Boerkoel, CF AF Valkanas, Elise Schaffer, Katherine Dunham, Christopher Maduro, Valerie du Souich, Christele Rupps, Rosemarie Adams, David R. Baradaran-Heravi, Alireza Flynn, Elise Malicdan, May C. Gahl, William A. Toro, Camilo Boerkoel, Cornelius F. TI Phenotypic Evolution of UNC80 Loss of Function SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE intellectual disability; growth restriction; failure to thrive; seizures; emaciation ID FEEDING DISORDERS; CHANNEL COMPLEX; CATION CHANNEL; SODIUM LEAK; NALCN CAUSE; MUTATIONS; HYPOTONIA; ENCEPHALOPATHY; PRIORITIZATION; INTERACTOME AB Failure to thrive arises as a complication of a heterogeneous group of disorders. We describe two female siblings with spastic paraplegia and global developmental delay but also, atypically for the HSPs, poor weight gain classified as failure to thrive. After extensive clinical and biochemical investigations failed to identify the etiology, we used exome sequencing to identify biallelic UNC80 mutations (NM_032504.1: c.[3983-3_3994delinsA];[2431C>T]. The paternally inherited NM_032504.1: c.3983-3_3994delinsA is predicted to encode p.Ser1328Argfs*19 and the maternally inherited NM_032504.1: c. 2431C>T is predicted to encode p.Arg811*. No UNC80 mRNA was detectable in patient cultured skin fibroblasts, suggesting UNC80 loss of function by nonsense mediated mRNA decay. Further supporting the UNC80 mutations as causative of these siblings' disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations. (C) 2016 Wiley Periodicals, Inc. C1 [Valkanas, Elise; Schaffer, Katherine; Maduro, Valerie; Adams, David R.; Flynn, Elise; Malicdan, May C.; Gahl, William A.; Toro, Camilo; Boerkoel, Cornelius F.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Dunham, Christopher] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada. [du Souich, Christele; Rupps, Rosemarie; Baradaran-Heravi, Alireza; Boerkoel, Cornelius F.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [du Souich, Christele; Rupps, Rosemarie; Baradaran-Heravi, Alireza; Boerkoel, Cornelius F.] Univ British Columbia, Child & Family Res Inst, Vancouver, BC, Canada. [Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Boerkoel, CF (reprint author), Univ British Columbia, Childrens & Womens Hlth Ctr BC, Dept Med Genet, 4500 Oak St,Rm C234, Vancouver, BC V6H 3N1, Canada. EM cboerkoel@gmail.com FU National Human Genome Research Institute; Common Fund, Office of the Director; Scottish Rite Foundation; Child and Family Research Institute Establishment Award FX Grant sponsor: National Human Genome Research Institute; Grant sponsor: Common Fund, Office of the Director; Grant sponsor: Scottish Rite Foundation (C.D.S.); Grant sponsor: Child and Family Research Institute Establishment Award (C.F.B.). NR 29 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC PY 2016 VL 170 IS 12 BP 3106 EP 3114 DI 10.1002/ajmg.a.37929 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EC5TL UT WOS:000388199100008 PM 27513830 ER PT J AU Prakash, SK Bondy, CA Maslen, CL Silberbach, M Lin, AE Perrone, L Limongelli, G Michelena, HI Bossone, E Citro, R Lemaire, SA Body, SC Milewicz, DM AF Prakash, Siddharth K. Bondy, Carolyn A. Maslen, Cheryl L. Silberbach, Michael Lin, Angela E. Perrone, Laura Limongelli, Giuseppe Michelena, Hector I. Bossone, Eduardo Citro, Rodolfo Lemaire, Scott A. Body, Simon C. Milewicz, Dianna M. CA BAVCon Investigators GenTAC Registry Investigators TI Autosomal and X Chromosome Structural Variants Are Associated with Congenital Heart Defects in Turner Syndrome: The NHLBI GenTAC Registry SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE genomics; Turner syndrome; valvular heart disease; congenital heart defects; X chromosome ID BICUSPID AORTIC-VALVE; COPY-NUMBER VARIATION; TRANSPORTER GENE SLC2A3; DISSECTION; EXPRESSION; ANEURYSMS; DELETION; GROWTH; CANCER; WOMEN AB Turner Syndrome(TS) is adevelopmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 timesmore frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. (C) 2016 Wiley Periodicals, Inc. C1 [Prakash, Siddharth K.; Milewicz, Dianna M.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Med Genet, Houston, TX 77030 USA. [Bondy, Carolyn A.] NICHHD, NIH, Bethesda, MD 20892 USA. [Maslen, Cheryl L.; Silberbach, Michael] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Maslen, Cheryl L.; Silberbach, Michael] Oregon Hlth & Sci Univ, Dept Pediat, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA. [Lin, Angela E.] MassGeneral Hosp Children, Dept Med Genet, Boston, MA USA. [Perrone, Laura; Limongelli, Giuseppe] Univ Naples 2, Dept Pediat F Fede, Naples, Italy. [Michelena, Hector I.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Bossone, Eduardo; Citro, Rodolfo] Univ Hosp Scuola Med Salernitana, Dept Cardiol & Cardiac Surg, Salerno, Italy. [Lemaire, Scott A.] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Cardiothorac Surg, Houston, TX 77030 USA. [Body, Simon C.] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. RP Prakash, SK (reprint author), Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Internal Med, 6431 Fannin St,MSB 6-106, Houston, TX 77030 USA. EM siddharth.k.prakash@uth.tmc.edu FU Baylor College of Medicine [1U54HD083092, 5R01HD039056, 5R01HL090506, 5R01HL091771]; Ohio State University and Nationwide Children's Hospital [5R01HL109758]; US Federal Government [HHSN268200648199C, HHSN268201000048C]; National Institute on Aging [U01AG009740, RC2AG036495, RC4AG039029]; National Eye Institute; Johns Hopkins University [HHSN268200782096C]; Collaborative Genetic Study of Nicotine Dependence ( COGEND) [P01 CA089392]; University of Wisconsin Transdisciplinary Tobacco Use Research Center [P50 DA019706, P50 CA084724] FX Grant sponsor: Baylor College of Medicine; Grant numbers: 1U54HD083092, 5R01HD039056, 5R01HL090506, 5R01HL091771; Grant sponsor: Ohio State University and Nationwide Children's Hospital; Grant number: 5R01HL109758; Grant sponsor: US Federal Government; Grant numbers : HHSN268200648199C, HHSN268201000048C; Grant sponsor: National Institute on Aging; Grant numbers: U01AG009740, RC2AG036495, RC4AG039029; Grant sponsor: National Eye Institute; Grant sponsor: The Johns Hopkins University; Grant number: HHSN268200782096C; Grant sponsor: Collaborative Genetic Study of Nicotine Dependence ( COGEND); Grant number: P01 CA089392; Grant sponsor: University of Wisconsin Transdisciplinary Tobacco Use Research Center; Grant numbers: P50 DA019706, P50 CA084724. NR 31 TC 2 Z9 2 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC PY 2016 VL 170 IS 12 BP 3157 EP 3164 DI 10.1002/ajmg.a.37953 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EC5TL UT WOS:000388199100015 PM 27604636 ER PT J AU Grobman, WA Parker, C Wadhwa, PD Willinger, M Simhan, H Silver, B Wapner, RJ Parry, S Mercer, B Haas, D Peaceman, AM Hunter, S Wing, D Caritis, S Esplin, S Hoffman, M Ludmir, J Iams, J Long, E Saade, G Reddy, UM AF Grobman, William A. Parker, Corette Wadhwa, Pathik D. Willinger, Marian Simhan, Hyagriv Silver, Bob Wapner, Ron J. Parry, Samuel Mercer, Brian Haas, David Peaceman, Alan M. Hunter, Shannon Wing, Deborah Caritis, Steve Esplin, Sean Hoffman, Matt Ludmir, Jack Iams, Jay Long, Emily Saade, George Reddy, Uma M. CA Eunice Kennedy Shriver Natl Inst C TI Racial/Ethnic Disparities in Measures of Self-reported Psychosocial States and Traits during Pregnancy SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE psychosocial; stress; disparities; pregnancy ID DEPRESSIVE SYMPTOMS; RACIAL DISPARITIES; STRESS; SCALE; POSTPARTUM; OUTCOMES AB Background The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas. Methods Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income. Results Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated (p < 0.001) with survey scores. Non-Hispanic black (NHB) women were most likely to score in the most unfavorable category for all measures, with the exception of the Pregnancy Experience Scale. The magnitude of these differences did not differ by income status (interaction, p > 0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction, p < 0.001). Conclusion Significant racial/ethnic disparities, independent of income status, exist in psychosocial measures during pregnancy. C1 [Grobman, William A.; Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, 250 East Super St,Suite 05-2175, Chicago, IL 60611 USA. [Parker, Corette; Hunter, Shannon] RTI Int, Div Biostat & Epidemiol, Res Triangle Pk, NC USA. [Wadhwa, Pathik D.; Wing, Deborah] Univ Calif Irvine, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Willinger, Marian; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Simhan, Hyagriv; Caritis, Steve] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Silver, Bob; Esplin, Sean] Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Wapner, Ron J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Parry, Samuel; Ludmir, Jack] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Mercer, Brian] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. [Haas, David; Long, Emily] Indiana Univ, Dept Obstet & Gynecol, Indianapolis, IN 46204 USA. [Hoffman, Matt] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Iams, Jay] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Saade, George] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. RP Grobman, WA (reprint author), Northwestern Univ, Dept Obstet & Gynecol, 250 East Super St,Suite 05-2175, Chicago, IL 60611 USA. EM w-grobman@northwestern.edu OI Ludmir, Jack/0000-0002-9728-7444 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD063036, U10 HD063072, U10 HD063047, U10 HD063037, U10 HD063041, U10 HD063020, U10 HD063046, U10 HD063048, U10 HD063053] FX This study was supported by the following grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD063036, RTI International; U10 HD063072, Case Western Reserve University; U10 HD063047, Columbia University; U10 HD063037, Indiana University; U10 HD063041, University of Pittsburgh; U10 HD063020, Northwestern University; U10 HD063046, University of California Irvine; U10 HD063048, University of Pennsylvania; and U10 HD063053, University of Utah. NR 27 TC 0 Z9 0 U1 4 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD DEC PY 2016 VL 33 IS 14 BP 1426 EP 1432 DI 10.1055/s-0036-1586510 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA ED0RH UT WOS:000388549100014 PM 27500932 ER PT J AU Barber, S Hickson, DA Wang, X Sims, M Nelson, C Diez-Roux, AV AF Barber, Sharrelle Hickson, DeMarc A. Wang, Xu Sims, Mario Nelson, Cheryl Diez-Roux, Ana V. TI Neighborhood Disadvantage, Poor Social Conditions, and Cardiovascular Disease Incidence Among African American Adults in the Jackson Heart Study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID GEOGRAPHIC LIFE ENVIRONMENTS; RESEARCH AGENDA; RISK-FACTORS; HEALTH; MULTILEVEL; ATHEROSCLEROSIS; COHESION; DISORDER; OBESITY; STROKE AB Objectives. To examine the impact of neighborhood conditions resulting from racial residential segregation on cardiovascular disease (CVD) risk in a socioeconomically diverse African American sample. Methods. The study included 4096 African American women (n = 2652) and men (n = 1444) aged 21 to 93 years from the Jackson Heart Study (Jackson, Mississippi; 20002011). We assessed neighborhood disadvantage with a composite measure of 8 indicators from the 2000 US Census. We assessed neighborhood-level social conditions, including social cohesion, violence, and disorder, with self-reported, validated scales. Results. Among African American women, each standard deviation increase in neighborhood disadvantage was associated with a 25% increased risk of CVD after covariate adjustment (hazard ratio = 1.25; 95% confidence interval = 1.05, 1.49). Risk also increased as levels of neighborhood violence and physical disorder increased after covariate adjustment. We observed no statistically significant associations among African American men in adjusted models. Conclusions. Worse neighborhood economic and social conditions may contribute to increased risk of CVD among African American women. Policies directly addressing these issues may alleviate the burden of CVD in this group. C1 [Barber, Sharrelle; Wang, Xu; Diez-Roux, Ana V.] Drexel Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nesbit Hall,5th Floor,3215 Market St, Philadelphia, PA 19104 USA. [Barber, Sharrelle; Wang, Xu; Diez-Roux, Ana V.] Ctr Integrat Approaches Hlth Dispar, Philadelphia, PA USA. [Hickson, DeMarc A.; Sims, Mario] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Nelson, Cheryl] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Barber, S (reprint author), Drexel Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nesbit Hall,5th Floor,3215 Market St, Philadelphia, PA 19104 USA. EM smb483@drexel.edu FU Center for Integrative Approaches to Health Disparities - National Institute of Minority Health and Health Disparities [NIMHD P60 MD002249]; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; NIMHD; National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL071759] FX This research was supported by the Center for Integrative Approaches to Health Disparities funded by National Institute of Minority Health and Health Disparities (NIMHD P60 MD002249; A. V. Diez-Roux). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the NIMHD. The creation of Jackson Heart Study neighborhood environment variables was supported by the Michigan Center for Integrative Approaches to Health Disparities funded by the NIMHD, by US Environmental Protection Agency and NIMHD: Environment Supplement P60 MD002249 05S1 (PI: A. V. Diez-Roux), and by the Multi-ethnic Study of Atherosclerosis Neighborhood Study R01 HL071759 (PI: A. V. Diez-Roux) funded by the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 36 TC 1 Z9 1 U1 8 U2 8 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2016 VL 106 IS 12 BP 2219 EP 2226 DI 10.2105/AJPH.2016.303471 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EC4IQ UT WOS:000388091700051 PM 27736207 ER PT J AU Miettinen, M Felisiak-Golabek, A Wasag, B Chmara, M Wang, ZF Butzow, R Lasota, J AF Miettinen, Markku Felisiak-Golabek, Anna Wasag, Bartosz Chmara, Magdalena Wang, Zengfeng Butzow, Ralf Lasota, Jerzy TI Fumarase-deficient Uterine Leiomyomas An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE leiomyoma; leiomyosarcoma; renal cell cancer; FH; immunohistochemistry ID RENAL-CELL CANCER; HEREDITARY LEIOMYOMATOSIS; CARCINOMA SYNDROME; HLRCC SYNDROME; FH MUTATIONS; HYDRATASE; FEATURES; LEIOMYOSARCOMAS; INACTIVATION; TUMORS AB Loss-of-function germline mutations in the fumarase (FH) gene of the Krebs cycle characterize hereditary leiomyomatosis and renal cell cancer syndrome. Fumarase (FH) deficiency can be diagnosed by the loss of immunohistochemical expression. In this study, we investigated the occurrence and clinicopathologic features of FH-deficient uterine smooth muscle tumors (SMTs). A total of 1583 uterine and 157 nonuterine SMTs were examined using a polyclonal FH antibody and automated immunohistochemistry, and 86 uterine leiomyomas with an FH loss were identified. The frequencies of FH deficiency for subcohorts of uterine SMTs were 1.6% for unselected nonatypical leiomyomas, 1.8% for cellular leiomyomas, 37.3% for atypical leiomyomas, and 0% for leiomyosarcomas. One extrauterine, retroperitoneal estrogen receptor-positive leiomyoma was also FH deficient. The patient age of FH-deficient uterine leiomyomas was 20 to 52 years (median, 38 y). Grossly, these tumors were often soft and amorphous resembling a fibrothecoma. Histologically, the FH-deficient nonatypical leiomyomas lacked cellular packeting and distinct collagenous zones and showed chain-like or palisading nuclear arrangements, prominent staghorn-shaped blood vessels, oval nuclei with no or at most mild atypia, small eosinophilic nucleoli, and a low mitotic rate (0 to 1/10HPF). The FH-deficient atypical leiomyomas had nuclear atypia often manifesting as multinucleation, prominent eosinophilic nucleoli, and mitotic activity up to 7/10HPF, with atypical mitoses seen in 32% of cases. However, similar histologic changes were seen in some non-FH-deficient atypical leiomyomas. Loss-of-function FH-gene mutations including 5 whole-gene deletions and 3 frameshift mutations were identified in 8 of 16 FH-deficient nonatypical leiomyomas using multiplex ligation-dependent probe amplification and Sanger sequencing, respectively. Follow-up data on patients with FH-deficient atypical uterine leiomyomas revealed 19 patients alive (median follow-up 27 y) and 5 patients dead. Deaths occurred 9 to 30 years after surgery at a median age of 72 years; causes of death could not be determined. These results indicate that FH-deficient uterine leiomyomas occur with a high frequency among atypical leiomyomas and infrequently in nonatypical leiomyomas and are often histologically distinctive. They seem to have a low biological potential and lack any significant association with leiomyosarcoma. C1 [Miettinen, Markku; Felisiak-Golabek, Anna; Wang, Zengfeng; Lasota, Jerzy] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wasag, Bartosz; Chmara, Magdalena] Med Univ Gdansk, Dept Biol & Genet, Gdansk, Poland. [Butzow, Ralf] HusLab, Helsinki, Finland. [Butzow, Ralf] Univ Helsinki, Helsinki, Finland. RP Miettinen, M (reprint author), NCI, Pathol Lab, Surg Pathol Sect, 9000 Rockville Pike,Bldg 10,Rm 2S235C, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NCI's intramural research program FX This work was supported as a part of NCI's intramural research program. NR 23 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2016 VL 40 IS 12 BP 1661 EP 1669 DI 10.1097/PAS.0000000000000703 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA EC6CI UT WOS:000388223500011 PM 27454940 ER PT J AU Duggan, MA Anderson, WF Altekruse, S Penberthy, L Sherman, ME AF Duggan, Maire A. Anderson, William F. Altekruse, Sean Penberthy, Lynne Sherman, Mark E. TI The Surveillance, Epidemiology, and End Results (SEER) Program and Pathology Toward Strengthening the Critical Relationship SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE SEER; Surveillance, Epidemiology, and End Results program, pathology ID POPULATION-BASED ANALYSIS; BREAST-CANCER; UNITED-STATES; CERVICAL-CANCER; SURVIVAL; REGISTRY; CLASSIFICATION; MORTALITY; CARCINOMA; DISEASE AB The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute collects data on cancer diagnoses, treatment, and survival for approximately 30% of the United States (US) population. To reflect advances in research and oncology practice, approaches to cancer control are evolving from simply enumerating the development of cancers by organ site in populations to including monitoring of cancer occurrence by histopathologic and molecular subtype, as defined by driver mutations and other alterations. SEER is an important population-based resource for understanding the implications of pathology diagnoses across demographic groups, geographic regions, and time and provides unique insights into the practice of oncology in the US that are not attainable from other sources. It provides incidence, survival, and mortality data for histopathologic cancer subtypes, and data by molecular subtyping are expanding. The program is developing systems to capture additional biomarker data, results from special populations, and expand biospecimen banking to enable cutting-edge cancer research and oncology practice. Pathology has always been central and critical to the effectiveness of SEER, and strengthening this relationship in this modern era of cancer diagnosis could be mutually beneficial. Achieving this goal requires close interactions between pathologists and the SEER program. This review provides a brief overview of SEER, focuses on facets relevant to pathology practice and research, and highlights the opportunities and challenges for pathologists to benefit from and enhance the value of SEER data. C1 [Duggan, Maire A.] Univ Calgary, Cumming Sch Med, Dept Pathol & Lab Med, Calgary, AB, Canada. [Anderson, William F.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Altekruse, Sean; Penberthy, Lynne] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Sherman, ME (reprint author), NCI, Breast & Gynecol Canc Res Grp, Canc Prevent Div, 9609 Med Ctr Dr,Room 5E334, Bethesda, MD 20892 USA. EM shermanm@exchange.nih.gov FU Intramural Research Program of the National Cancer Institute FX Funded in part by the Intramural Research Program of the National Cancer Institute. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 40 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2016 VL 40 IS 12 BP E94 EP E102 DI 10.1097/PAS.0000000000000749 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA EC6CI UT WOS:000388223500001 PM 27740970 ER PT J AU Karami, S Yanik, EL Moore, LE Pfeiffer, RM Copeland, G Gonsalves, L Hernandez, BY Lynch, CF Pawlish, K Engels, EA AF Karami, S. Yanik, E. L. Moore, L. E. Pfeiffer, R. M. Copeland, G. Gonsalves, L. Hernandez, B. Y. Lynch, C. F. Pawlish, K. Engels, E. A. TI Risk of Renal Cell Carcinoma Among Kidney Transplant Recipients in the United States SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID CANCER INCIDENCE; NATIVE KIDNEYS; DISEASE; DIALYSIS; SPECTRUM; ORGAN; EXPERIENCE; SURVIVAL; PEOPLE; ESRD AB Renal cell carcinoma (RCC) is a common malignancy following kidney transplantation. We describe RCC risk and examine RCC risk factors among US kidney recipients (1987-2010). The Transplant Cancer Match Study links the US transplant registry with 15 cancer registries. Standardized incidence ratios (SIRs) were used to compare RCC risk (overall and for clear cell [ccRCC] and papillary subtypes) to the general population. Associations with risk factors were assessed using Cox models. We identified 683 RCCs among 116 208 kidney recipients. RCC risk was substantially elevated compared with the general population (SIR 5.68, 95% confidence interval 5.27-6.13), especially for papillary RCC (SIR 13.3 versus 3.98 for ccRCC). Among kidney recipients, RCC risk was significantly elevated for blacks compared to whites (hazard ratio [HR] 1.50) and lower in females than males (HR 0.56). RCC risk increased with prolonged dialysis preceding transplantation (p-trend < 0.0001). Risk was variably associated for RCC subtypes with some medical conditions that were indications for transplantation: ccRCC risk was reduced with polycystic kidney disease (HR 0.54), and papillary RCC was increased with hypertensive nephrosclerosis (HR 2.02) and vascular diseases (HR 1.86). In conclusion, kidney recipients experience substantially elevated risk of RCC, especially for papillary RCC, and multiple factors contribute to these cancers. C1 [Karami, S.; Yanik, E. L.; Moore, L. E.; Pfeiffer, R. M.; Engels, E. A.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Copeland, G.] Michigan Dept Community Hlth, Michigan Canc Surveillance Program, Lansing, MI USA. [Gonsalves, L.] Connecticut Dept Publ Hlth, Hartford, CT USA. [Hernandez, B. Y.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lynch, C. F.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Pawlish, K.] New Jersey Dept Hlth, New Jersey State Canc Registry, Canc Epidemiol Serv, Trenton, NJ USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM karamis@mail.nih.gov FU Intramural Research Program of the National Cancer Institute; Minneapolis Medical Research Foundation, Minneapolis, MN [HHSH250201000018C]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261 201000034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN2612 01000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN261201 000032C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201300021I, N01-PC-2013-00021]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN2612013000171]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Illinois [5U58DP003883-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Maryland [U58DP12-1205 3919-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Michigan [5U58DP003921-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New York [U58DP003879]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement) [5458DP003920]; state of New Jersey; state of New York (including the Cancer Surveillance Initiative); state of Texas; state of Utah; state of Washington; University of Utah; Fred Hutchinson Cancer Research Center in Seattle, WA; [HHSH234200537009C] FX This research was supported in part by the Intramural Research Program of the National Cancer Institute. The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Tina Clarke), Colorado (Jack Finch), Connecticut, Georgia (Rana Bayakly), Hawaii (Michael Green), Iowa, Illinois (Lori Koch), Michigan, New Jersey (Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Matthew Chaloux, Michael Curry, and Ruth Parsons). The authors also thank David Check (National Cancer Institute) for assistance in producing the figures. The SRTR is currently operated under contract number HHSH250201000018C (Health Resources and Services Administration) by the Minneapolis Medical Research Foundation, Minneapolis, MN. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261 201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN2612 01000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201 000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN2612013000171). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5U58DP003883-03), Maryland (U58DP12-1205 3919-03), Michigan (5U58DP003921-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832), and Texas (5U58DP000824-04). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, Massachusetts (Massachusetts Cancer Prevention and Control Cooperative Agreement 5458DP003920), New Jersey, New York (including the Cancer Surveillance Initiative), Texas, Utah, and Washington, as well as the University of Utah and Fred Hutchinson Cancer Research Center in Seattle, WA. NR 45 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2016 VL 16 IS 12 BP 3479 EP 3489 DI 10.1111/ajt.13862 PG 11 WC Surgery; Transplantation SC Surgery; Transplantation GA EC5WS UT WOS:000388208600019 ER PT J AU Sotzny, F Schormann, E Kuhlewindt, I Koch, A Brehm, A Goldbach-Mansky, R Gilling, KE Kruger, E AF Sotzny, Franziska Schormann, Eileen Kuehlewindt, Ina Koch, Annett Brehm, Anja Goldbach-Mansky, Raphaela Gilling, Kate E. Krueger, Elke TI TCF11/Nrf1-Mediated Induction of Proteasome Expression Prevents Cytotoxicity by Rotenone SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article DE neurodegeneration; oxidative stress; proteasome; rotenone; transcription factor TCF11/Nrf1; ubiquitin ID MITOCHONDRIAL COMPLEX-I; FACTOR E2-RELATED FACTOR-1; BZIP TRANSCRIPTION FACTOR; OXIDATIVE-STRESS; PARKINSONS-DISEASE; ANTIOXIDANT RESPONSE; SUBSTANTIA-NIGRA; ALPHA-SYNUCLEIN; 20S PROTEASOME; ENDOPLASMIC-RETICULUM AB Aims: Precise regulation of cellular protein degradation is essential for maintaining protein and redox homeostasis. The ubiquitin proteasome system (UPS) represents one of the major degradation machineries, and UPS disturbances are strongly associated with neurodegeneration. We have previously shown that the transcription factor TCF11/Nrf1 induces antioxidant response element-mediated upregulation of UPS components in response to proteotoxic stress. Knockout of TCF11/Nrf1 is embryonically lethal, and therefore, the present investigation describes the role of oxidative stress in regulating TCF11/Nrf1-dependent proteasome expression in a model system relevant to Parkinson's disease. Results: Using the human dopaminergic neuroblastoma cell line SH-SY5Y and mouse nigrostriatal organotypic slice cultures, gene and protein expression analysis and functional assays revealed oxidative stress is induced by the proteasome inhibitor epoxomicin or the mitochondrial complex I inhibitor rotenone and promotes the upregulation of proteasome expression and function mediated by TCF11/Nrf1 activation. In addition, we show that these stress conditions induce the unfolded protein response. TCF11/Nrf1, thus, has a cytoprotective function in response to oxidative and proteotoxic stress. Innovation and Conclusion: We here demonstrate that adaption of the proteasome system in response to oxidative stress is dependent on TCF11/Nrf1 in this model system. We conclude that TCF11/Nrf1, therefore, plays a vital role in maintaining redox and protein homeostasis. This work provides a vital insight into the molecular mechanisms of neurodegeneration due to oxidative stress by rotenone, and further studies investigating the role of TCF11/Nrf1 in the human condition would be of considerable interest. C1 [Sotzny, Franziska; Schormann, Eileen; Kuehlewindt, Ina; Koch, Annett; Brehm, Anja; Gilling, Kate E.; Krueger, Elke] Charite Univ Med Berlin, Inst Biochem, Charitepl 1, D-10117 Berlin, Germany. [Goldbach-Mansky, Raphaela] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. RP Kruger, E (reprint author), Charite Univ Med Berlin, Inst Biochem, Charitepl 1, D-10117 Berlin, Germany. EM elke.krueger@charite.de FU Deutsche Forschungsgemeinschaft [KO 4144/1-1, KR 1915/5-1, SFB740 B3, SFBTRR 43 B7] FX This work was supported by the Deutsche Forschungsgemeinschaft (KO 4144/1-1; KR 1915/5-1; SFB740 B3; SFBTRR 43 B7). Elke Burger (Charite) is acknowledged for her excellent technical assistance and Yin Liu (NIH, Bethesda) for his support with cells from PRAAS patients. NR 69 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD DEC 1 PY 2016 VL 25 IS 16 BP 870 EP 885 DI 10.1089/ars.2015.6539 PG 16 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EC6RA UT WOS:000388262600002 PM 27345029 ER PT J AU Kannan, M Sivaprakasam, C Prinz, WA Nachiappan, V AF Kannan, Muthukumar Sivaprakasam, Chinnarasu Prinz, William A. Nachiappan, Vasanthi TI Endoplasmic reticulum stress affects the transport of phosphatidylethanolamine from mitochondria to the endoplasmic reticulum in S. cerevisiae SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE ER stress; Mitochondria; Phosphatidylcholine; ERMES; Lipid transport ID YEAST SACCHAROMYCES-CEREVISIAE; PHOSPHATIDYLCHOLINE BIOSYNTHESIS; PHOSPHATIDYLSERINE DECARBOXYLASE2; LIPID-METABOLISM; ER STRESS; GENE; PHOSPHOLIPIDS; TRAFFICKING; METHYLATION; PROTEINS AB Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are two of the most abundant phospholipids in cells. Although both lipids can be synthesized in the endoplasmic reticulum (ER), in S. cerevisiae PE can also be produced in mitochondria and endosomes; this PE can be transported back to the ER where it is converted to PC. In this study we found that dithiothreitol (DTT), which induces ER stress, decreases PE export from mitochondria to the ER. This results in decreased levels of total cellular PC and mitochondrial PC. These decreases were not caused by changes in levels of PC synthesizing or degrading enzymes. PE export from mitochondria to the ER during ER stress was further reduced in cells lacking Mdm10p, a component of an ER-mitochondrial tethering complex that may facilitated lipid exchange between these compartments. We also found that reducing mitochondrial PC levels induces mitophagy. In conclusion, we show that ER stress affected PE export from mitochondria to ER and the Mdm10p is important for this process. (C) 2016 Elsevier B.V. All rights reserved. C1 [Kannan, Muthukumar; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Sivaprakasam, Chinnarasu; Nachiappan, Vasanthi] Bharathidasan Univ, Sch Life Sci, Dept Biochem, Biomembrane Lab, Tiruchchirappalli 620024, Tamil Nadu, India. RP Nachiappan, V (reprint author), Bharathidasan Univ, Sch Life Sci, Dept Biochem, Biomembrane Lab, Tiruchchirappalli 620024, Tamil Nadu, India. EM vasanthibch@gmail.com FU Bharathidasan University, Tiruchirappalli; Council of Scientific & Industrial Research-CSIR, India FX The financial support from Bharathidasan University, Tiruchirappalli, Council of Scientific & Industrial Research-CSIR, India, and the instrumentation facility provided by the Department of Science & Technology (DST) under the DST-PURSE and DST-FIST programsare gratefully acknowledged. The authors sincerely thank Prof. Ram Rajasekharan, Dept of Biochemistry, Indian Institute of Science (Bangalore - India), for his critical comments about this manuscript and also for generously providing the reagents used in this study. We thank Prof. Ewald H. Hettema, (University of Sheffield, Sheffield, UK) for providing the OM45-GFP yeast strains, as well as Prof. Yoshinori Ohsumi, Prof. Kuninori Suzuki (University of Tokyo, Japan), Prof. Jeffrey Brodsky (University of Pittsburgh, PA, USA), and Prof. Marco Foiani, (University of Milan, Italy) for providing Ape1, Atg8, Kart and Pgk1 antiserum, respectively. NR 39 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD DEC PY 2016 VL 1861 IS 12 BP 1959 EP 1967 DI 10.1016/j.bbalip.2016.09.015 PN A PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ED0QC UT WOS:000388546000009 PM 27678054 ER PT J AU Shuch, B Syed, J Nguyen, K Hoffman, J Devesa, S Suarez, A AF Shuch, Brian Syed, Jamil Nguyen, Kevin Hoffman, Jonathan Devesa, Susan Suarez, Alfie TI Predictive factors of metachronous bilateral renal cell carcinoma: a surveillance, epidemiology, and end results analysis SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Shuch, Brian; Syed, Jamil] Yale Sch Med, Dept Urol, New Haven, CT USA. [Nguyen, Kevin; Suarez, Alfie] Yale Dept Urol, New Haven, CT USA. [Hoffman, Jonathan; Devesa, Susan] NCI, 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 8 EP 8 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200010 ER PT J AU Simpkin, AJ Donovan, JL Tilling, K Lane, JA Martin, RM Albertsen, PC Bill-Axelson, A Carter, HB Bosch, JLHR Ferrucci, L Hamdy, FC Holmberg, L Metter, EJ Neal, DE Parker, CC Metcalfe, C AF Simpkin, Andrew J. Donovan, Jenny L. Tilling, Kate Lane, J. Athene Martin, Richard M. Albertsen, Peter C. Bill-Axelson, Anna Carter, H. Ballentine Bosch, J. L. H. Ruud Ferrucci, Luigi Hamdy, Freddie C. Holmberg, Lars Metter, E. Jeffrey Neal, David E. Parker, Christopher C. Metcalfe, Chris TI Prostate-specific antigen patterns in US and European populations: comparison of six diverse cohorts SO BJU INTERNATIONAL LA English DT Article DE active surveillance; prostate specific antigen; prostate cancer ID DOUBLING TIME CALCULATION; ACTIVE SURVEILLANCE; FOLLOW-UP; RADICAL TREATMENT; JOHNS-HOPKINS; CANCER; VELOCITY; INTERVENTION; KINETICS; OUTCOMES AB Objective To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa). Subjects and Methods We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. Results The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. Conclusion We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies. C1 [Simpkin, Andrew J.; Donovan, Jenny L.; Tilling, Kate; Lane, J. Athene; Martin, Richard M.; Metcalfe, Chris] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Martin, Richard M.] Univ Bristol, NIHR Bristol Nutr Biomed Res Unit, Bristol, Avon, England. [Albertsen, Peter C.] Univ Connecticut, Ctr Hlth, Div Urol, Farmington, CT USA. [Bill-Axelson, Anna] Uppsala Univ, Inst Surg Sci, Dept Urol, Uppsala, Sweden. [Carter, H. Ballentine] Johns Hopkins Sch Med, Dept Urol, Baltimore, MA USA. [Bosch, J. L. H. Ruud] Univ Med Ctr Utrecht, Dept Urol, Utrecht, Netherlands. [Ferrucci, Luigi] NIA, NIH, Baltimore, MA USA. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Holmberg, Lars] Kings Coll London, Fac Life Sci & Med, London, England. [Holmberg, Lars] Reg Canc Ctr, Uppsala, Uppsala Orebro, Sweden. [Metter, E. Jeffrey] Univ Tennessee, Hlth Sci Ctr, Dept Neurol, Memphis, TN USA. [Neal, David E.] Univ Cambridge, Dept Oncol, Cambridge, England. [Parker, Christopher C.] Royal Marsden Hosp, Acad Urol Unit, Inst Canc Res, London, England. RP Simpkin, AJ (reprint author), Oakfield House,Oakfield Rd, Bristol BS8 2BN, Avon, England. EM andrew.simpkin@bristol.ac.uk OI Tilling, Kate/0000-0002-1010-8926 FU National Institute for Health Research (NIHR) Health Services and Delivery Research Programme [09/2000/63]; Medical Research Council [MR/L011824/1]; NIHR Health Services and Delivery Research programme [09/2000/63]; UK National Institute for Health Research, Health Technology Assessment Programme [HTA 96/20/99]; Cancer Research UK/UK Department of Health [C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064]; World Cancer Research Fund; University of Bristol Cancer Research Fund; National Cancer Research Institute; NIHR; University Hospitals Bristol NHS Foundation Trust; University of Bristol; Prostate Cancer Foundation; National Institute on Aging, National Institutes of Health, USA FX This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research Programme (project number 09/2000/63), published in full in the NIHR Journals Library [42]. Further information is available at http://www.journalslibrary.nihr.ac.uk/hsdr. This report presents independent research commissioned by the NIHR. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the Health Services and Delivery Research programme, NIHR, NHS or the Department of Health (UK).; Dr. Simpkin is funded by the Medical Research Council (MR/L011824/1) and previously by the NIHR Health Services and Delivery Research programme (project number 09/2000/63).; Professors Donovan, Hamdy and Neal are the Principal Investigators and Dr. Lane is the Trial Coordinator of the Prostate Testing for Cancer and Treatment (ProtecT) trial. Professors Martin, Donovan, Hamdy and Neal are the Principal Investigators of the Comparison Arm to ProtecT (CAP) trial. The ProtecT trial is funded by the UK National Institute for Health Research, Health Technology Assessment Programme (HTA 96/20/99) and the CAP trial by Cancer Research UK/UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326 and C18281/A15064). Funding for additional research has been received from the World Cancer Research Fund, the University of Bristol Cancer Research Fund and the National Cancer Research Institute (formed by the Department of Health, Medical Research Council and Cancer Research UK).; The NIHR Bristol Nutrition Biomedical Research Unit (RMM) is funded by the NIHR and is a partnership between the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Funding for the Johns Hopkins Hospital cohort was provided by the Prostate Cancer Foundation. The BLSA is funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 IS 6 BP 911 EP 918 DI 10.1111/bju.13422 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EC9QL UT WOS:000388479100016 PM 26799945 ER PT J AU Mai, PL Best, AF Peters, JA DeCastro, RM Khincha, PP Loud, JT Bremer, RC Rosenberg, PS Savage, SA AF Mai, Phuong L. Best, Ana F. Peters, June A. DeCastro, Rosamma M. Khincha, Payal P. Loud, Jennifer T. Bremer, Renee C. Rosenberg, Philip S. Savage, Sharon A. TI Risks of First and Subsequent Cancers Among TP53 Mutation Carriers in the National Cancer Institute Li-Fraumeni Syndrome Cohort SO CANCER LA English DT Article DE cumulative cancer risk; Li-Fraumeni syndrome; second cancer; second cancer risk; TP53 ID BREAST-CANCER; P53 MUTATIONS; GERMLINE MUTATIONS; FAMILIAL SYNDROME; GENE; SARCOMA; NEOPLASMS; CRITERIA; PANEL; SEX AB BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS: The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or >= 3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS: This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS: The cumulative cancer risk in TP53+ individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. (C) 2016 American Cancer Society. C1 [Mai, Phuong L.; Peters, June A.; DeCastro, Rosamma M.; Khincha, Payal P.; Loud, Jennifer T.; Bremer, Renee C.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 6E-456 MSC 9772, Rockville, MD 20850 USA. [Best, Ana F.; Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Rm 6E-456 MSC 9772, Rockville, MD 20850 USA. EM savagesh@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Supported by funding from the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 34 TC 1 Z9 1 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2016 VL 122 IS 23 BP 3673 EP 3681 DI 10.1002/cncr.30248 PG 9 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300015 PM 27496084 ER PT J AU Silver, MI Schiffman, M Fetterman, B Poitras, NE Gage, JC Wentzensen, N Lorey, T Kinney, WK Castle, PE AF Silver, Michelle I. Schiffman, Mark Fetterman, Barbara Poitras, Nancy E. Gage, Julia C. Wentzensen, Nicolas Lorey, Thomas Kinney, Walter K. Castle, Philip E. TI The Population Impact of Human Papillomavirus/Cytology Cervical Cotesting at 3-Year Intervals: Reduced Cervical Cancer Risk and Decreased Yield of Precancer per Screen SO CANCER LA English DT Article DE biopsy; cervical cancer; cervical intraepithelial neoplasia; colposcopy; cotest; human papillomavirus; screening ID FOLLOW-UP; HPV; PREVENTION; GUIDELINES; CYTOLOGY; DNA AB BACKGROUND: The objective of cervical screening is to detect and treat precancer to prevent cervical cancer mortality and morbidity while minimizing overtreatment of benign human papillomavirus (HPV) infections and related minor abnormalities. HPV/cytology cotesting at extended 5-year intervals currently is a recommended screening strategy in the United States, but the interval extension is controversial. In the current study, the authors examined the impact of a decade of an alternative, 3-year cotesting, on rates of precancer and cancer at Kaiser Permanente Northern California. The effect on screening efficiency, defined as numbers of cotests/colposcopy visits needed to detect a precancer, also was considered. METHODS: Two cohorts were defined. The "open cohort" included all women screened at least once during the study period; >1 million cotests were performed. In a fixed "long-term screening cohort," the authors considered the cumulative impact of repeated screening at 3-year intervals by restricting the cohort to women first cotested in 2003 through 2004 (ie, no women entering screening later were added to this group). RESULTS: Detection of cervical intraepithelial neoplasia 3/adenocarcinoma in situ (CIN3/AIS) increased in the open cohort (2004-2006: 82.0/100,000 women screened; 2007-2009: 140.6/100,000 women screened; and 2010-2012: 126.0/100,000 women screened); cancer diagnoses were unchanged. In the long-term screening cohort, the detection of CIN3/AIS increased and then decreased to the original level (20042006: 80.5/100,000 women screened; 2007-2009: 118.6/100,000 women screened; and 2010-2012: 84.9./100,000 women screened). The number of cancer diagnoses was found to decrease. When viewed in terms of screening efficiency, the number of colposcopies performed to detect a single case of CIN3/AIS increased in the cohort with repeat screening. CONCLUSIONS: Repeated cotesting at a 3-year interval eventually lowers population rates of precancer and cancer. However, a greater number of colposcopies are required to detect a single precancer. (C) 2016 American Cancer Society. C1 [Silver, Michelle I.; Schiffman, Mark; Gage, Julia C.; Wentzensen, Nicolas] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Kinney, Walter K.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Castle, Philip E.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Silver, MI (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E584, Bethesda, MD 20892 USA. EM michelle.silver@nih.gov FU Intramural Research Program at the National Cancer Institute; Kaiser Permanente Northern California FX Funding provided by a collaboration between the Intramural Research Program at the National Cancer Institute and Kaiser Permanente Northern California. NR 13 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2016 VL 122 IS 23 BP 3682 EP 3686 DI 10.1002/cncr.30277 PG 5 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300016 PM 27657992 ER PT J AU Kumar, P Thudium, E Laliberte, K Zaccardelli, D Nelsen, A AF Kumar, Parag Thudium, Emily Laliberte, Kevin Zaccardelli, David Nelsen, Andrew TI A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration SO CLINICAL PHARMACOKINETICS LA English DT Review ID PULMONARY-ARTERIAL-HYPERTENSION; CONTINUOUS SUBCUTANEOUS INFUSION; HEALTHY ADULT VOLUNTEERS; INHALED TREPROSTINIL; ORAL TREPROSTINIL; CONTROLLED-TRIAL; DIOLAMINE; THERAPY; BOSENTAN; EFFICACY AB Treprostinil is available in three different formulations and four different routes of administration: Remodulin(A (R)) (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso(A (R)) (treprostinil sodium, inhaled administration), and Orenitram(A (R)) (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). Pharmacokinetic studies have been performed in healthy volunteers and patients with PAH. The intent of this review is to outline pharmacokinetic considerations of the three treprostinil formulations and provide clinicians with a resource that may support clinical decisions in treating patients with PAH. C1 [Kumar, Parag; Thudium, Emily; Laliberte, Kevin; Zaccardelli, David; Nelsen, Andrew] United Therapeutics Corp, 55 TW Alexander Dr,POB 14186, Res Triangle Pk, NC 27709 USA. [Kumar, Parag] NIH, Clin Pharmacokinet Res Lab, Bldg 10, Bethesda, MD 20892 USA. RP Nelsen, A (reprint author), United Therapeutics Corp, 55 TW Alexander Dr,POB 14186, Res Triangle Pk, NC 27709 USA. EM ANelsen@unither.com NR 39 TC 0 Z9 0 U1 1 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD DEC PY 2016 VL 55 IS 12 BP 1495 EP 1505 DI 10.1007/s40262-016-0409-0 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC5IV UT WOS:000388169000002 PM 27286723 ER PT J AU Stoff, DM Colosi, D Rubtsova, A Wingood, G AF Stoff, David M. Colosi, Deborah Rubtsova, Anna Wingood, Gina TI HIV and Aging Research in Women: An Overview SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; Aging; Women; Women's Interagency HIV Study (WIHS); Aging/HIV definitions; Aging/HIV models ID OLDER-ADULTS; UNITED-STATES; COGNITIVE RESERVE; SOCIAL NETWORKS; INFECTION; HEALTH; POPULATION; HIV/AIDS; TIME; CARE AB This paper reviews some background issues as a foundation to place the ensuing supplement papers of this special issue section in context. The articles in this special supplement issue deepen and expand our understanding of biomedical, neurocognitive, and psychosocial aspects involved in human immunodeficiency virus (HIV) of older women, primarily through the use of the Women's Interagency HIV Study (WIHS) prospective cohort study. As it relates to research on the intersection between HIV and aging in women, we discuss (i) epidemiology as introduction, (ii) the cohort study design featuring the WIHS, (iii) definitions, (iv) models, and (v) section articles. C1 [Stoff, David M.; Colosi, Deborah] NIMH, Bethesda, MD 20892 USA. [Rubtsova, Anna] Emory Univ, Atlanta, GA 30322 USA. [Wingood, Gina] Columbia Univ, New York, NY USA. RP Stoff, DM (reprint author), NIMH, Bethesda, MD 20892 USA. EM dstoff@mail.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI); National Institute on Drug Abuse (NIDA); National Institute on Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Deafness and other Communication Disorders (NIDCD); NIH Office of Research on Women's Health FX Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS principal investigators are the following: UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Seble Kassaye), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; and Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I-WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). NR 59 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD DEC PY 2016 VL 13 IS 6 BP 383 EP 391 DI 10.1007/s11904-016-0338-4 PG 9 WC Infectious Diseases SC Infectious Diseases GA EC4TO UT WOS:000388127000009 PM 27771876 ER PT J AU Fraser, JL Venditti, CP AF Fraser, Jamie L. Venditti, Charles P. TI Methylmalonic and propionic acidemias: clinical management update SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE brain injury; liver transplantation; medical foods; methylmalonic acidemia; propionic acidemia ID DONOR LIVER-TRANSPLANTATION; TANDEM MASS-SPECTROMETRY; PERFORMANCE LIQUID-CHROMATOGRAPHY; CLASSICAL ORGANIC ACIDURIAS; COA CARBOXYLASE DEFICIENCY; COBALAMIN C DEFICIENCY; LONG-TERM MANAGEMENT; 10-YEAR FOLLOW-UP; COENZYME-A MUTASE; INBORN-ERRORS AB Purpose of review Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. Recent findings Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. Summary Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner. C1 [Fraser, Jamie L.] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Venditti, Charles P.] NHGRI, Med Genom & Metab Genet Branch, NIH, BG 10 RM 7N248A,10 Ctr Dr, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, BG 10 RM 7N248A,10 Ctr Dr, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov FU National Human Genome Research Institute; Child Health Research Career Development Award via Children's National Medical Center FX The work was supported by the Intramural Research Program of the National Human Genome Research Institute (CPV) and the Child Health Research Career Development Award (K12) via Children's National Medical Center (JLF). NR 239 TC 0 Z9 0 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD DEC PY 2016 VL 28 IS 6 BP 682 EP 693 DI 10.1097/MOP.0000000000000422 PG 12 WC Pediatrics SC Pediatrics GA EC0JF UT WOS:000387785900002 PM 27653704 ER PT J AU Alawad, AS Levy, C AF Alawad, Ahmad Samer Levy, Cynthia TI FXR Agonists: From Bench to Bedside, a Guide for Clinicians SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review ID FARNESOID-X-RECEPTOR; PRIMARY BILIARY-CIRRHOSIS; PLACEBO-CONTROLLED TRIAL; BILE-ACID; OBETICHOLIC ACID; NONALCOHOLIC STEATOHEPATITIS; NUCLEAR RECEPTOR; METABOLIC SYNDROME; SPONTANEOUS HEPATOCARCINOGENESIS; HEPATOCELLULAR-CARCINOMA C1 [Alawad, Ahmad Samer] Natl Inst Hlth, NIDDK Liver Dis Branch, 10 Ctr Dr,CRC Bldg 10,RM 4-5722, Bethesda, MD 20892 USA. [Levy, Cynthia] Univ Miami, Miller Sch Med, Div Hepatol, 1500 NW 12th Ave,Suite 1101, Miami, FL 33136 USA. RP Levy, C (reprint author), Univ Miami, Miller Sch Med, Div Hepatol, 1500 NW 12th Ave,Suite 1101, Miami, FL 33136 USA. EM clevy@med.miami.edu NR 49 TC 1 Z9 1 U1 3 U2 3 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 DEC PY 2016 VL 61 IS 12 BP 3395 EP 3404 DI 10.1007/s10620-016-4334-8 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC6DT UT WOS:000388227400007 PM 27734248 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 (vol 61, pg 2741, 2016) SO DIGESTIVE DISEASES AND SCIENCES LA English DT Correction ID HEPATOTOXICITY; SUPPLEMENTS C1 [Heidemann, Lauren A.; Fontana, Robert J.] Univ Michigan, Med Ctr, Dept Internal Med, 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 Med Ctr, Dept Med, New York, NY USA. [Hayashi, Paul H.] Univ N Carolina, Chapel Hill, NC USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Kleiner, David E.] Natl Canc Inst, Natl Inst Hlth, Pathol Lab, Bethesda, MD USA. RP Fontana, RJ (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu NR 5 TC 0 Z9 0 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 DEC PY 2016 VL 61 IS 12 BP 3638 EP 3638 DI 10.1007/s10620-016-4290-3 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC6DT UT WOS:000388227400039 PM 27714508 ER PT J AU Papadakis, GZ Holland, SM Quezado, M Patronas, NJ AF Papadakis, Georgios Z. Holland, Steven M. Quezado, Martha Patronas, Nicholas J. TI Adrenal cryptococcosis in an immunosuppressed patient showing intensely increased metabolic activity on F-18-FDG PET/CT SO ENDOCRINE LA English DT Article DE F-18-FDG PET/CT; Adrenal cryptococcosis; Primary adrenal insufficiency AB Disseminated cryptococcosis most commonly occurs in immunosuppressed patients and can rarely affect the adrenal glands. We report on a patient with biopsy proven bilateral adrenal cryptococcosis resulting in primary adrenal insufficiency, which was evaluated with whole-body positron emission tomography/computed tomography scan using F-18-FDG. Both enlarged adrenal glands presented intensely increased F-18-FDG activity in the periphery, while central necrotic regions were photopenic. Although diagnosis was established by adrenal gland biopsy, F-18-FDG positron emission tomography/computed tomography scan can significantly contribute to the assessment of disease activity and monitoring of treatment response. Furthermore, fungal infections should always be considered when encountering hypermetabolic adrenal masses, especially in the setting of immunodeficient patients. C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] NIH, Radiol & Imaging Sci Warren Grant Magnuson Clin C, Bldg 10, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Patronas, NJ (reprint author), NIH, Radiol & Imaging Sci Warren Grant Magnuson Clin C, Bldg 10, Bethesda, MD 20892 USA. EM NPatronas@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 3 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD DEC PY 2016 VL 54 IS 3 BP 834 EP 836 DI 10.1007/s12020-016-1040-4 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC5TA UT WOS:000388197900031 PM 27473097 ER PT J AU Murray, AJ Knight, NS Cole, MA Cochlin, LE Carter, E Tchabanenko, K Pichulik, T Gulston, MK Atherton, HJ Schroeder, MA Deacon, RMJ Kashiwaya, Y King, MT Pawlosky, R Rawlins, JNP Tyler, DJ Griffin, JL Robertson, J Veech, RL Clarke, K AF Murray, Andrew J. Knight, Nicholas S. Cole, Mark A. Cochlin, Lowri E. Carter, Emma Tchabanenko, Kirill Pichulik, Tica Gulston, Melanie K. Atherton, Helen J. Schroeder, Marie A. Deacon, Robert M. J. Kashiwaya, Yoshihiro King, M. Todd Pawlosky, Robert Rawlins, J. Nicholas P. Tyler, Damian J. Griffin, Julian L. Robertson, Jeremy Veech, Richard L. Clarke, Kieran TI Novel ketone diet enhances physical and cognitive performance SO FASEB JOURNAL LA English DT Article DE metabolism; muscle; energetics; exercise; heart ID BETA-HYDROXYBUTYRATE; UNCOUPLING PROTEINS; KETOGENIC DIET; HEART-FAILURE; ESTER DIET; RAT-HEART; (R)-3-HYDROXYBUTYL (R)-3-HYDROXYBUTYRATE; MITOCHONDRIAL BIOGENESIS; EXERCISE PERFORMANCE; MAGNETIC-RESONANCE AB Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [P-31]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance. C1 [Murray, Andrew J.; Knight, Nicholas S.; Cochlin, Lowri E.; Carter, Emma; Pichulik, Tica; Atherton, Helen J.; Schroeder, Marie A.; Tyler, Damian J.; Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Cole, Mark A.; Tchabanenko, Kirill; Robertson, Jeremy] Univ Oxford, Dept Chem, Oxford, England. [Deacon, Robert M. J.; Rawlins, J. Nicholas P.] Univ Oxford, Dept Expt Psychol, Oxford, England. [Murray, Andrew J.] Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3EG, England. [Gulston, Melanie K.; Griffin, Julian L.] Univ Cambridge, Dept Biochem, Cambridge, England. [Gulston, Melanie K.; Griffin, Julian L.] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge, England. [Kashiwaya, Yoshihiro; King, M. Todd; Pawlosky, Robert; Veech, Richard L.] NIAAA, Lab Metab Control, NIH, Rockville, MD 20852 USA. [Cole, Mark A.] Univ Nottingham, Fac Med & Hlth Sci, Nottingham, England. [Tchabanenko, Kirill] Queens Univ Belfast, Sch Chem & Chem Engn, Belfast, Antrim, North Ireland. RP Murray, AJ (reprint author), Univ Cambridge, Dept Physiol Dev & Neurosci, Downing St, Cambridge CB2 3EG, England. EM ajm267@cam.ac.uk FU Defense Advanced Research Projects Agency; Research Councils UK FX The authors thank Dr. Joseph Bielitsky, the late Dr. Catherine Golden, Dr. Brett Giroir, and Dr. Kerrie DeMarco (Defense Advanced Research Projects Agency, Arlington, VA, USA), whose constant support and advice made this study possible. A.J.M. thanks the Research Councils UK for supporting his Academic Fellowship. This work was supported by the Defense Advanced Research Projects Agency. The intellectual property covering the uses of ketone bodies and esters are owned by BTG, Ltd., the University of Oxford, and the U.S. National Institutes of Health. Should royalties ever accrue from these patents, A.J.M., R.L.V., M.T.K., and K.C., as named inventors, may receive a share of royalties as determined by the terms of the respective institutions. K.C. is director of T Delta S, Ltd., a company spun out of the University of Oxford to develop products on the basis of ketone ester nutrition. NR 67 TC 5 Z9 5 U1 30 U2 30 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD DEC PY 2016 VL 30 IS 12 BP 4021 EP 4032 DI 10.1096/fj.201600773R PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA EC5UG UT WOS:000388201500010 PM 27528626 ER PT J AU Goetzl, EJ Kapogiannis, D Schwartz, JB Lobach, IV Goetzl, L Abner, EL Jicha, GA Karydas, AM Boxer, A Miller, BL AF Goetzl, Edward J. Kapogiannis, Dimitrios Schwartz, Janice B. Lobach, Iryna V. Goetzl, Laura Abner, Erin L. Jicha, Gregory A. Karydas, Anna M. Boxer, Adam Miller, Bruce L. TI Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease SO FASEB JOURNAL LA English DT Article DE cognition; proteinopathy; neurotransmission; biomarkers ID CEREBROSPINAL-FLUID BIOMARKER; CLINICAL-TRIALS; BLOOD EXOSOMES; ADAS-COG; SYNAPTOPHYSIN; NEUROGRANIN; IDENTIFICATION; PLASTICITY; CRITERIA; DECLINE AB Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia inpatients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid beta-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias. C1 [Goetzl, Edward J.; Schwartz, Janice B.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Schwartz, Janice B.] Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94143 USA. [Lobach, Iryna V.] Univ Calif San Francisco, Clin Translat Sci Inst, San Francisco, CA 94143 USA. [Karydas, Anna M.; Boxer, Adam; Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Goetzl, Edward J.; Schwartz, Janice B.] Jewish Home San Francisco, San Francisco, CA USA. [Kapogiannis, Dimitrios] NIA, Lab Neurosci, Baltimore, MD 21224 USA. [Goetzl, Laura] Temple Univ, Dept Obstet Gynecol & Reprod Sci, Philadelphia, PA 19122 USA. [Abner, Erin L.; Jicha, Gregory A.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RP Goetzl, EJ (reprint author), Univ Calif San Francisco, Geriatr Res Ctr, 1719 Broderick St, San Francisco, CA 94115 USA. EM edward.goetzl@ucsf.edu FU BAND2 Program of the Michael J. Fox Foundation for Parkinson's Research; Alzheimer's Association; Weston Brain Institute (Toronto, ON, Canada); Nanosomix; Intramural Program of the U.S. National Institutes of Health, National Institute on Aging (NIA); NIA [P30 AG028383]; Acetylon; iPierian; Archer Biosciences; Alzheimer's Research UK FX The authors thank Sonya Anderson (University of Kentucky Alzheimer's Disease Center) for organizing and distributing biospecimens and Judith H. Goetzl (Jewish Home of San Francisco) for expert production of graphic illustrations. This work was supported by a grant from the BAND2 Program of the Michael J. Fox Foundation for Parkinson's Research, the Alzheimer's Association, Alzheimer's Research UK, and the Weston Brain Institute (Toronto, ON, Canada), by a grant for methodological development from Nanosomix (to E.J.G.), the Intramural Program of the U.S. National Institutes of Health, National Institute on Aging (NIA; to D.K.), and NIA Grant P30 AG028383 (to E.L.A.). E.J.G. has filed an application with the U.S. Patent Office for the platform and methodologies described in this report; he is a founder of Nanosomix, but now receives no salary or consulting fees, but only support for laboratory supplies. E.L.A. received travel support from Nanosomix for the 2015 annual meeting of the American Association for the Advancement of Science. A.B. declares that outside the submitted studies, he has grants from the NIA, Tau Research Consortium, Allon Therapeutics, Genentech, Bristol-Myers Squibb, TauRx, Alzheimer's Association, Bluefield Project to Cure FTD, the Association for Frontotemporal Degeneration, Alzheimer's Drug Discovery Foundation, EnVivo, C2N Diagnostics, Pfizer, Eli Lilly, and Corticobasal Degeneration Solutions; grants, personal fees, and nonfinancial support from Archer Biosciences; personal fees from Acetylon; and personal fees from iPierian. The remaining authors declare no conflicts of interest. NR 36 TC 0 Z9 0 U1 5 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD DEC PY 2016 VL 30 IS 12 BP 4141 EP 4148 DI 10.1096/fj.201600816R PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA EC5UG UT WOS:000388201500020 PM 27601437 ER PT J AU Rauzi, F Kirkby, NS Edin, ML Whiteford, J Zeldin, DC Mitchell, JA Warner, TD AF Rauzi, Francesca Kirkby, Nicholas S. Edin, Matthew L. Whiteford, James Zeldin, Darryl C. Mitchell, Jane A. Warner, Timothy D. TI Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1 SO FASEB JOURNAL LA English DT Article DE angiogenesis; eicosanoids; endothelium; prostaglandins ID ANGIOGENESIS; ACID; AGGREGOMETRY; METABOLITES; EXPRESSION; MECHANISM; VEGF; A(2) AB Regular consumption of low-dose aspirin reduces the occurrence of colorectal, esophageal, stomach, and gastrointestinal cancers. The underlying mechanism is unknown but may be linked to inhibition of angiogenesis. Because the effective doses of aspirin are consistent with the inhibition of cyclooxygenase-1 in platelets, we used liquid chromatography with tandem mass spectrometry analyses and immunoassays of human platelet releasates coupled with angiogenesis assays to search for the mediators of these effects. Blood or platelet-rich plasma from healthy volunteers stimulated with platelet activators produced a broad range of eicosanoids. Notably, preincubation of platelets with aspirin, but not with a P2Y12 receptor antagonist, caused a marked reduction in the production of 11-hydroxyeicosatetraenoic acid (HETE) and 15(S)-HETE, in addition to prostanoids such as thromboxane A(2). Releasates from activated platelets caused cell migration and tube formation in cultured human endothelial cells and stimulated the sprouting of rat aortic rings in culture. These proangiogenic effects were absent when platelets were treated with aspirin but returned by coincubation with exogenous 15(S)-HETE. These results reveal 15(S)-HETE as a major platelet cyclooxygenase-1 product with strong proangiogenic effects. Thus, 15(S)-HETE represents a potential target for the development of novel antiangiogenic therapeutics, and blockade of its production may provide a mechanism for the anticancer effects of aspirin. C1 [Rauzi, Francesca; Kirkby, Nicholas S.; Whiteford, James; Warner, Timothy D.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Kirkby, Nicholas S.; Mitchell, Jane A.] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Warner, TD (reprint author), Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England. EM t.d.warner@qmul.ac.uk FU Wellcome Trust [085255/Z/08/Z]; British Heart Foundation [FS/10/033/28271]; William Harvey Research Foundation; Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences [Z01-025034] FX This research was supported by the Wellcome Trust (Grant 085255/Z/08/Z), the British Heart Foundation (Grant FS/10/033/28271), the William Harvey Research Foundation, and the Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences (Grant Z01-025034). NR 26 TC 0 Z9 0 U1 3 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD DEC PY 2016 VL 30 IS 12 BP 4256 EP 4266 DI 10.1096/fj.201600530R PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA EC5UG UT WOS:000388201500030 PM 27633788 ER PT J AU Yang, F Ma, HW Belcher, J Butler, MR Redmond, TM Boye, SL Hauswirth, WW Ding, XQ AF Yang, Fan Ma, Hongwei Belcher, Joshua Butler, Michael R. Redmond, T. Michael Boye, Sanford L. Hauswirth, William W. Ding, Xi-Qin TI Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration SO FASEB JOURNAL LA English DT Article DE thyroid hormone; photoreceptor; cone degeneration; iopanoic acid ID THYROID-HORMONE RECEPTOR; ENDOPLASMIC-RETICULUM STRESS; CONE CELL-DEATH; TYPE-3 DEIODINASE; GENE DELIVERY; MOUSE MODEL; PHOTORECEPTOR DEGENERATION; CHANNEL DEFICIENCY; KNOCKOUT MOUSE; IN-VITRO AB Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65(-/-) mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management. C1 [Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R.; Ding, Xi-Qin] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, 940 Stanton L Young Blvd,BMSB 553, Oklahoma City, OK 73104 USA. [Butler, Michael R.] NEI, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL USA. [Hauswirth, William W.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. RP Ding, XQ (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, 940 Stanton L Young Blvd,BMSB 553, Oklahoma City, OK 73104 USA. EM xi-qin-ding@ouhsc.edu FU NIH NEI [P30EY021725, P30EY021721, T32EY023202, R01EY019490, R21EY024583]; Research to Prevent Blindness; Foundation Fighting Blindness; Knights Templar Eye Foundation FX The authors thank Dr. Anand Swaroop [U.S. National Institutes of Health (NIH) National Eye Institute (NEI)] for the Nrl-/- mouse line; Dr. P. Reed Larsen (Brigham and Women's Hospital Boston, MA, USA) for human DIO3 cDNA; Bruce Baretz (Lipoid LLC, Newark, NJ, USA) for phospholipon 90G; Dr. Cheryl Craft (The University of Southern California, Los Angeles, CA, USA) for anti-M-opsin and anti-cone arrestin antibodies; Dr. Muna Naash (University of Houston, Houston, TX, USA) for anti-S-opsin antibody; Dr. Robert Molday (University of British Columbia, Vancouver, BC, Canada) for mouse anti-rhodopsin antibody 1D4; and Imaging Core Facility of the Department of Cell Biology at the University of Oklahoma Health Sciences Center for technical assistance. This work was supported by NIH NEI Grants P30EY021725, P30EY021721, T32EY023202, R01EY019490, and R21EY024583; an unrestricted grant to the Department of Ophthalmology, University of Florida, from Research to Prevent Blindness; the Foundation Fighting Blindness; and the Knights Templar Eye Foundation. The authors declare no conflicts of interest. NR 67 TC 0 Z9 0 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD DEC PY 2016 VL 30 IS 12 BP 4313 EP 4325 DI 10.1096/fj.201600715R PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA EC5UG UT WOS:000388201500035 PM 27623928 ER PT J AU Prentoe, J Verhoye, L Moctezuma, RV Buysschaert, C Farhoudi, A Wang, R Alter, H Meuleman, P Bukh, J AF Prentoe, Jannick Verhoye, Lieven Moctezuma, Rodrigo Velazquez Buysschaert, Caroline Farhoudi, Ali Wang, Richard Alter, Harvey Meuleman, Philip Bukh, Jens TI HVR1-mediated antibody evasion of highly infectious in vivo adapted HCV in humanised mice SO GUT LA English DT Article ID HEPATITIS-C VIRUS; BROADLY NEUTRALIZING ANTIBODIES; CROSS-GENOTYPE NEUTRALIZATION; HUMORAL IMMUNE-RESPONSE; CELL-CULTURE-SYSTEMS; B TYPE-I; HUMAN LIVER; VACCINE; CHALLENGE; MUTATIONS AB Objective HCV is a major cause of chronic liver disease worldwide, but the role of neutralising antibodies (nAbs) in its natural history remains poorly defined. We analysed the in vivo role of hypervariable region 1 (HVR1) for HCV virion properties, including nAb susceptibility. Design Analysis of HCV from human liver chimeric mice infected with cell-culture-derived prototype genotype 2a recombinant J6/JFH1 or HVR1-deleted variant J6/JFH1(Delta HVR1) identified adaptive mutations, which were analysed by reverse genetics in Huh7.5 and CD81-deficient S29 cells. The increased in vivo genomic stability of the adapted viruses facilitated ex vivo density analysis by ultracentrifugation and in vivo neutralisation experiments addressing the role of HVR1. Results In vivo, J6/JFH1 and J6/JFH1(Delta HVR1) depended on single substitutions within amino acids 867-876 in non-structural protein, NS2. The identified A876P-substitution resulted in a 4.7-fold increase in genomic stability. In vitro, NS2 substitutions enhanced infectivity 5-10-fold by increasing virus assembly. Mouse-derived mJ6/JFH1(A876P) and mJ6/JFH1(Delta HVR1/A876P) viruses displayed similar heterogeneous densities of 1.02-1.1 g/mL. Human liver chimeric mice loaded with heterologous patient H (genotype 1a) immunoglobulin had partial protection against mJ6/JFH1(A876P) and complete protection against mJ6/JFH1(Delta HVR1/A876P). Interestingly, we identified a putative escape mutation, D476G, in mJ6/JFH1(A876P). This mutation in hypervariable region 2 conferred 6.6-fold resistance against H06 IgG in vitro. Conclusions The A876P-substitution bridges in vitro and in vivo studies using J6/JFH1-based recombinants. We provide the first in vivo evidence that HVR1 protects cross-genotype conserved HCV neutralisation epitopes, which advocates the possibility of using HVR1-deleted viruses as vaccine antigens to boost broadly reactive protective nAb responses. C1 [Prentoe, Jannick; Moctezuma, Rodrigo Velazquez; Bukh, Jens] Hvidovre Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis C Program CO HEP, Copenhagen, Denmark. [Prentoe, Jannick; Moctezuma, Rodrigo Velazquez; Bukh, Jens] Hvidovre Univ Hosp, Clin Res Ctr, Copenhagen, Denmark. [Prentoe, Jannick; Moctezuma, Rodrigo Velazquez; Bukh, Jens] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, Copenhagen, Denmark. [Verhoye, Lieven; Buysschaert, Caroline; Farhoudi, Ali; Meuleman, Philip] Univ Ghent, Ctr Vaccinol, Ghent, Belgium. [Wang, Richard; Alter, Harvey] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), Hvidovre Univ Hosp, Dept Infect Dis, 144,Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. EM jbukh@sund.ku.dk FU Faculty of Health and Medical Sciences, University of Copenhagen; Danish Council for Independent Research, Medical Sciences; Lundbeck Foundation; Novo Nordisk Foundation; Danish Council for Independent Research; Ghent University [01G01712]; Research Foundation-Flanders [G.0521.12N]; Belgian state [IUAP P7/47-HEPRO-2] FX This study was supported by Ph.D. stipends from Faculty of Health and Medical Sciences, University of Copenhagen (JP, RVM), an individual DFF-postdoctoral grant from the Danish Council for Independent Research, Medical Sciences (JP), and research grants from the Lundbeck Foundation (JP, JB), the Novo Nordisk Foundation (JB), the Danish Council for Independent Research, Medical Sciences (JB), and an advanced top researcher grant from the Danish Council for Independent Research (JB). Additional support was provided to PM by the Ghent University (Concerted Action Grant 01G01712), The Research Foundation-Flanders (Project G.0521.12N) and the Belgian state (IUAP P7/47-HEPRO-2). NR 48 TC 3 Z9 3 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD DEC PY 2016 VL 65 IS 12 BP 1988 EP 1997 DI 10.1136/gutjnl-2015-310300 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EC4MV UT WOS:000388106600010 PM 26589670 ER PT J AU Geiger, JL Bauman, JE Gibson, MK Gooding, WE Varadarajan, P Kotsakis, A Martin, D Gutkind, JS Hedberg, ML Grandis, JR Argiris, A AF Geiger, Jessica L. Bauman, Julie E. Gibson, Michael K. Gooding, William E. Varadarajan, Prakash Kotsakis, Athanasios Martin, Daniel Gutkind, Jorge Silvio Hedberg, Matthew L. Grandis, Jennifer R. Argiris, Athanassios TI Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE head and neck squamous cell carcinoma (HNSCC); everolimus; mammalian target of rapamycin (mTOR) inhibitors; PIK3CA mutations; clinical trial ID MAMMALIAN TARGET; CANCER STATISTICS; RANDOMIZED-TRIAL; RAPAMYCIN KINASE; CETUXIMAB; PREVALENCE; INHIBITOR; MORTALITY; ERLOTINIB AB Background. Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. Methods. This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. Results. Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. Conclusion. Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. (C) 2016 Wiley Periodicals, Inc. C1 [Geiger, Jessica L.; Bauman, Julie E.] Univ Pittsburgh, Div Hematol Oncol, Dept Internal Med, Pittsburgh, PA USA. [Gibson, Michael K.] Case Western Univ, Div Hematol Oncol, Dept Internal Med, Cleveland, OH USA. [Gooding, William E.] Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA USA. [Varadarajan, Prakash; Argiris, Athanassios] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol Oncol, San Antonio, TX 78229 USA. [Kotsakis, Athanasios] Univ Crete, Sch Med, Iraklion, Greece. [Martin, Daniel; Gutkind, Jorge Silvio] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Hedberg, Matthew L.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Grandis, Jennifer R.] Univ Calif San Francisco, Dept Otolaryngol, San Francisco, CA 94143 USA. [Argiris, Athanassios] Hygeia Hosp, Dept Med Oncol, Athens, Greece. RP Argiris, A (reprint author), Hygeia Hosp, Erythrou Stavrou 5, Athens 15123, Greece. EM athanassios.argiris@gmail.com FU University of Pittsburgh Cancer Institute [P30CA47904]; [F30CA180235]; [R01DE023685] FX Contract grant sponsor: Hedberg; contract grant number: F30CA180235; Grandis; contract grant number: R01DE023685; University of Pittsburgh Cancer Institute; contract grant number: P30CA47904. NR 27 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD DEC PY 2016 VL 38 IS 12 BP 1759 EP 1764 DI 10.1002/hed.24501 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EC8CI UT WOS:000388367400005 PM 27232378 ER PT J AU Kaess, BM Preis, SR Beiser, A Sawyer, DB Chen, TC Seshadri, S Vasan, RS AF Kaess, Bernhard M. Preis, Sarah R. Beiser, Alexa Sawyer, Douglas B. Chen, Tai C. Seshadri, Sudha Vasan, Ramachandran S. TI Circulating vascular endothelial growth factor and the risk of cardiovascular events SO HEART LA English DT Article ID CORONARY-HEART-DISEASE; ANGIOGENESIS; FRAMINGHAM; ATHEROSCLEROSIS; METAANALYSIS; RECEPTOR; THERAPY; BIOLOGY; PLASMA; MICE AB Objective To investigate the relation of circulating concentrations of vascular endothelial growth factor (VEGF) for the risk of developing cardiovascular disease (CVD) in a large community-based sample. Methods We prospectively assessed the relation of circulating VEGF concentrations with the incidence of CVD among 3041 Framingham Heart Study participants (mean age 63.4 +/- 11.1 years, 59% women). Multivariable Cox proportional hazards models were estimated adjusting for standard risk factors to VEGF quartiles to incident CVD. Restricted cubic splines were used to examine the linearity of the association. Results After a mean follow-up of 8.8 (+/- 2.8) years, 527 individuals experienced a first CVD event. Compared with participants in the first VEGF quartile, individuals in the second VEGF quartile had a 34% increased risk for future CVD (HR 1.34, 95% CI 1.03 to 1.74; p value=0.03) and individuals in third quartile had a 59% higher risk (HR 1.59; 95% CI 1.23 to 2.05, p value=0.0003). Individuals in the highest VEGF quartile had a similar cardiovascular risk as compared with those in the lowest VEGF quartile (HR 1.18, 95% CI 0.91 to 1.53, p value=0.21). Evaluation of restricted cubic splines confirmed the nonlinear, inverted U-shaped relation of serum VEGF and CVD events (p< 0.0001 for model fit, p=0.006 for non-linearity). Conclusions Circulating VEGF concentrations exhibit a complex non-linear (inverted U-shaped) relation with the risk of developing CVD events, with the lowest risk experienced at the lower and upper end of the distribution. The underlying pathophysiological mechanisms remain to be elucidated. C1 [Kaess, Bernhard M.; Preis, Sarah R.; Beiser, Alexa; Seshadri, Sudha; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kaess, Bernhard M.] Tech Univ, German Heart Ctr, Lazarettstr 36, D-80838 Munich, Germany. [Preis, Sarah R.; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Beiser, Alexa; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA USA. [Sawyer, Douglas B.] Maine Med Ctr, Cardiol Div, Portland, ME 04102 USA. [Chen, Tai C.] Boston Univ, Sch Med, Endocrinol Sect, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Sect Diabet, Boston, MA 02118 USA. [Chen, Tai C.] Boston Univ, Sch Med, Sect Nutr, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Kaess, BM (reprint author), Tech Univ, German Heart Ctr, Lazarettstr 36, D-80838 Munich, Germany. EM bernhard_kaess@gmx.de OI Beiser, Alexa/0000-0001-8551-7778 FU Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Heart, Lung, and Blood Institute [HL-077477, HL093029, HL-K24-04334]; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [AG031287]; [AG008122]; [AG033040] FX This work was supported by the Framingham Heart Study (contract nos N01-HC-25195 and HHSN268201500001I) and by grants from the National Heart, Lung, and Blood Institute (HL-077477, HL093029 and HL-K24-04334), the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (AG031287). SS, AB and SRP were also supported by AG008122 and AG033040. NR 23 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD DEC 1 PY 2016 VL 102 IS 23 BP 1898 EP 1901 DI 10.1136/heartjnl-2015-309155 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EC9VF UT WOS:000388491700012 PM 27354275 ER PT J AU Bornstein, MH Hahn, CS Putnick, DL AF Bornstein, Marc H. Hahn, Chun-Shin Putnick, Diane L. TI Stability of core language skill across the first decade of life in children at biological and social risk SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Language development; health risk; social risk ID COMMUNICATIVE DEVELOPMENT INVENTORIES; BEHAVIOR PROBLEMS; GRAMMATICAL DEVELOPMENT; EARLY-CHILDHOOD; VOCABULARY; SPEECH; AGE; INTELLIGENCE; ADOLESCENCE; ABILITY AB BackgroundCommand of language is a fundamental skill, a cornerstone of multiple cognitive and socioemotional aspects of development, and a necessary ingredient of successful adjustment and functioning in society. Little is known about the developmental stability of language in at-risk youth or which biological and social risk factors moderate stability. MethodsThis four-wave 10-year prospective longitudinal study evaluated stability of core language skill in 1,780 children in varying categories of biological and social risk in a multiage, multidomain, multimeasure, and multireporter framework. ResultsStructural equationmodeling supported loadings of diverse age-appropriate measures of child language on single latent variables of core language skill at 15 and 25months and 5 and 11years, respectively. Core language skill was stable over the first decade of life; significant and comparable stability coefficients were obtained for children with diverse biological and social risks, including poor health, welfare status, teen motherhood, ethnicity, gender, birth order, and families that changed in income and maternal education over the study period; stability in language was strong even accounting for child nonverbal intelligence and social competence, maternal education and language, and the family home environment. ConclusionsCore language skill varies in stability with age but is robustly stable in children regardless of multiple biological and social risk factors. C1 [Bornstein, Marc H.; Hahn, Chun-Shin; Putnick, Diane L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, NIH, Publ Hlth Serv, 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 NIH, NICHD FX This research was supported by the Intramural Research Program of the NIH, NICHD. The authors have declared that they have no competing or potential conflicts of interest. NR 84 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD DEC PY 2016 VL 57 IS 12 BP 1434 EP 1443 DI 10.1111/jcpp.12632 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA EC9YN UT WOS:000388500300011 PM 27605246 ER PT J AU Shaw, P AF Shaw, Philip TI Commentary: Mapping the young, resilient brain - reflections on Burt etal. (2016) SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Editorial Material DE Resilience; neuroanatomy; executive functions AB The resilience of many children in the face of adversity has long been a research focus. The study by Burt etal. delineates the neuroanatomy of resilience, using invivo magnetic resonance images acquired on 1,800 youth. They find that resilient youth had a larger right lateral prefrontal cortex compared to youth who either lacked resilience or did not experience adversity. The size of the right lateral prefrontal cortex was further associated with a likelihood of a maladaptive problem of alcohol use. These findings implicate high-order regulatory processes supported by the right lateral prefrontal cortex as pivotal in resilience. The study also sets the stage for exploring how neuroimaging data, combined with behavioral and genomic information might be used to assess treatment efficacy and identify children who need therapeutic interventions to boost their resilience. Read the full article at doi: C1 [Shaw, Philip] NHGRI, Neurobehav Clin Res Sect, Social & Behav Res Branch, Blgd 31,B1 B37, Bethesda, MD 20892 USA. [Shaw, Philip] NIH, Blgd 31,B1 B37, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NHGRI, Neurobehav Clin Res Sect, Social & Behav Res Branch, Blgd 31,B1 B37, Bethesda, MD 20892 USA.; Shaw, P (reprint author), NIH, Blgd 31,B1 B37, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov NR 9 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 57 IS 12 BP 1465 EP 1466 DI 10.1111/jcpp.12613 PG 2 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA EC9YN UT WOS:000388500300016 PM 27859344 ER PT J AU Similuk, M Rao, VK Churpek, J Lenardo, M AF Similuk, Morgan Rao, V. Koneti Churpek, Jane Lenardo, Michael TI Predispositions to Lymphoma: A Practical Review for Genetic Counselors SO JOURNAL OF GENETIC COUNSELING LA English DT Review DE Lymphoma; Heredity; Predisposition; Cancer; Mechanism; Genetic counseling; Risk assessment; Immunology ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; PRIMARY IMMUNODEFICIENCY DISEASES; EPSTEIN-BARR-VIRUS; HODGKIN-LYMPHOMA; CANCER-RISK; HEMATOLOGIC MALIGNANCIES; ATAXIA-TELANGIECTASIA; GERMLINE MUTATIONS; DOCK8 DEFICIENCY; PERSONAL CONTROL AB This review provides a synopsis for genetic counselors of the major concepts of lymphoma predisposition: genomic instability, immune deficiency, inappropriate lymphoproliferation, and chronic antigen stimulation. We discuss syndromes typifying each of these mechanisms. Importantly, our review of the genetic counseling literature reveals sparse discussion of genetically-based immune-mediated lymphoma predisposition, which we address in depth here. We aim to increase awareness among genetic counselors and colleagues in oncology about familial susceptibility and facilitate critical thinking about lymphoma risk assessment. Clinical application of this knowledge is aided by recommendations for collection of personal and family history to guide risk assessment and testing. Lastly, we include a special discussion of genetic counseling issues including perceptions of the context, nature, and magnitude of lymphoma risk, as well as coping with awareness of susceptibility to lymphoma. C1 [Similuk, Morgan; Rao, V. Koneti; Lenardo, Michael] NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. [Churpek, Jane] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. RP Similuk, M (reprint author), NIAID, NIH, 10 Ctr Dr,Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM morgan.similuk@nih.gov FU NIH, National Institute of Allergy and Infectious Disease FX This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease. Thank you to June Peters for her thoughtful review and input. NR 82 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD DEC PY 2016 VL 25 IS 6 BP 1157 EP 1170 DI 10.1007/s10897-016-9979-0 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EC5LP UT WOS:000388177100003 PM 27265405 ER PT J AU Mitchell, GF Hwang, SJ Larson, MG Hamburg, NM Benjamin, EJ Vasan, RS Levy, D Vita, JA AF Mitchell, Gary F. Hwang, Shih-Jen Larson, Martin G. Hamburg, Naomi M. Benjamin, Emelia J. Vasan, Ramachandran S. Levy, Daniel Vita, Joseph A. TI Transfer function-derived central pressure and cardiovascular disease events: the Framingham Heart Study Reply SO JOURNAL OF HYPERTENSION LA English DT Letter ID ARTERIAL STIFFNESS C1 [Mitchell, Gary F.] Cardiovasc Engn Inc, 1 Edge Water Dr,Suite 201, Norwood, MA 02062 USA. [Hwang, Shih-Jen; Larson, Martin G.; Vasan, Ramachandran S.; Levy, Daniel] NHLBIs Framingham Study, Framingham, MA USA. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Populat Sci Branch, Bethesda, MD USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hamburg, Naomi M.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Hamburg, Naomi M.; Benjamin, Emelia J.; Vasan, Ramachandran S.; Vita, Joseph A.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edge Water Dr,Suite 201, Norwood, MA 02062 USA. EM GaryFMitchell@mindspring.com NR 6 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 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD DEC PY 2016 VL 34 IS 12 BP 2489 EP 2490 DI 10.1097/HJH.0000000000001136 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EC0HM UT WOS:000387780100027 PM 27805916 ER PT J AU Choi, Y Abdelmegeed, MA Song, BJ AF Choi, Youngshim Abdelmegeed, Mohamed A. Song, Byoung-Joon TI Preventive effects of dietary walnuts on high-fat-induced hepatic fat accumulation, oxidative stress and apoptosis in mice SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Walnut; High-fat diet; Liver; CYP2E1; Oxidative stress; JNK; Apoptosis ID NITRIC-OXIDE SYNTHASE; INDUCED NONALCOHOLIC STEATOHEPATITIS; MITOCHONDRIAL RESPIRATORY-CHAIN; LIVER-DISEASE; HEPATOCYTE APOPTOSIS; CYTOCHROME-P450 2E1; LIPID-PEROXIDATION; INSULIN-RESISTANCE; MURINE STEATOHEPATITIS; ENDOTHELIAL FUNCTION AB We hypothesized that dietary walnut would prevent high-fat-diet (HFD)-induced hepatic apoptosis based on its antioxidant properties. Male C57BL/6J mice were fed a rodent chow or HFD (45% energy-derived)+/- walnuts (21.5% energy-derived) for 6 weeks. Liver histological and biochemical analyses revealed significantly elevated fat accumulation in mice fed HFD compared to mice fed the chow or HFD +/- walnuts. Walnut supplementation prevented HFD-mediated alteration of the levels of key proteins in lipid homeostasis such as Sirt1, AMPK and FAS, leading to decreased fat accumulation. In addition, walnut supplementation to HFD significantly decreased the hepatic levels of cytochrome P450-2E1, nitrated proteins and lipid peroxidation. Furthermore, walnut supplementation decreased the activated cell-death-associated p-JNK and p-p38K accompanied with increased hepatocyte apoptosis in HFD group. The beneficial effects of dietary walnut likely result, at least partially, from its antioxidant ingredients and attenuating HFD-induced hepatic steatosis, nitroxidative stress and apoptosis. Published by Elsevier Inc. C1 [Choi, Youngshim; Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism; KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program); Korea Research Institute of Bioscience and Biotechnology, Republic of Korea FX This work was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism and a grant to Youngshim Choi from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. We are thankful to Dr. Klaus Gawrisch for supporting this study. We also appreciate Dr. Carol Sloan at California Walnut Commission for providing fresh walnuts used for our experiments. NR 92 TC 0 Z9 0 U1 9 U2 9 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 DEC PY 2016 VL 38 BP 70 EP 80 DI 10.1016/j.jnutbio.2016.08.013 PG 11 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EC8ZG UT WOS:000388431000008 PM 27732911 ER EF