FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Larsson, HE Vehik, K Gesualdo, P Akolkar, B Hagopian, W Krischer, J Lernmark, A Rewers, M Simell, O She, JX Ziegler, A Haller, MJ AF Larsson, Helena Elding Vehik, Kendra Gesualdo, Patricia Akolkar, Beena Hagopian, William Krischer, Jeffery Lernmark, Ake Rewers, Marian Simell, Olli She, Jin-Xiong Ziegler, Anette Haller, Michael J. CA TEDDY Study Grp TI Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease SO PEDIATRIC DIABETES LA English DT Article DE TEDDY study; type 1 diabetes; follow-up studies; autoantibodies; diagnosis ID GLUTAMIC-ACID DECARBOXYLASE; YOUNG-CHILDREN; ENVIRONMENTAL DETERMINANTS; ISLET ANTIGEN-2; KETOACIDOSIS; RISK; MELLITUS; ONSET; AUTOANTIBODIES; ADOLESCENTS AB Objective The Environmental Determinants of Diabetes in the Young (TEDDY) study is designed to identify environmental exposures triggering islet autoimmunity and type 1 diabetes (T1D) in genetically high-risk children. We describe the first 100 participants diagnosed with T1D, hypothesizing that (i) they are diagnosed at an early stage of disease, (ii) a high proportion are diagnosed by an oral glucose tolerance test (OGTT), and (iii) risk for early T1D is related to country, population, human leukocyte antigen (HLA)-genotypes and immunological markers. Methods Autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2) and insulin (IAA) were analyzed from 3 months of age in children with genetic risk. Symptoms and laboratory values at diagnosis were obtained and reviewed for ADA criteria. Results The first 100 children to develop T1D, 33 first-degree relatives (FDRs), with a median age 2.3 yr (0.69-6.27), were diagnosed between September 2005 and November 2011. Although young, 36% had no symptoms and ketoacidosis was rare (8%). An OGTT diagnosed 9/30 (30%) children above 3 yr of age but only 4/70 (5.7%) below the age of 3 yr. FDRs had higher cumulative incidence than children from the general population (p < 0.0001). Appearance of all three autoantibodies at seroconversion was associated with the most rapid development of T1D (HR = 4.52, p = 0.014), followed by the combination of GADA and IAA (HR = 2.82, p < 0.0001). Conclusions Close follow-up of children with genetic risk enables early detection of T1D. Risk factors for rapid development of diabetes in this young population were FDR status and initial positivity for GADA, IA-2, and IAA or a combination of GADA and IAA. C1 [Larsson, Helena Elding; Lernmark, Ake] Lund Univ, Skane Univ Hosp SUS, Dept Clin Sci, Malmo, Sweden. [Vehik, Kendra; Krischer, Jeffery] Univ S Florida, Morsani Coll Med, Pediat Epidemiol Ctr, Tampa, FL USA. [Gesualdo, Patricia; Rewers, Marian] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Denver, CO 80202 USA. [Akolkar, Beena] NIDDK, Diabet Div, Bethesda, MD 20892 USA. [Hagopian, William] Pacific Northwest Diabet Res Inst, Washington, DC USA. [Simell, Olli] Univ Turku, Dept Pediat, Turku, Finland. [She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Ziegler, Anette] Helmholtz Zentrum Munchen, Inst Diabet Res, Neuherberg, Germany. [Ziegler, Anette] Forschergrp Diabet eV, Neuherberg, Germany. [Haller, Michael J.] Univ Florida, Dept Pediat, Gainesville, FL USA. RP Larsson, HE (reprint author), Skane Univ Hosp SUS, CRC 60 11,Waldenstroms Gata 35, S-20502 Malmo, Sweden. EM helena.larsson@med.lu.se RI Ziegler, Anette-Gabriele/M-4614-2014; OI Ziegler, Anette-Gabriele/0000-0002-6290-5548; Elding Larsson, Helena/0000-0003-3306-1742; Bonifacio, Ezio/0000-0002-8704-4713 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK 63829, 63861, 63821, 63865, 63863, 63836, 63790, UC4DK095300, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC) FX Funded by DK 63829, 63861, 63821, 63865, 63863, 63836, 63790 and UC4DK095300 and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). NR 23 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-543X EI 1399-5448 J9 PEDIATR DIABETES JI Pediatr. Diabetes PD MAR PY 2014 VL 15 IS 2 BP 118 EP 126 DI 10.1111/pedi.12066 PG 9 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AD2JF UT WOS:000333060300006 ER PT J AU Ma, GY Cao, YF Hu, CM Fang, ZZ Sun, XY Hong, M Zhu, ZT AF Ma, Guang-You Cao, Yun-Feng Hu, Cui-Min Fang, Zhong-Ze Sun, Xiao-Yu Hong, Mo Zhu, Zhi-Tu TI Comparison of Inhibition Capability of Scutellarein and Scutellarin Towards Important Liver UDP-Glucuronosyltransferase (UGT) Isoforms SO PHYTOTHERAPY RESEARCH LA English DT Article DE enzyme inhibition; UDP-glucuronosyltransferase (UGT); scutellarin; scutellarein ID HERB-DRUG INTERACTIONS; IDENTIFICATION; METABOLISM; BIOACTIVATION; 1A3 AB Scutellarin is an important bioactive flavonoid extracted from Erigeron breviscapus (Vant.) Hand-Mazz, and scutellarein is the corresponding aglycone of scutellarin. The present study aims to compare the inhibition potential of scutellarin and scutellarein towards several important UDP-glucuronosyltransferase (UGT) isoforms, including UGT1A1, UGT1A6, UGT1A9 and UGT2B7. It was demonstrated that scutellarein exerted stronger inhibition towards the tested UGT isoforms than scutellarin. Furthermore, the inhibition kinetic type and parameters (K-i) were determined for the scutellarein's inhibition towards these UGT isoforms. Competitive inhibition of scutellarein towards all these UGT isoforms was demonstrated, and the K-i values were calculated to be 0.02, 5.0, 5.8 and 35.9 mu M for UGT1A1, 1A6, 1A9 and 2B7, respectively. Using in vivo maximum plasma concentration of scutellarein in rat, the in vitro-in vivo extrapolation was performed to predict in vivo situation, indicating the most possible in vivo adverse effects due to the inhibition of scutellarein towards UGT1A1. All these results remind us to monitor the utilization of scutellarin and scutellarein, and the herbs containing these two components. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Ma, Guang-You; Hu, Cui-Min; Fang, Zhong-Ze; Zhu, Zhi-Tu] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. [Cao, Yun-Feng; Hu, Cui-Min; Fang, Zhong-Ze; Sun, Xiao-Yu; Hong, Mo] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Cao, Yun-Feng; Hu, Cui-Min; Fang, Zhong-Ze; Sun, Xiao-Yu; Hong, Mo] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Fang, Zhong-Ze] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhu, ZT (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. EM zhuzhitu@163.com FU Science and Technology Planning Project of Liaoning province [2011225015]; Project of Education Department of Liaoning Province [L2010277]; National Natural Science Foundation of China [81202586] FX This work was supported by the Science and Technology Planning Project of Liaoning province (No. 2011225015), Project of Education Department of Liaoning Province (No. L2010277) and National Natural Science Foundation of China (No. 81202586). NR 22 TC 7 Z9 7 U1 5 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-418X EI 1099-1573 J9 PHYTOTHER RES JI Phytother. Res. PD MAR PY 2014 VL 28 IS 3 BP 382 EP 386 DI 10.1002/ptr.4990 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AD1IQ UT WOS:000332988100006 PM 23620377 ER PT J AU Pepin, KM Spackman, E Brown, JD Pabilonia, KL Garber, LP Weaver, JT Kennedy, DA Patyk, KA Huyvaert, KP Miller, RS Franklin, AB Pedersen, K Bogich, TL Rohani, P Shriner, SA Webb, CT Riley, S AF Pepin, K. M. Spackman, E. Brown, J. D. Pabilonia, K. L. Garber, L. P. Weaver, J. T. Kennedy, D. A. Patyk, K. A. Huyvaert, K. P. Miller, R. S. Franklin, A. B. Pedersen, K. Bogich, T. L. Rohani, P. Shriner, S. A. Webb, C. T. Riley, S. TI Using quantitative disease dynamics as a tool for guiding response to avian influenza in poultry in the United States of America SO PREVENTIVE VETERINARY MEDICINE LA English DT Review DE Avian influenza; USA; Between-farm spread; Disease-dynamic model; Quantitative data; Poultry ID MALLARDS ANAS-PLATYRHYNCHOS; LIVE-BIRD MARKETS; MONTE-CARLO-SIMULATION; SWINE-FEVER EPIDEMICS; LOW-PATHOGENICITY; WILD BIRDS; A VIRUSES; ENVIRONMENTAL TRANSMISSION; BIOLOGIC CHARACTERIZATION; HETEROSUBTYPIC IMMUNITY AB Wild birds are the primary source of genetic diversity for influenza A viruses that eventually emerge in poultry and humans. Much progress has been made in the descriptive ecology of avian influenza viruses (AIVs), but contributions are less evident from quantitative studies (e.g., those including disease dynamic models). Transmission between host species, individuals and flocks has not been measured with sufficient accuracy to allow robust quantitative evaluation of alternate control protocols. We focused on the United States of America (USA) as a case study for determining the state of our quantitative knowledge of potential AIV emergence processes from wild hosts to poultry. We identified priorities for quantitative research that would build on existing tools for responding to AIV in poultry and concluded that the following knowledge gaps can be addressed with current empirical data: (1) quantification of the spatio-temporal relationships between AIV prevalence in wild hosts and poultry populations, (2) understanding how the structure of different poultry sectors impacts within-flock transmission, (3) determining mechanisms and rates of between-farm spread, and (4) validating current policy-decision tools with data. The modeling studies we recommend will improve our mechanistic understanding of potential AIV transmission patterns in USA poultry, leading to improved measures of accuracy and reduced uncertainty when evaluating alternative control strategies. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved. C1 [Pepin, K. M.; Webb, C. T.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Pepin, K. M.; Kennedy, D. A.; Bogich, T. L.; Rohani, P.; Webb, C. T.; Riley, S.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Spackman, E.] ARS, Southeast Poultry Res Lab, USDA, Athens, GA USA. [Brown, J. D.] Univ Georgia, Coll Vet Med, Dept Populat Hlth, Athens, GA USA. [Pabilonia, K. L.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Garber, L. P.; Weaver, J. T.; Patyk, K. A.; Miller, R. S.] Anim & Plant Hlth Inspect Serv, Ctr Epidemiol, USDA, Ft Collins, CO USA. [Garber, L. P.; Weaver, J. T.; Patyk, K. A.; Miller, R. S.] Anim & Plant Hlth Inspect Serv, Ctr Anim Hlth, USDA, Ft Collins, CO USA. [Kennedy, D. A.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, State Coll, PA USA. [Huyvaert, K. P.] Colorado State Univ, Warner Coll Nat Resources, Ft Collins, CO 80523 USA. [Franklin, A. B.; Pedersen, K.; Shriner, S. A.] Anim & Plant Hlth Inspect Serv, Natl Wildlife Res Ctr, USDA, Ft Collins, CO USA. [Bogich, T. L.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Rohani, P.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Riley, S.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London W2 1PG, England. RP Pepin, KM (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, Norfolk Pl, London W2 1PG, England. EM kimpepin@gmail.com; Erica.Spackman@ars.usda.gov; jubrown1@uga.edu; Kristy.Pabilonia@ColoState.edu; Lindsey.p.Garber@aphis.usda.gov; Todd.Weaver@aphis.usda.gov; dak30@psu.edu; Kelly.A.Patyk@aphis.usda.gov; kate.huyvaert@colostate.edu; Ryan.S.Miller@aphis.usda.gov; alan.b.franklin@aphis.usda.gov; Kerri.Pedersen@aphis.usda.gov; tiff.bogich@gmail.com; rohani@uga.edu; susan.a.shriner@aphis.usda.gov; Colleen.Webb@colostate.edu; s.riley@imperial.ac.uk RI Huyvaert, Kathryn/A-2710-2009; OI Huyvaert, Kathryn/0000-0003-3302-030X; Bogich, Tiffany/0000-0002-8143-5289; Shriner, Susan/0000-0003-0349-7182; Miller, Ryan/0000-0003-3892-0251 FU RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security; Fogarty International Center, NIH; Wellcome Trust [093488/Z/10/Z]; Medical Research Council (UK) [MR/J008761/1] FX Thanks to the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH for funding the workshop and this output. SR thanks The Wellcome Trust (093488/Z/10/Z) and The Medical Research Council (UK, MR/J008761/1) for support. Also, thanks to Kim Forde-Folle for providing expert opinion and helpful comments on the manuscript. NR 154 TC 2 Z9 2 U1 3 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 EI 1873-1716 J9 PREV VET MED JI Prev. Vet. Med. PD MAR 1 PY 2014 VL 113 IS 4 BP 376 EP 397 DI 10.1016/j.prevetmed.2013.11.011 PG 22 WC Veterinary Sciences SC Veterinary Sciences GA AC8UJ UT WOS:000332810300004 PM 24462191 ER PT J AU Pavletic, AJ Pao, M AF Pavletic, Adriana J. Pao, Maryland TI Popular Dietary Supplement Causes False-Positive Drug Screen for Amphetamines SO PSYCHOSOMATICS LA English DT Letter C1 [Pavletic, Adriana J.; Pao, Maryland] NIMH, Bethesda, MD 20892 USA. RP Pavletic, AJ (reprint author), NIMH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 5 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD MAR-APR PY 2014 VL 55 IS 2 BP 206 EP 207 PG 3 WC Psychiatry; Psychology SC Psychiatry; Psychology GA AD2SN UT WOS:000333085600015 PM 23932535 ER PT J AU Bosch-Marce, M Mohan, KV Gelderman, MP Ryan, PL Russek-Cohen, E Atreya, CD AF Bosch-Marce, Marta Mohan, Ketha V. K. Gelderman, Monique P. Ryan, Patricia L. Russek-Cohen, Estelle Atreya, Chintamani D. TI Preclinical safety evaluation of human platelets treated with antimicrobial peptides in severe combined immunodeficient mice SO TRANSFUSION LA English DT Article ID IN-VIVO RECOVERY; APHERESIS PLATELETS; MOUSE MODEL; BACTERIAL-CONTAMINATION; TRANSFUSION REACTIONS; FLOW-CYTOMETRY; RABBIT MODEL; EXPERIENCE; SURVIVAL; AGENTS AB BackgroundBacterial sepsis is a complication attributed to room temperature (RT)-stored platelets (PLTs) in transfusion medicine. Antimicrobial peptides (AMPs) are emerging as new therapeutic agents against microbes. We had previously demonstrated bactericidal activity of select synthetic AMPs against six types of bacteria in stored PLTs. In this report, we tested these AMPs for their potential antibody response and interference with the recovery and survival of human PLTs in an animal model. Study Design and MethodsTwo separate studies were conducted to evaluate the safety of the synthetic AMPs. 1) Two AMPs (PD3 and PD4), derived from thrombin-induced human PLT microbicidal protein, and four repeats of arginine-tryptophan (RW), containing two to five repeats (RW2-RW5), were tested in rabbits for potential antibody response. 2) RT-stored human PLTs treated for 2 hours with each of the six AMPs individually or with phosphate-buffered saline (PBS) alone were infused into severe combined immunodeficient (SCID) mice to evaluate their in vivo recovery and survival by flow cytometry. ResultsExcept for PD3, which showed a weak immune response, all other peptides did not induce any detectable antibodies in rabbits. Furthermore, all six AMPs tested did not significantly affect the in vivo recovery and survival of human PLTs in SCID mice compared to PBS alone-treated PLTs. ConclusionPreclinical evaluation studies reported here demonstrate that the selected AMPs used in the study did not adversely affect the human PLT recovery and survival in the SCID mouse model, suggesting further study of AMPs toward addressing the bacterial contamination of PLTs. C1 [Atreya, Chintamani D.] US FDA, Div Hematol, Sect Cell Biol, Lab Cellular Hematol, Bethesda, MD 20014 USA. US FDA, Ctr Biol Evaluat & Res, Div Biostat, Bethesda, MD 20014 USA. RP Atreya, CD (reprint author), Bldg 29A,Room 2C-11,NIH Campus, Bethesda, MD 20892 USA. EM chintamani.atreya@fda.hhs.gov FU Center for Biologics Evaluation and Research (CBER); U.S. Department of Energy; U.S. Food and Drug Administration FX MBM and PLR are recipients of a postdoctoral fellowship at the Center for Biologics Evaluation and Research (CBER) administered by the Oak Ridge Institute for Science and Education (ORISE) through an intraagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. We thank J.G. Vostal for allowing us to use his animal protocol for these studies. NR 34 TC 2 Z9 2 U1 1 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 MAR PY 2014 VL 54 IS 3 BP 569 EP 576 DI 10.1111/trf.12318 PG 8 WC Hematology SC Hematology GA AC4MC UT WOS:000332494400013 PM 23808572 ER PT J AU Jackman, RP Deng, X Bolgiano, D Utter, GH Schechterly, C Lebedeva, M Operskalski, E Luban, NL Alter, H Busch, MP Slichter, SJ Norris, PJ AF Jackman, Rachael P. Deng, Xutao Bolgiano, Douglas Utter, Garth H. Schechterly, Cathy Lebedeva, Mila Operskalski, Eva Luban, Naomi L. Alter, Harvey Busch, Michael P. Slichter, Sherrill J. Norris, Philip J. TI Leukoreduction and ultraviolet treatment reduce both the magnitude and the duration of the HLA antibody response SO TRANSFUSION LA English DT Article ID SICKLE-CELL-DISEASE; TRANSFUSION-TRANSMITTED VIRUSES; LEUKOCYTE ANTIGEN ANTIBODIES; VERSUS-HOST-DISEASE; PLATELET TRANSFUSION; BLOOD COMPONENTS; IMMUNE MODULATION; RANDOMIZED TRIAL; ALLOIMMUNIZATION; DONORS AB BackgroundBoth leukoreduction and ultraviolet (UV) light treatment of blood products have been shown to reduce the incidence of HLA antibody development in recipients, but the impact of these treatments on the magnitude and persistence of the antibody response is less clear. Study Design and MethodsLongitudinal samples from 319 subjects taken from four different study cohorts were evaluated for HLA antibodies to determine the effects of leukoreduction and UV treatment on HLA antibody generation and persistence. ResultsSubjects receiving leukoreduced or UV-treated blood products were less likely to generate Class I HLA antibodies, and those receiving leukoreduced blood were also less likely to generate Class II HLA antibodies. Among those receiving nonleukoreduced blood, 55% developed Class I HLA antibodies and 51% developed ClassII HLA antibodies compared with 28% (ClassI) and 15% (ClassII) for those receiving leukoreduced blood and 36% (ClassI) and 54% (ClassII) for those receiving UV-treated blood. Among alloimmunized subjects, leukoreduction resulted in a significant twofold reduction in the magnitude of ClassI HLA antibodies, and UV treatment resulted in a significant threefold reduction in the magnitude of ClassII HLA antibodies. Both treatments resulted in shorter persistence of ClassI HLA antibodies. ConclusionsThese data demonstrate that leukoreduction and UV treatment of blood products results not only in a reduction in the incidence of HLA antibody production, but also in lower and more transient HLA antibody levels among sensitized transfusion recipients. C1 Blood Syst Res Inst, San Francisco, CA 94118 USA. Puget Sound Blood Ctr, Seattle, WA 98104 USA. Univ Calif Davis, Davis, CA 95616 USA. NIH, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Washington, Sch Med, Seattle, WA USA. RP Jackman, RP (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM rjackman@bloodsystems.org OI Utter, Garth/0000-0001-7747-3429 FU NIH [R01 HL-095470, R01 HL-083388, U01 HL-42799, N01 HB-42972, RO1 HL-067229] FX This work was supported by NIH R01 HL-095470, NIH R01 HL-083388, NIH U01 HL-42799, NIH N01 HB-42972, and NIH RO1 HL-067229. NR 48 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD MAR PY 2014 VL 54 IS 3 BP 672 EP 680 DI 10.1111/trf.12317 PG 9 WC Hematology SC Hematology GA AC4MC UT WOS:000332494400026 PM 23808544 ER PT J AU Messina, JP Brady, OJ Scott, TW Zou, CT Pigott, DM Duda, KA Bhatt, S Katzelnick, L Howes, RE Battle, KE Simmons, CP Hay, SI AF Messina, Jane P. Brady, Oliver J. Scott, Thomas W. Zou, Chenting Pigott, David M. Duda, Kirsten A. Bhatt, Samir Katzelnick, Leah Howes, Rosalind E. Battle, Katherine E. Simmons, Cameron P. Hay, Simon I. TI Global spread of dengue virus types: mapping the 70 year history SO TRENDS IN MICROBIOLOGY LA English DT Review DE dengue; serotypes ID ARBOVIRAL INFECTIONS; HEMORRHAGIC-FEVER; SOUTHEASTERN SENEGAL; ANTIBODY-RESPONSE; YELLOW-FEVER; DISEASE; EMERGENCE; HUMANS; TRANSMISSION; AMERICA AB Since the first isolation of dengue virus (DENV) in 1943, four types have been identified. Global phenomena such as urbanization and international travel are key factors in facilitating the spread of dengue. Documenting the type-specific record of DENV spread has important implications for understanding patterns in dengue hyperendemicity and disease severity as well as vaccine design and deployment strategies. Existing studies have examined the spread of DENV types at regional or local scales, or described phylogeographic relationships within a single type. Here we summarize the global distribution of confirmed instances of each DENV type from 1943 to 2013 in a series of global maps. These show the worldwide expansion of the types, the expansion of disease hyperendemicity, and the establishment of an increasingly important infectious disease of global public health significance. C1 [Messina, Jane P.; Brady, Oliver J.; Zou, Chenting; Pigott, David M.; Duda, Kirsten A.; Bhatt, Samir; Howes, Rosalind E.; Battle, Katherine E.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Scott, Thomas W.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Katzelnick, Leah] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Simmons, Cameron P.] Univ Oxford, Hosp Trop Dis, Clin Res Unit, Ho Chi Minh City, Vietnam. [Simmons, Cameron P.] Univ Oxford, Churchill Hosp, Ctr Trop Med, Oxford OX3 7LJ, England. [Simmons, Cameron P.] Univ Melbourne, Nossal Inst Global Hlth, Parkville, Vic 3052, Australia. RP Messina, JP (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford OX1 3PS, England. EM jane.messina@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Simmons, Cameron P./0000-0002-9039-7392; Brady, Oliver/0000-0002-3235-2129; Battle, Katherine/0000-0003-2401-2615 FU Wellcome Trust [095066] NR 66 TC 79 Z9 84 U1 6 U2 65 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD MAR PY 2014 VL 22 IS 3 BP 138 EP 146 DI 10.1016/j.tim.2013.12.011 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AD0DP UT WOS:000332905000006 PM 24468533 ER PT J AU Desai, SA AF Desai, Sanjay A. TI Why do malaria parasites increase host erythrocyte permeability? SO TRENDS IN PARASITOLOGY LA English DT Review DE host-pathogen interactions; erythrocyte remodeling; parasite ion channels; nutrient acquisition; intracellular parasitism; antimalarial drug discovery; clag3 ID SURFACE ANION CHANNEL; RED-BLOOD-CELLS; FALCIPARUM-INFECTED ERYTHROCYTES; PATCH-CLAMP TECHNIQUES; X-RAY-MICROANALYSIS; PLASMODIUM-FALCIPARUM; NUTRIENT-UPTAKE; NUCLEOSIDE TRANSPORTER; INVITRO CULTURES; RHOPTRY PROTEIN AB Malaria parasites increase erythrocyte permeability to diverse solutes including anions, some cations, and organic solutes, as characterized with several independent methods. Over the past decade, patch-clamp studies have determined that the permeability results from one or more ion channels on the infected erythrocyte host membrane. However, the biological role(s) served by these channels, if any, remain controversial. Recent studies implicate the plasmodial surface anion channel (PSAC) and a role in parasite nutrient acquisition. A debated alternative role in remodeling host ion composition for the benefit of the parasite appears to be non-essential. Because both channel activity and the associated clag3 genes are strictly conserved in malaria parasites, channel-mediated permeability is an attractive target for development of new therapies. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX I thank N. Mita-Mendoza, K. Rayavara, and S. Spellicy for critical comments on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 90 TC 11 Z9 11 U1 0 U2 19 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 MAR PY 2014 VL 30 IS 3 BP 151 EP 159 DI 10.1016/j.pt.2014.01.003 PG 9 WC Parasitology SC Parasitology GA AD0DV UT WOS:000332905600007 PM 24507014 ER PT J AU Danilenko, DM Nambiar, PR Cesta, MF AF Danilenko, D. M. Nambiar, P. R. Cesta, M. F. TI A Brief Overview of the 32nd Annual STP Symposium on the Toxicologic Pathology of the Digestive Tract and Pancreas SO VETERINARY PATHOLOGY LA English DT Editorial Material DE digestive tract; tissue; toxicologic; gastrointestinal; disease process; other; digestive tract; tissue C1 [Danilenko, D. M.] Genentech Inc, San Francisco, CA 94080 USA. [Nambiar, P. R.] Pfizer Inc, Groton, CT 06340 USA. [Cesta, M. F.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Danilenko, DM (reprint author), Genentech Inc, Dept Safety Assessment, One DNA Way,MS 59, San Francisco, CA 94080 USA. EM ddanilen@gene.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2014 VL 51 IS 2 SI SI BP 541 EP 544 DI 10.1177/0300985813519133 PG 4 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA AC6DC UT WOS:000332610500021 PM 24442576 ER PT J AU Huang, QF Luo, Y Cheng, F Best, SM Bloom, ME Qiu, JM AF Huang, Qinfeng Luo, Yong Cheng, Fang Best, Sonja M. Bloom, Marshall E. Qiu, Jianming TI Molecular characterization of the small nonstructural proteins of parvovirus Aleutian mink disease virus (AMDV) during infection SO VIROLOGY LA English DT Article DE Parvovirus; Non-structural protein; DNA replication; Aleutian mink disease virus ID ANTIBODY-DEPENDENT ENHANCEMENT; PRE-MESSENGER-RNAS; MINUTE VIRUS; AUTONOMOUS PARVOVIRUS; TRANSCRIPTION MAP; MURINE CELLS; NS2; MICE; REPLICATION; DNA AB Aleutian mink disease virus (AMDV) is the only member in genus Amdovirus of the family Parvoviridae. During AMDV infection, six species of viral transcripts are generated from one precursor mRNA through alternative splicing and alternative polyadenylation. In addition to the large non-structural protein NS1, two small non-structural proteins, NS2 and NS3, are putatively encoded (Qiu J, et al., 2006. J. Virol. 80 654-662). However, these two proteins have not been experimentally demonstrated during virus infection, and nothing is known about their function. Here, we studied the nonstructural protein expression profile of AMDV, and for the first time, confirmed expression of NS2 and NS3 during infection, and identified their intracellular localization. More importantly, we provided evidence that both NS2 and NS3 are necessary for AMDV replication. (C) 2014 Elsevier Inc. All rights reserved. C1 [Huang, Qinfeng; Luo, Yong; Cheng, Fang; Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. [Best, Sonja M.; Bloom, Marshall E.] NIAID, Rocky Mt Lab, NIH, Virol Lab, Hamilton, MT 59840 USA. RP Qiu, JM (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66160 USA. EM jqiu@kumc.edu FU PHS from NIAID [R01 AI070723]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by PHS grant R01 AI070723 from NIAID. We thank all the members of the Qiu lab for valuable discussions. The work is supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 47 TC 9 Z9 14 U1 0 U2 24 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 MAR PY 2014 VL 452 BP 23 EP 31 DI 10.1016/j.virol.2014.01.005 PG 9 WC Virology SC Virology GA AD1NJ UT WOS:000333000400003 PM 24606679 ER PT J AU Yamamoto, T Ali, MA Liu, XQ Cohen, JI AF Yamamoto, Takenobu Ali, Mir A. Liu, XueQiao Cohen, Jeffrey I. TI Activation of H2AX and ATM in varicella-zoster virus (VZV)-infected cells is associated with expression of specific VZV genes SO VIROLOGY LA English DT Article DE Varicella-zoster virus; ATM; H2AX; DNA damage; Herpesvirus; Herpes simplex virus ID DNA-DAMAGE RESPONSE; LATENCY-ASSOCIATED PROTEIN; REPLICATION IN-VITRO; DOUBLE-STRAND BREAKS; BINDING PROTEIN; MRN COMPLEX; PHOSPHORYLATION; INFECTION; KINASE; TYPE-1 AB Mammalian cells activate DNA damage response pathways in response to virus infections. Activation of these pathways can enhance replication of many viruses, including herpesviruses. Activation of cellular ATM results in phosphorylation of H2AX and recruits proteins to sites of DNA damage. We found that varicella-zoster (VZV) infected cells had elevated levels of phosphorylated H2AX and phosphorylated ATM and that these levels increased in cells infected with VZV deleted for ORF61 or ORF63, but not deleted for ORF67. Expression of VZV ORF61, ORF62, or ORF63 alone did not result in phosphorylation of H2AX. While BGLF4, the Epstein-Barr virus homolog of VZV ORF47 protein kinase, phosphorylates H2AX and ATM, neither VZV ORF47 nor ORF66 protein kinase phosphorylated H2AX or ATM. Cells lacking ATM had no reduction in VZV replication. Thus, VZV induces phosphorylation of H2AX and ATM and this effect is associated with the presence of specific VZV genes in virus-infected cells. Published by Elsevier Inc. C1 [Yamamoto, Takenobu; Ali, Mir A.; Liu, XueQiao; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Bldg 50,Room 6134,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; Japan Herpesvirus Infection Forum (JHIF) Scholarship Award in Herpesvirus Infections Research FX This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. Takenobu Yamamoto was supported by a Japan Herpesvirus Infection Forum (JHIF) Scholarship Award in Herpesvirus Infections Research. We thank Drs. Paul Kinchington (University of Pittsburgh, Pittsburgh, PA) for antibody to VZV proteins, and Anthony Davis for help with Image J analysis software. NR 49 TC 4 Z9 4 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR PY 2014 VL 452 BP 52 EP 58 DI 10.1016/j.virol.2013.12.039 PG 7 WC Virology SC Virology GA AD1NJ UT WOS:000333000400006 PM 24606682 ER PT J AU Kastenmayer, RJ Maruri-Avidal, L Americo, JL Earl, PL Weisberg, AS Moss, B AF Kastenmayer, Robin J. Maruri-Avidal, Liliana Americo, Jeffrey L. Earl, Patricia L. Weisberg, Andrea S. Moss, Bernard TI Elimination of A-type inclusion formation enhances cowpox virus replication in mice: Implications for orthopoxvirus evolution SO VIROLOGY LA English DT Article DE Poxvirus pathogenicity; Cowpox virus inclusions; Respiratory virus infection ID MATURE VIRIONS; MAJOR PROTEIN; A27 PROTEINS; GENE; FUSION; RABBITPOX; COMPLEX; BODIES; BINDS; BODY AB Some orthopoxviruses including cowpox virus embed virus particles in dense bodies, comprised of the A-type inclusion (ATI) protein, which may provide long-term environmental protection. This strategy could be beneficial if the host population is sparse or spread is inefficient or indirect However, the formation of ATI may be neutral or disadvantageous for orthopoxviruses that rely on direct respiratory spread. Disrupted ATI open reading frames in orthopoxviruses such as variola virus, the agent of smallpox, and monkeypox virus suggests that loss of this feature provided positive selection. To test this hypothesis, we constructed cowpox virus mutants with deletion of the ATI gene or another gene required for embedding virions. The ATI deletion mutant caused greater weight loss and higher replication in the respiratory tract than control viruses, supporting our hypothesis. Deletion of the gene for embedding virions had a lesser effect, possibly due to known additional functions of the encoded protein. Published by Elsevier Inc. C1 [Kastenmayer, Robin J.; Maruri-Avidal, Liliana; Americo, Jeffrey L.; Earl, Patricia L.; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX We thank Catherine Cotter for help with cell culture and Linda Wyatt for discussions. Herman Meyer and David Pickup kindly provided CPXV_GER1991_3 and antibody to the ATI protein, respectively. The research was supported by the Division of Intramural Research, NIAID, NIH. NR 26 TC 2 Z9 2 U1 0 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 MAR PY 2014 VL 452 BP 59 EP 66 DI 10.1016/j.virol.2013.12.030 PG 8 WC Virology SC Virology GA AD1NJ UT WOS:000333000400007 PM 24606683 ER PT J AU Raiten, DJ Raghavan, R Porter, A Obbagy, JE Spahn, JM AF Raiten, Daniel J. Raghavan, Ramkripa Porter, Alexandra Obbagy, Julie E. Spahn, Joanne M. TI Executive summary: evaluating the evidence base to support the inclusion of infants and children from birth to 24 mo of age in the Dietary Guidelines for Americans - "the B-24 Project" SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop on Evaluating the Diet-Related Scientific Literature for Children from Birth to 24 Months - The B-24 Project CY FEB 05-07, 2013 CL Rockville, MD SP US Dept Hlth & Human Serv, Off Dis Prevent & Hlth Promot ID RANDOMIZED CONTROLLED-TRIAL; POOR LACTATION PERFORMANCE; FOOD-CONSUMPTION PATTERNS; IRON-DEFICIENCY ANEMIA; HUMAN-MILK COMPOSITION; BREAST-FED INFANTS; BODY-MASS INDEX; FEEDING INFANTS; US INFANTS; VITAMIN-D AB The Dietary Guidelines for Americans (DGA) are the cornerstone of US government efforts to promote health and prevent disease through diet and nutrition. The DGA currently provides guidelines for ages >= 2 y. In an effort to determine the strength of the evidence to support the inclusion of infants and children from birth to age 24 mo, the partner agencies led by the Department of Health and Human Services Office of Disease Prevention and Health Promotion and the USDA Center for Nutrition Program and Policy initiated the project entitled "Evaluating the evidence base to support the inclusion of infants and children from birth to 24 months of age in the Dietary Guidelines for Americans-the B-24 Project." This project represents the first step in the process of applying systematic reviews to the process of deciding whether the evidence is sufficient to include this age group in future editions of the DGA. This supplement includes the B-24 Executive Summary, which describes the B-24 Project and the deliberations of the 4 working groups during the process of developing priority topics for the systematic review, and a research agenda to address the critical gaps. Also included in this supplement issue is an article on the Nutrition Evidence Library methodology for developing systematic review questions and articles from the invited content presenters at the B-24 Prime meeting. C1 [Raiten, Daniel J.; Raghavan, Ramkripa; Porter, Alexandra] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Obbagy, Julie E.; Spahn, Joanne M.] USDA, Ctr Nutr Policy & Promot, Evidence Anal Lib Div, Alexandria, VA USA. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov NR 153 TC 19 Z9 19 U1 5 U2 22 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 MAR PY 2014 VL 99 IS 3 SU S BP 663S EP 691S DI 10.3945/ajcn.113.072140 PG 29 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AB9VO UT WOS:000332144000001 PM 24500158 ER PT J AU Eltoukhi, HM Modi, MN Weston, M Armstrong, AY Stewart, EA AF Eltoukhi, Heba M. Modi, Monica N. Weston, Meredith Armstrong, Alicia Y. Stewart, Elizabeth A. TI The health disparities of uterine fibroid tumors for African American women: a public health issue SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE disparity; hysterectomy; leiomyoma; Patient Protection and Affordable Care Act; uterine fibroid tumor ID UNITED-STATES; ABDOMINAL MYOMECTOMY; RACIAL-DIFFERENCES; WHITE WOMEN; LEIOMYOMATA; RISK; HYSTERECTOMY; OUTCOMES; PREGNANCIES; PREDISPOSITION AB Uterine fibroid tumors (leiomyomas) are the most common benign pelvic tumors in women and are the major indication for hysterectomy. Fibroid tumors are more common and more severe among African American women. Although this disease disproportionately affects the African American population, we understand little about what causes the disparity. Fibroid tumors should be considered a public health issue, given the magnitude of the problem and the costs of health care for this disease. In this review, we examine the burden of disease from fibroid tumors in the African American population and review the natural history, diagnosis, and treatment of uterine fibroid tumors, with emphasis on how these can differ, depending on race. We also focus on the socioeconomic burden caused by the disease and describe the anticipated influence of new health care reforms and funding mechanisms for fibroid tumor research. C1 [Eltoukhi, Heba M.; Modi, Monica N.; Armstrong, Alicia Y.] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Eltoukhi, Heba M.] Suez Canal Univ, Fac Med, Dept Obstet & Gynecol, Ismailia, Egypt. [Weston, Meredith] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Stewart, Elizabeth A.] Mayo Clin, Div Reprod Endocrinol & Infertil, Rochester, MN 55905 USA. RP Stewart, EA (reprint author), Mayo Clin, Div Reprod Endocrinol & Infertil, 200 First St SW, Rochester, MN 55905 USA. EM stewart.elizabeth@mayo.edu FU National Institutes of Health [R01060503] FX Supported in part by grant R01060503 (E.A.S.) from the National Institutes of Health. NR 55 TC 19 Z9 19 U1 1 U2 6 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 MAR PY 2014 VL 210 IS 3 BP 194 EP 199 DI 10.1016/j.ajog.2013.08.008 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AC3FV UT WOS:000332402000003 PM 23942040 ER PT J AU Ahrens, K Mumford, SL Schliep, KC Kissell, KA Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Ahrens, Katherine Mumford, Sunni L. Schliep, Karen C. Kissell, Kerri A. Perkins, Neil J. Wactawski-Wende, Jean Schisterman, Enrique F. TI Serum leptin levels and reproductive function during the menstrual cycle SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE anovulation; leptin; menstrual cycle; reproductive hormone ID NORMAL-WEIGHT WOMEN; LUTEINIZING-HORMONE; HYPOTHALAMIC AMENORRHEA; CIRCULATING LEPTIN; GENE-EXPRESSION; CORPUS-LUTEUM; ESTROUS-CYCLE; PLASMA LEPTIN; RAT OVARY; PREGNANCY AB OBJECTIVE: The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation. STUDY DESIGN: The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for <= 2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured <= 8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age. RESULTS: Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22). CONCLUSION: The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility. C1 [Ahrens, Katherine; Mumford, Sunni L.; Schliep, Karen C.; Kissell, Kerri A.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH,DHHS, Bethesda, MD 20892 USA. [Kissell, Kerri A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD 20892 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, MSC 7510,6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts number HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). NR 53 TC 1 Z9 1 U1 0 U2 12 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 MAR PY 2014 VL 210 IS 3 AR 248.e1 DI 10.1016/j.ajog.2013.11.009 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AC3FV UT WOS:000332402000021 PM 24215851 ER PT J AU Luchman, HA Villemaire, ML Bismar, TA Carlson, BA Jirik, FR AF Luchman, H. Artee Villemaire, Michelle L. Bismar, Tarek A. Carlson, Bradley A. Jirik, Frank R. TI Prostate Epithelium-Specific Deletion of the Selenocysteine tRNA Gene Trsp Leads to Early Onset Intraepithelial Neoplasia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID OXIDATIVE STRESS; CANCER PREVENTION; SELENOPROTEIN-P; SELENIUM; POLYMORPHISMS; APOPTOSIS; RISK; CARCINOGENESIS; EXPRESSION; ENZYMES AB Although various lines of evidence suggest that oxidative stress plays a rote in human prostate cancer initiation and progression, there is a paucity of direct evidence for its role in tumor initiation. To begin to address this issue, we developed a novel tumorigenesis model by reducing the expression of multiple selenoproteins (SPs) in mouse prostatic epithelium. This was accomplished via the prostate-specific deletion of Trsp, a gene that encodes a transfer RNA (Sec tRNA) required for the insertion of selenocysteine residues into SPs during their translation. By 6 weeks of age, Trsp-deficient mice exhibited widespread prostatic intraepithelial neoplasia lesions in all prostatic lobes, which then progressed to high-grade dysplasia and microinvasive carcinoma by 24 weeks. In contrast to other murine prostate cancer models, Trsp-deficient mice required neither the deletion of a tumor suppressor nor the transgenic introduction of an oncogene for prostatic intraepithelial neoplasia lesion development. In keeping with the antioxidant functions of several SPs, we found increases in lipid peroxidation markers in Trsp-deficient epithelial cells. This novel model of prostate neoplasia provides evidence for the existence of a selenoprotein or selenoproteins capable of acting as a tumor suppressor in the murine prostate. C1 [Luchman, H. Artee] McCaig Inst Bone & Joint Hlth, Fac Med, Hotchkiss Brain Inst, Calgary, AB, Canada. [Luchman, H. Artee] McCaig Inst Bone & Joint Hlth, Fac Med, Dept Cell Biol & Anat, Calgary, AB, Canada. [Villemaire, Michelle L.; Jirik, Frank R.] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Bismar, Tarek A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada. [Bismar, Tarek A.] Univ Calgary, Dept Biochem, Calgary, AB, Canada. [Bismar, Tarek A.] Calgary Lab Serv, Calgary, AB, Canada. [Carlson, Bradley A.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD USA. RP Jirik, FR (reprint author), 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jirik@ucalgary.ca FU Alberta Cancer Foundation, Alberta Innovates-Health Solutions; Canada Research Chairs award FX Supported by a grant from the Alberta Cancer Foundation, Alberta Innovates-Health Solutions (F.R.J.). F.R.J. was the recipient of a Canada Research Chairs award. NR 35 TC 5 Z9 5 U1 0 U2 4 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 MAR PY 2014 VL 184 IS 3 BP 871 EP 877 DI 10.1016/j.ajpath.2013.11.025 PG 7 WC Pathology SC Pathology GA AB8QQ UT WOS:000332055500027 PM 24447801 ER PT J AU de Vega, S Suzuki, N Nonaka, R Sasaki, T Forcinito, P Arikawa-Hirasawa, E Yamada, Y AF de Vega, Susana Suzuki, Nobuharu Nonaka, Risa Sasaki, Takako Forcinito, Patricia Arikawa-Hirasawa, Eri Yamada, Yoshihiko TI A C-terminal fragment of fibulin-7 interacts with endothelial cells and inhibits their tube formation in culture SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Fibulin-7 fragment; Endothelial cells; Angiogenesis ID BASEMENT-MEMBRANE; TUMOR-GROWTH; CYTOSKELETAL DYNAMICS; ENDOGENOUS INHIBITOR; EXTRACELLULAR-MATRIX; FOCAL ADHESIONS; ANGIOGENESIS; BINDING; ANGIOSTATIN; ENDOSTATIN AB We have previously demonstrated that fibulin-7 (Fbln7) is expressed in teeth by pre-odontoblast and odontoblast cells, localized in the basement membrane and dentin matrices, and is an adhesion molecule for dental mesenchyme cells and odontoblasts. Fbln7 is also expressed in blood vessels by endothelial cells. In this report, we show that a recombinant C-terminal Fbln7 fragment (Fbln7-C) bound to Human Umbilical Vein Endothelial Cells (HUVECs) but did not promote cell spreading and actin stress fiber formation. Fbln7-C binding to HUVECs induced integrin clustering at cell adhesion sites with other focal adhesion molecules, and sustained activation of PAK, p130Cas, and Ran. In addition, RhoA activation was inhibited, thereby preventing HUVEC spreading. As endothelial cell spreading is an important step for angiogenesis, we examined the effect of Fbln7-C on angiogenesis using in vitro assays for endothelial cell tube formation and vessel sprouting from aortic rings. We found that Fbln7-C inhibited the HUVEC tube formation and the vessel sprouting in aortic ring assays. Our findings suggest potential anti-angiogenic activity of the Fbln7 C-terminal region. Published by Elsevier Inc. C1 [de Vega, Susana; Suzuki, Nobuharu; Forcinito, Patricia; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [de Vega, Susana; Nonaka, Risa; Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Res Inst Dis Old Age, Tokyo 1138421, Japan. [Suzuki, Nobuharu] Tokyo Med & Dent Univ, Grad Sch Hlth Care Sci, Dept Biochem & Biophys, Tokyo 1138510, Japan. [Sasaki, Takako] Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Dept Expt Med, D-91054 Erlangen, Germany. RP Yamada, Y (reprint author), NIDCR, NIH, Bldg 30,Rm 407,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov FU NIDCR, NIH, USA; Ministry of Education, Culture, Sports, Science and Technology (MEXT) FX We thank Deborah Philp and Vira Artym for their valuable suggestions, and Kenneth Yamada for the beta1 integrin antibody. This work was supported by the Intramural Research Program of the NIDCR, NIH, USA (Y.Y.) and by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) supported program for the Strategic Research Foundation at private universities 2011-2015 in Japan (E.A.-H. and S.V.). NR 33 TC 2 Z9 2 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAR 1 PY 2014 VL 545 BP 148 EP 153 DI 10.1016/j.abb.2014.01.013 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AC7ZB UT WOS:000332751700018 PM 24480309 ER PT J AU Harris, EA Fletcher, OJ Anderson, KE Petitte, JN Kopelovich, L Mozdziak, PE AF Harris, Elizabeth A. Fletcher, Oscar J. Anderson, Kenneth E. Petitte, James N. Kopelovich, Levy Mozdziak, Paul E. TI Epithelial Cell Tumors of the Hen Reproductive Tract SO AVIAN DISEASES LA English DT Article DE hen; egg-laying; cancer; oviductal; ovarian; malignancy ID OVARIAN-CANCER; LAYING HENS; MODEL; EXPRESSION; ADENOCARCINOMAS; CARCINOMA AB There is a paucity of preclinical models that simulate the development of ovarian tumors in humans. At present, the egg-laying hen appears to be the most promising model to study the spontaneous occurrence of ovarian tumors in the clinical setting. Although gross classification and histologic grade of tumors have been used prognostically in women with ovarian tumors, there is currently no single system that is universally used to classify reproductive tumors in the hen. Four hundred and one 192-wk-old egg-laying hens were necropsied to determine the incidence of reproductive tumors using both gross pathology and histologic classification. Gross pathologic classifications were designated as follows: birds presenting with ovarian tumors only (class 1), those presenting with oviductal and ovarian tumors (class 2), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract (class 3), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract and other distant organs (class 4), those with oviductal tumors only (class 5), those with oviductal tumors that metastasized to other organs with no ovarian involvement (class 6), and those with ovarian tumors that metastasized to other organs with no oviductal involvement (class 7), including birds with gastrointestinal tumors and no reproductive involvement (GI only) and those with no tumors (normal). Histopathologic classifications range from grades 1 to 3 and are based on mitotic developments and cellular differentiation. An updated gross pathology and histologic classification systems for the hen reproductive malignancies provides a method to report the range of reproductive tumors revealed in a flock of aged laying hens. C1 [Harris, Elizabeth A.; Mozdziak, Paul E.] N Carolina State Univ, Physiol Grad Program, Raleigh, NC 27695 USA. [Fletcher, Oscar J.] N Carolina State Univ, Dept Populat Hlth & Pathobiol, Coll Vet Med, Raleigh, NC 27695 USA. [Anderson, Kenneth E.; Petitte, James N.] N Carolina State Univ, Prestage Dept Poultry Sci, Raleigh, NC 27695 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Mozdziak, PE (reprint author), N Carolina State Univ, Physiol Grad Program, Campus Box 7608,134 Scott Hall, Raleigh, NC 27695 USA. EM pemozdzi@unity.ncsu.edu NR 16 TC 0 Z9 0 U1 1 U2 5 PU AMER ASSOC AVIAN PATHOLOGISTS PI ATHENS PA 953 COLLEGE STATION RD, ATHENS, GA 30602-4875 USA SN 0005-2086 EI 1938-4351 J9 AVIAN DIS JI Avian Dis. PD MAR PY 2014 VL 58 IS 1 BP 95 EP 101 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA AD5FF UT WOS:000333276600015 PM 24758120 ER PT J AU Mueller, E AF Mueller, Elisabetta TI Understanding the variegation of fat: Novel regulators of adipocyte differentiation and fat tissue biology SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE White adipose depots; Transcriptional regulators; Brown fat; Brite/beige fat cells; PPARgamma; White fat browning ID BROWN ADIPOSE-TISSUE; ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; WHITE FAT; TRANSCRIPTIONAL COACTIVATOR; GENE-EXPRESSION; ADAPTIVE THERMOGENESIS; INSULIN SENSITIVITY; ADULT HUMANS; ADIPOGENESIS AB The differentiation of uncommitted cells into specialized adipocytes occurs through a cascade of transcriptional events culminating in the induction and activation of the nuclear receptor PPAR gamma, the central coordinator of fat cell function. Since the discovery of PPAR gamma, two decades ago, our views of how this molecule is activated have been significantly refined. Beyond the cell, we also now know that diverse signals and regulators control PPAR gamma function in a fat-depot specific manner. The goal of this article is to review the latest in our understanding of the early and late transcriptional events that regulate adipocyte development and their potential impact on energy storage and expenditure in different fat depots. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. (C) 2013 The Author. Published by Elsevier B.V. All rights reserved. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mueller, E (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM elisabettam@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX I would like to thank Pasha Sarraf for reading the manuscript. The research performed in the laboratory of Elisabetta Mueller was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 61 TC 9 Z9 12 U1 4 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD MAR PY 2014 VL 1842 IS 3 SI SI BP 352 EP 357 DI 10.1016/j.bbadis.2013.05.031 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AB3EM UT WOS:000331674100003 PM 23735215 ER PT J AU Bonifaci, N Colas, E Serra-Musach, J Karbalai, N Brunet, J Gomez, A Esteller, M Fernandez-Taboada, E Berenguer, A Reventos, J Muller-Myhsok, B Amundadottir, L Duell, EJ Pujana, MA AF Bonifaci, Nuria Colas, Eva Serra-Musach, Jordi Karbalai, Nazanin Brunet, Joan Gomez, Antonio Esteller, Manel Fernandez-Taboada, Enrique Berenguer, Antoni Reventos, Jaume Mueller-Myhsok, Bertram Amundadottir, Laufey Duell, Eric J. Angel Pujana, Miquel TI Integrating gene expression and epidemiological data for the discovery of genetic interactions associated with cancer risk SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; PANCREATIC-CANCER; PROTEIN LPP; SUSCEPTIBILITY; CELL; NETWORKS; RECONSTRUCTION; TRANSCRIPTION; EPISTASIS AB Dozens of common genetic variants associated with cancer risk have been identified through genome-wide association studies (GWASs). However, these variants only explain a modest fraction of the heritability of disease. The missing heritability has been attributed to several factors, among them the existence of genetic interactions (G G). Systematic screens for G G in model organisms have revealed their fundamental influence in complex phenotypes. In this scenario, G G overlap significantly with other types of gene and/or protein relationships. Here, by integrating predicted G G from GWAS data and complex- and context-defined gene coexpression profiles, we provide evidence for G G associated with cancer risk. G G predicted from a breast cancer GWAS dataset identified significant overlaps [relative enrichments (REs) of 836%, empirical P values < 0.05 to 10(4)] with complex (non-linear) gene coexpression in breast tumors. The use of gene or protein data not specific for breast cancer did not reveal overlaps. According to the predicted G G, experimental assays demonstrated functional interplay between lipoma-preferred partner and transforming growth factor- signaling in the MCF10A non-tumorigenic mammary epithelial cell model. Next, integration of pancreatic tumor gene expression profiles with pancreatic cancer G G predicted from a GWAS corroborated the observations made for breast cancer risk (REs of 2559%). The method presented here can potentially support the identification of genetic interactions associated with cancer risk, providing novel mechanistic hypotheses for carcinogenesis. C1 [Bonifaci, Nuria; Serra-Musach, Jordi; Fernandez-Taboada, Enrique; Angel Pujana, Miquel] Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Translat Res Lab, Breast Canc & Syst Biol Unit, Barcelona 08908, Catalonia, Spain. [Colas, Eva; Reventos, Jaume] Vall dHebron Res Inst & Hosp, Res Unit Biomed & Translat & Pediat Oncol, Barcelona 08035, Catalonia, Spain. [Colas, Eva; Reventos, Jaume] Autonomous Univ Barcelona, E-08035 Barcelona, Catalonia, Spain. [Serra-Musach, Jordi; Brunet, Joan] Girona Biomed Res Inst IDIBGI, ICO, Hereditary Canc Programme, Girona 17007, Catalonia, Spain. [Karbalai, Nazanin; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Karbalai, Nazanin; Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-80804 Munich, Germany. [Gomez, Antonio; Esteller, Manel] IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona 08908, Catalonia, Spain. [Esteller, Manel] Catalan Inst Res & Adv Studies ICREA, Barcelona 08010, Catalonia, Spain. [Berenguer, Antoni] IDIBELL, ICO, Unit Biomarkers & Susceptibil, Barcelona 08908, Catalonia, Spain. [Reventos, Jaume] Univ Int Catalunya, Basic Sci Dept, Barcelona 08017, Catalonia, Spain. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-80336 Munich, Germany. [Amundadottir, Laufey] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Duell, Eric J.] IDIBELL, ICO, Canc Epidemiol Program, Unit Nutr Environm & Canc, Barcelona 08908, Catalonia, Spain. RP Pujana, MA (reprint author), Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Translat Res Lab, Breast Canc & Syst Biol Unit, Barcelona 08908, Catalonia, Spain. EM mapujana@iconcologia.net RI pujana, Miguel Angel/N-3127-2014; Gomez Moruno, Antonio/H-7574-2015; Esteller, Manel/L-5956-2014; Amundadottir, Laufey/L-7656-2016; OI pujana, Miguel Angel/0000-0003-3222-4044; Gomez Moruno, Antonio/0000-0001-5308-981X; Esteller, Manel/0000-0003-4490-6093; Amundadottir, Laufey/0000-0003-1859-8971; Duell, Eric J/0000-0001-5256-0163; Berenguer-LLergo, Antoni/0000-0002-3742-8161; Brunet, Joan/0000-0003-1945-3512 FU Fundacion Eugenio Rodriguez Pascual; Fundacion Ramon Areces (XV Enfermedades Raras); Fundacion Roses Contra el Cancer; Generalitat de Catalunya [2009-SGR283]; Red Tematica de Investigacion Colaborativa en Cancer [12/0036/0008]; Spanish Ministry of Health, Instituto Salud Carlos III, Fondo de Investigacion Sanitaria [12/01528] FX Fundacion Eugenio Rodriguez Pascual (2012-13); Fundacion Ramon Areces (XV Enfermedades Raras); Fundacion Roses Contra el Cancer (2012); Generalitat de Catalunya (2009-SGR283); Red Tematica de Investigacion Colaborativa en Cancer (12/0036/0008); Spanish Ministry of Health, Instituto Salud Carlos III, Fondo de Investigacion Sanitaria (12/01528). NR 50 TC 1 Z9 1 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2014 VL 35 IS 3 BP 578 EP 585 DI 10.1093/carcin/bgt403 PG 8 WC Oncology SC Oncology GA AC7RZ UT WOS:000332730900009 PM 24296589 ER PT J AU Abrigo, M Alvarez, R Paparella, ML Calb, DE Joffe, EBD Gutkind, JS Raimondi, AR AF Abrigo, Marianela Alvarez, Romina Paparella, Maria L. Calb, Diego E. Joffe, Elisa Bal de Kier Gutkind, J. Silvio Raimondi, Ana R. TI Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice SO CARCINOGENESIS LA English DT Article ID KRUPPEL-LIKE FACTOR; CELL CARCINOMA; TUMOR-SUPPRESSOR; MOUSE SKIN; CANCER; CARCINOGENESIS; EXPRESSION; HEAD; GROWTH; NOTCH AB Oral squamous cell carcinoma (SCC) is among the most prevalent cancers in the world and is characterized by high morbidity and few therapeutic options. Like most cancers, oral SCC arises from a multistep process involving alterations of genes responsible for balancing proliferation and differentiation. Among these, Kr?ppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation and thus helps to maintain epithelial homeostasis. However, the prevailing role of Klf4 in maintenance of normal homeostasis in oral epithelium has not been established in vivo. Here, we used an inducible oral-specific mice model to selectively ablate Klf4 in the oral cavity. We generated K14-CreER(Tam)/Klf4(f/f) mice that survived to adulthood and did not present overt phenotype. However, histologically these mice showed dysplastic lesions, increased cell proliferation and abnormal differentiation in the tongue 4 months after induction, supporting a homeostatic role of Klf4 in the oral epithelia. Furthermore, by breeding these mutants with a transgenic line expressing at endogenous levels K-ras(G12D), we assessed the role of disrupting differentiation gene programs to the carcinogenesis process. The K14-CreER(TAM)/K-ras(G12D)/Klf4(/) mice rapidly develop oral SCC in the tongue. Thus, our findings support the emerging notion that activation of differentiating gene programs may represent a barrier preventing carcinogenesis in epithelial cells harboring oncogenic mutations, and thus that molecules acting upstream and downstream of Klf4 may represent components of a novel tumor-suppressive pathway. C1 [Abrigo, Marianela; Alvarez, Romina; Calb, Diego E.; Joffe, Elisa Bal de Kier; Raimondi, Ana R.] Univ Buenos Aires, Res Area, Inst Oncol Angel H Roffo, Sch Med, Buenos Aires, DF, Argentina. [Paparella, Maria L.] Univ Buenos Aires, Oral Pathol Dept, Sch Dent, Buenos Aires, DF, Argentina. [Gutkind, J. Silvio] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Raimondi, AR (reprint author), Univ Buenos Aires, Res Area, Inst Oncol Angel H Roffo, Sch Med, C1417DTN, Buenos Aires, DF, Argentina. EM anaraimondi@conicet.gov.ar FU Argentinean National Research Council [PIP 2010-0302]; National Agency for the Promotion of Science and Technology, Argentina [PICT 2008-2052, PICT 2011-1366] FX Argentinean National Research Council (PIP 2010-0302); National Agency for the Promotion of Science and Technology, Argentina (PICT 2008-2052, PICT 2011-1366). NR 43 TC 9 Z9 9 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2014 VL 35 IS 3 BP 662 EP 669 DI 10.1093/carcin/bgt349 PG 8 WC Oncology SC Oncology GA AC7RZ UT WOS:000332730900017 PM 24148820 ER PT J AU Tettelin, H Davidson, RM Agrawal, S Aitken, ML Shallom, S Hasan, NA Strong, M de Moura, VCN De Groote, MA Duarte, RS Hine, E Parankush, S Su, Q Daugherty, SC Fraser, CM Brown-Elliott, BA Wallace, RJ Holland, SM Sampaio, EP Olivier, KN Jackson, M Zelazny, AM AF Tettelin, Herve Davidson, Rebecca M. Agrawal, Sonia Aitken, Moira L. Shallom, Shamira Hasan, Nabeeh A. Strong, Michael de Moura, Vinicius Calado Nogueira De Groote, Mary Ann Duarte, Rafael S. Hine, Erin Parankush, Sushma Su, Qi Daugherty, Sean C. Fraser, Claire M. Brown-Elliott, Barbara A. Wallace, Richard J., Jr. Holland, Steven M. Sampaio, Elizabeth P. Olivier, Kenneth N. Jackson, Mary Zelazny, Adrian M. TI High-level Relatedness among Mycobacterium abscessus subsp massiliense Strains from Widely Separated Outbreaks SO EMERGING INFECTIOUS DISEASES LA English DT Article ID RAPIDLY GROWING MYCOBACTERIA; CYSTIC-FIBROSIS; GENOME SEQUENCE; CLARITHROMYCIN RESISTANCE; INFECTIONS; ALIGNMENT; BOLLETII; IDENTIFICATION; TRANSMISSION; CHELONAE AB Three recently sequenced strains isolated from patients during an outbreak of Mycobacterium abscessus subsp. massiliense infections at a cystic fibrosis center in the United States were compared with 6 strains from an outbreak at a cystic fibrosis center in the United Kingdom and worldwide strains. Strains from the 2 cystic fibrosis outbreaks showed high-level relatedness with each other and major-level relatedness with strains that caused soft tissue infections during an epidemic in Brazil. We identified unique single-nucleotide polymorphisms in cystic fibrosis and soft tissue outbreak strains, separate single-nucleotide polymorphisms only in cystic fibrosis outbreak strains, and unique genomic traits for each subset of isolates. Our findings highlight the necessity of identifying M. abscessus to the subspecies level and screening all cystic fibrosis isolates for relatedness to these outbreak strains. We propose 2 diagnostic strategies that use partial sequencing of rpoB and secA1 genes and a multilocus sequence typing protocol. C1 [Tettelin, Herve; Agrawal, Sonia; Hine, Erin; Parankush, Sushma; Su, Qi; Daugherty, Sean C.; Fraser, Claire M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Davidson, Rebecca M.; Hasan, Nabeeh A.; Strong, Michael] Natl Jewish Hlth, Denver, CO USA. [Aitken, Moira L.] Univ Washington, Seattle, WA 98195 USA. [Shallom, Shamira; Holland, Steven M.; Sampaio, Elizabeth P.; Olivier, Kenneth N.; Zelazny, Adrian M.] NIH, Bethesda, MD 20892 USA. [Hasan, Nabeeh A.; Strong, Michael] Univ Colorado Denver, Aurora, CO USA. [de Moura, Vinicius Calado Nogueira; De Groote, Mary Ann; Jackson, Mary] Colorado State Univ, Ft Collins, CO 80523 USA. [Duarte, Rafael S.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Brown-Elliott, Barbara A.; Wallace, Richard J., Jr.] Univ Texas Hlth Northeast, Tyler, TX USA. RP Zelazny, AM (reprint author), NIH, Dept Lab Med, Ctr Clin, 10 Ctr Dr,Bldg 10-2C385, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov RI Jackson, Mary/D-5345-2017; OI Fraser, Claire/0000-0003-1462-2428 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Department of Health and Human Services [HHSN272200900009C]; Intramural Research Program (NIAID, NIH, Department of Health and Human Services); Amon G. Carter Foundation; Colorado Bioscience Program; Eppley Foundation; Boettcher Foundation; NIH Biomedical Informatics training grant [2T15LM009451-06]; NIH/NIAID [AI089718] FX This study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institutes of Health (NIH), the Department of Health and Human Services (contract no. HHSN272200900009C to C.M.F), and the Intramural Research Program (NIAID, NIH, Department of Health and Human Services). R.M.D, N.A.H, and M.S. were supported by the Amon G. Carter Foundation, the Colorado Bioscience Program, the Eppley Foundation, and the Boettcher Foundation. N.A.H. was supported by NIH Biomedical Informatics training grant 2T15LM009451-06. M.J. was supported by NIH/NIAID grant AI089718. B.B.-E. and R.J.W. were supported by Amon G. Carter Foundation. NR 40 TC 37 Z9 37 U1 1 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2014 VL 20 IS 3 BP 364 EP 371 DI 10.3201/eid2003.131106 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AC3PO UT WOS:000332433900003 PM 24565502 ER PT J AU Koethe, Y Xu, S Velusamy, G Wood, BJ Venkatesan, AM AF Koethe, Yilun Xu, Sheng Velusamy, Gnanasekar Wood, Bradford J. Venkatesan, Aradhana M. TI Accuracy and efficacy of percutaneous biopsy and ablation using robotic assistance under computed tomography guidance: a phantom study SO EUROPEAN RADIOLOGY LA English DT Article DE Interventional radiology; Robotics; Image-guided biopsy; Ablation techniques ID HEPATOCELLULAR-CARCINOMA; RADIOFREQUENCY ABLATION; INTERVENTIONAL RADIOLOGY; COMPLICATION RATES; TUMOR ABLATION; LIVER-TUMORS; METAANALYSIS; FEASIBILITY; MANAGEMENT; NAVIGATION AB Objective To compare the accuracy of a robotic interventional radiologist (IR) assistance platform with a standard freehand technique for computed-tomography (CT)-guided biopsy and simulated radiofrequency ablation (RFA). Methods The accuracy of freehand single-pass needle insertions into abdominal phantoms was compared with insertions facilitated with the use of a robotic assistance platform (n = 20 each). Post-procedural CTs were analysed for needle placement error. Percutaneous RFA was simulated by sequentially placing five 17-gauge needle introducers into 5-cm diameter masses (n = 5) embedded within an abdominal phantom. Simulated ablations were planned based on pre-procedural CT, before multi-probe placement was executed freehand. Multi-probe placement was then performed on the same 5-cm mass using the ablation planning software and robotic assistance. Post-procedural CTs were analysed to determine the percentage of untreated residual target. Results Mean needle tip-to-target errors were reduced with use of the IR assistance platform (both P < 0.0001). Reduced percentage residual tumour was observed with treatment planning (P = 0.02). Conclusion Improved needle accuracy and optimised probe geometry are observed during simulated CT-guided biopsy and percutaneous ablation with use of a robotic IR assistance platform. This technology may be useful for clinical CT-guided biopsy and RFA, when accuracy may have an impact on outcome. Key points: A recently developed robotic intervention radiology assistance platform facilitates CT-guided interventions. Improved accuracy of complex needle insertions is achievable. IR assistance platform use can improve target ablation coverage. C1 [Koethe, Yilun; Xu, Sheng; Wood, Bradford J.; Venkatesan, Aradhana M.] NIH, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. [Koethe, Yilun; Wood, Bradford J.; Venkatesan, Aradhana M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Koethe, Yilun] Duke Univ, Sch Med, Durham, NC USA. [Velusamy, Gnanasekar] Perfint Healthcare Pvt Ltd, Madras, Tamil Nadu, India. [Venkatesan, Aradhana M.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Venkatesan, AM (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10 CRC,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM venkatesana@cc.nih.gov FU National Institutes of Health (NIH) Medical Research Scholars Program; NIH; NIH Intramural Research Program; NIH Center for Interventional Oncology FX A year-long research fellowship for Y.K. was 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 Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program). 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.; B.J.W. and A. M. V: This research was supported by the NIH Intramural Research Program and the NIH Center for Interventional Oncology. The interventional radiologist assistance platform was supplied by Perfint Healthcare Pvt. Ltd. (Chennai, India) under a Materials Transfer Agreement between the NIH Center for Interventional Oncology and Perfint Healthcare. NIH and Perfint Healthcare have discussed details of a draft Cooperative Research and Development Agreement (CRADA). The content 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 organisations imply endorsement by the U. S. Government. NR 30 TC 12 Z9 12 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD MAR PY 2014 VL 24 IS 3 BP 723 EP 730 DI 10.1007/s00330-013-3056-y PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AC6TO UT WOS:000332658100022 PM 24220755 ER PT J AU Nestorovich, EM Bezrukov, SM AF Nestorovich, Ekaterina M. Bezrukov, Sergey M. TI Designing inhibitors of anthrax toxin SO EXPERT OPINION ON DRUG DISCOVERY LA English DT Review DE antitoxins; Bacillus anthracis; binary toxins; polyvalent interactions; rational drug design ID SMALL-MOLECULE INHIBITORS; SYMMETRICAL TETRAALKYLAMMONIUM IONS; PHOSPHOLIPID-BILAYER MEMBRANES; PROTECTIVE ANTIGEN COMPONENT; ADENYLYL-CYCLASE TOXIN; LETHAL FACTOR PROTEASE; VOLTAGE-DEPENDENT BLOCK; PLANAR LIPID-BILAYERS; IN-VIVO EFFICACY; BACILLUS-ANTHRACIS AB Introduction: Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded 'for the development of multiscale models for complex chemical systems' once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial-and-error approach to a minimum. The intentional dissemination of Bacillus anthracis spores in 2001 via the so-called anthrax letters has led to increased efforts, politically and scientifically, to develop medical countermeasures that will protect people from the threat of anthrax bioterrorism. Areas covered: This article provides an overview of the recent rational drug design approaches for discovering inhibitors of anthrax toxin. The review also directs the readers to the vast literature on the recognized advances and future possibilities in the field. Expert opinion: Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (protective antigen-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, the situation, in our view, is still insecure. Further, the FDA's animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Better identification and validation of anthrax toxin therapeutic targets at the molecular level as well as elucidation of the parameters determining the corresponding therapeutic windows are still necessary for more effective therapeutic options. C1 [Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Phys Biol, Bethesda, MD 20892 USA. RP Nestorovich, EM (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. EM NESTOROVICH@cua.edu; BEZRUKOS@mail.nih.gov FU Catholic University of America; Intramural Research Program of the NICHD, National Institutes of Health FX EM Nestorovich has received startup funds from the Catholic University of America. SM Bezrukov has received funding from the Intramural Research Program of the NICHD, National Institutes of Health. NR 162 TC 13 Z9 14 U1 2 U2 34 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1746-0441 EI 1746-045X J9 EXPERT OPIN DRUG DIS JI Expert. Opin. Drug Discov. PD MAR PY 2014 VL 9 IS 3 BP 299 EP 318 DI 10.1517/17460441.2014.877884 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AC7ZA UT WOS:000332751600007 PM 24447197 ER PT J AU Lerchner, W Corgiat, B Minassian, VD Saunders, RC Richmond, BJ AF Lerchner, W. Corgiat, B. Minassian, V. Der Saunders, R. C. Richmond, B. J. TI Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain SO GENE THERAPY LA English DT Article DE old-world monkeys; adeno-associated virus; lentivirus; injection techniques; brain injections; tyrosine hydroxylase promoter ID GENE-THERAPY; PARKINSONS-DISEASE; LENTIVIRAL VECTORS; CEREBRAL-CORTEX; RHINAL CORTEX; DELIVERY; MONKEYS; ACTIVATION; EXPRESSION; BEHAVIOR AB We, like many others, wish to use modern molecular methods to alter neuronal functionality in primates. For us, this requires expression in a large proportion of the targeted cell population. Long generation times make germline modification of limited use. The size and intricate primate brain anatomy poses additional challenges. We surved methods using lentiviruses and serotypes of adeno-associated viruses (AAVs) to introduce active molecular material into cortical and subcortical regions of old-world monkey brains. Slow injections of AAV2 give well-defined expression of neurons in the cortex surrounding the injection site. Somewhat surprisingly we find that in the monkey the use of cytomegalovirus promoter in lentivirus primarily targets glial cells but few neurons. In contrast, with a synapsin promoter fragment the lentivirus expression is neuron specific at high transduction levels in all cortical layers. We also achieve specific targeting of tyrosine hydroxlase (TH)- rich neurons in the locus coeruleus and substantia nigra with a lentvirus carrying a fragment of the TH promoter. Lentiviruses carrying neuron specific promoters are suitable for both cortical and subcortical injections even when injected quickly. C1 [Lerchner, W.; Corgiat, B.; Minassian, V. Der; Saunders, R. C.; Richmond, B. J.] NIMH, Neuropsychol Lab, DHHS, Bethesda, MD 20814 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, DHHS, 49 Convent Dr Bldg 49-1B80, Bethesda, MD 20814 USA. EM bjr@ln.nimh.nih.gov FU Intramural Research Program of the National Institute of Mental Health FX We thank Sebastien Bouret for crucial help with locating and injecting the locus coeruleus, and Rachel Reoli for her kind support with MRI scans. This study was supported by the Intramural Research Program of the National Institute of Mental Health. NR 42 TC 9 Z9 9 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD MAR PY 2014 VL 21 IS 3 BP 233 EP 241 DI 10.1038/gt.2013.75 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AC6HE UT WOS:000332621300001 PM 24401836 ER PT J AU Klippel, ZK Chou, J Towlerton, AM Voong, LN Robbins, P Bensinger, WI Warren, EH AF Klippel, Z. K. Chou, J. Towlerton, A. M. Voong, L. N. Robbins, P. Bensinger, W. I. Warren, E. H. TI Immune escape from NY-ESO-1-specific T-cell therapy via loss of heterozygosity in the MHC SO GENE THERAPY LA English DT Article DE NY-ESO-1; adoptive immunotherapy; immune escape ID CHIMERIC ANTIGEN RECEPTOR; CANCER-TESTIS ANTIGENS; DONOR LYMPHOCYTE INFUSION; BONE-MARROW-TRANSPLANTATION; GRAFT-VERSUS-MYELOMA; MULTIPLE-MYELOMA; CLASS-I; MISMATCHED HLA; GENE-TRANSFER; REACTIVE TCR AB Adoptive immunotherapy of tumors with T cells specific for the cancer-testis antigen NY-ESO-1 has shown great promise in preclinical models and in early stage clinical trials. Tumor persistence or recurrence after NY-ES0-1-specific therapy occurs, however, and the mechanisms of recurrence remain poorly defined. In a murine xenograft model of NY-60-1(+) multiple myeloma, we observed tumor recurrence after adoptive transfer of CD8(+) T cells genetically redirected to the prototypic NY-ESO-1(157-165) peptide presented by HLA-A*02:01. Analysis of the myeloma cells that had escaped from T-cell control revealed intact expression of NY-FSO-1 and B2M, but selective, complete loss of HLA-A*02:01 expression from the cell surface. Loss of heterozygosity (LOH) in the major histocompatibility complex (MHC) involving the HLA-A locus was identified in the tumor cells, and further analysis revealed selective loss of the allele encoding HLA-A*02:01. Although LOH involving the MHC has not been described in myeloma patients with persistent or recurrent disease after immune therapies such as allogeneic hematopoietic cell transplantation (HCT), it has been described in patients with acute myelogenous leukemia who relapsed after allogeneic HCT. These results suggest that MHC loss should be evaluated in patients with myeloma and other cancers who relapse after adoptive NY-ESO-1-specific T-cell therapy. C1 [Klippel, Z. K.; Chou, J.; Towlerton, A. M.; Voong, L. N.; Bensinger, W. I.; Warren, E. H.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Klippel, Z. K.; Chou, J.; Bensinger, W. I.; Warren, E. H.] Univ Washington, Dept Med, Seattle, WA USA. [Voong, L. N.] Northwestern Univ, Dept Mol Biosci, Bethesda, MD USA. [Robbins, P.] NCI, Surg Branch, Bethesda, MD 20892 USA. RP Warren, EH (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D3-100 19024, Seattle, WA USA. EM ehwarren@u.washington.edu OI Warren, Edus/0000-0002-9570-2755 FU Edson Fund for Immunotherapy; Senior Research Award from the Multiple Myeloma Research Foundation; NIH [P30 CA015704-34, P30 DK56465, 5T32HL007093-39] FX We thank Melissa Comstock and LaKeisha Perkins of the FHCRC NOD/Scid Core Facility for their assistance with the murine xenograft studies. The authors also thank the patients who have donated their blood and tissues for our work. These studies were supported by the J. Orin Edson Fund for Immunotherapy, a Senior Research Award from the Multiple Myeloma Research Foundation (to EHW), and NIH grants P30 CA015704-34, P30 DK56465 PI: B. Torok-Storb, and 5T32HL007093-39. NR 48 TC 10 Z9 12 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD MAR PY 2014 VL 21 IS 3 BP 337 EP 342 DI 10.1038/gt.2013.87 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AC6HE UT WOS:000332621300012 PM 24451117 ER PT J AU Hwang, JY Lee, C Lam, KH Kim, HH Lee, J Shung, KK AF Hwang, Jae Youn Lee, Changyang Lam, Kwok Ho Kim, Hyung Ham Lee, Jungwoo Shung, K. Kirk TI Cell Membrane Deformation Induced by a Fibronectin-Coated Polystyrene Microbead in a 200-MHz Acoustic Trap SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID OPTICAL TWEEZERS; HIGH-FREQUENCY; CANCER; MANIPULATION; SYSTEMS; MICROPARTICLES; TRANSDUCERS; MICROSCOPY; INTEGRINS; FORCES AB The measurement of cell mechanics is crucial for a better understanding of cellular responses during the progression of certain diseases and for the identification of the cell's nature. Many techniques using optical tweezers, atomic force microscopy, and micro-pipettes have been developed to probe and manipulate cells in the spatial domain. In particular, we recently proposed a two-dimensional acoustic trapping method as an alternative technique for small particle manipulation. Although the proposed method may have advantages over optical tweezers, its applications to cellular mechanics have not yet been vigorously investigated. This study represents an initial attempt to use acoustic tweezers as a tool in the field of cellular mechanics in which cancer cell membrane deformability is studied. A press-focused 193-MHz single-element lithium niobate (LiNbO3) transducer was designed and fabricated to trap a 5-mu m polystyrene microbead near the ultrasound beam focus. The microbeads were coated with fibronectin, and trapped before being attached to the surface of a human breast cancer cell (MCF-7). The cell membrane was then stretched by remotely pulling a cell-attached microbead with the acoustic trap. The maximum cell membrane stretched lengths were measured to be 0.15, 0.54, and 1.41 mu m at input voltages to the transducer of 6.3, 9.5, and 12.6 V-pp, respectively. The stretched length was found to increase nonlinearly as a function of the voltage input. No significant cytotoxicity was observed to result from the bead or the trapping force on the cell during or after the deformation procedure. Hence, the results convincingly demonstrated the possible application of the acoustic trapping technique as a tool for cell manipulation. C1 [Hwang, Jae Youn] Daegu Gyeongbuk Inst Sci & Technol, Dept Informat & Commun Engn, Taegu, South Korea. [Lee, Changyang; Kim, Hyung Ham; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. [Lam, Kwok Ho] Hong Kong Polytech Univ, Dept Elect Engn, Kowloon, Hong Kong, Peoples R China. [Lee, Jungwoo] Kwangwoon Univ, Dept Elect Engn, Seoul, South Korea. RP Hwang, JY (reprint author), Daegu Gyeongbuk Inst Sci & Technol, Dept Informat & Commun Engn, Taegu, South Korea. EM jwlee@kw.ac.kr RI Lam, K.H./B-7765-2014; OI Lam, K.H./0000-0003-1456-9049; Lee, Changyang/0000-0002-3746-7304 FU National Institutes of Health (NIH) [R01-EB012058, P41-EB002182]; National Research Foundation of Korea (NRF); Korea government (MEST) [2012R1A1A1015778]; Research Grant of Kwangwoon University; International Collaborative RD Program; Ministry of Knowledge Economy, Korea [N01150049] FX This work was supported by the National Institutes of Health (NIH) grants R01-EB012058 and P41-EB002182, and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (grant number 2012R1A1A1015778), the Research Grant of Kwangwoon University in 2013, and the International Collaborative R&D Program funded by the Ministry of Knowledge Economy, Korea (grant number N01150049). NR 36 TC 9 Z9 9 U1 1 U2 28 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 EI 1525-8955 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD MAR PY 2014 VL 61 IS 3 BP 399 EP 406 DI 10.1109/TUFFC.2014.2925 PG 8 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA AC6CT UT WOS:000332609400003 PM 24569245 ER PT J AU Compton, WM Lopez, MF AF Compton, Wilson M. Lopez, Marsha F. TI Accuracy in Reporting Past Psychiatric Symptoms The Role of Cross-sectional Studies in Psychiatric Research SO JAMA PSYCHIATRY LA English DT Editorial Material ID COMMON C1 [Compton, Wilson M.; Lopez, Marsha F.] NIDA, Bethesda, MD 20892 USA. RP Compton, WM (reprint author), NIDA, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 5 TC 4 Z9 4 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR PY 2014 VL 71 IS 3 BP 233 EP 234 DI 10.1001/jamapsychiatry.2013.4111 PG 2 WC Psychiatry SC Psychiatry GA AC8FU UT WOS:000332769700003 PM 24401961 ER PT J AU Rasetti, R Mattay, VS White, MG Sambataro, F Podell, JE Zoltick, B Chen, Q Berman, KF Callicott, JH Weinberger, DR AF Rasetti, Roberta Mattay, Venkata S. White, Michael G. Sambataro, Fabio Podell, Jamie E. Zoltick, Brad Chen, Qiang Berman, Karen F. Callicott, Joseph H. Weinberger, Daniel R. TI Altered Hippocampal-Parahippocampal Function During Stimulus Encoding A Potential Indicator of Genetic Liability for Schizophrenia SO JAMA PSYCHIATRY LA English DT Article ID EPISODIC MEMORY; INTERMEDIATE-PHENOTYPE; COGNITIVE DEFICITS; PUTATIVE ENDOPHENOTYPES; HEALTHY SIBLINGS; METAANALYSIS; ACTIVATION; RELATIVES; FMRI; LATERALIZATION AB IMPORTANCE Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. OBJECTIVE To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry. MAIN OUTCOMES AND MEASURES All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples. RESULTS Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score. CONCLUSIONS AND RELEVANCE These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia. C1 [Rasetti, Roberta; Mattay, Venkata S.; White, Michael G.; Sambataro, Fabio; Podell, Jamie E.; Zoltick, Brad; Chen, Qiang; Berman, Karen F.; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Mattay, Venkata S.; White, Michael G.; Chen, Qiang; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Sambataro, Fabio] Ist Italiano Tecnol UNIPr, Brain Ctr Motor & Social Cognit, Parma, Italy. [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, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Weinberger, DR (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 N Wolfe St, Baltimore, MD 21205 USA. EM drweinberger@libd.org RI Callicott, Joseph/C-9102-2009; Sambataro, Fabio/E-3426-2010 OI Callicott, Joseph/0000-0003-1298-3334; Sambataro, Fabio/0000-0003-2102-416X FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 46 TC 12 Z9 13 U1 2 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR PY 2014 VL 71 IS 3 BP 236 EP 247 DI 10.1001/jamapsychiatry.2013.3911 PG 12 WC Psychiatry SC Psychiatry GA AC8FU UT WOS:000332769700005 PM 24382711 ER PT J AU PrabhuDas, M Bowdish, D Drickamer, K Febbraio, M Herz, J Kobzik, L Krieger, M Loike, J Means, TK Moestrup, SK Post, S Sawamura, T Silverstein, S Wang, XY El Khoury, J AF PrabhuDas, Mercy Bowdish, Dawn Drickamer, Kurt Febbraio, Maria Herz, Joachim Kobzik, Lester Krieger, Monty Loike, John Means, Terry K. Moestrup, Soren K. Post, Steven Sawamura, Tatsuya Silverstein, Samuel Wang, Xiang-Yang El Khoury, Joseph TI Standardizing Scavenger Receptor Nomenclature SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; PATTERN-RECOGNITION RECEPTOR; HOST-DEFENSE; SR-BI; CHOLESTEROL DEPOSITION; EXTRACELLULAR DOMAIN; INTERNATIONAL UNION; MACROPHAGE ADHESION; EXPRESSION CLONING; ENDOTHELIAL-CELLS AB Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a variety of ligands, including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the U. S. National Institute of Allergy and Infectious Diseases, National Institutes of Health to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of non-self or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. The discussion and nomenclature recommendations described in this report only refer to mammalian scavenger receptors. The purpose of this article is to describe the proposed mammalian nomenclature and classification developed at the workshop and to solicit additional feedback from the broader research community. C1 [PrabhuDas, Mercy] NIAID, NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Bowdish, Dawn] McMaster Univ, McMaster Immunol Res Ctr, MG DeGroote Inst Infect Dis Res, Dept Pathol & Mol Med, Hamilton, ON L8S 4K1, Canada. [Drickamer, Kurt] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England. [Febbraio, Maria] Univ Alberta, Fac Med & Dent, Katz Grp Ctr Pharm & Hlth Res, Dept Dent, Edmonton, AB T6G 2E1, Canada. [Herz, Joachim] Univ Texas SW Med Ctr Dallas, Dept Mol Genet Neurosc & Neurol & Neurotherapeut, Dallas, TX 75390 USA. [Kobzik, Lester] Harvard Univ, Sch Med, Dept Environm Hlth, Boston, MA 02115 USA. [Krieger, Monty] MIT, Dept Biol, Cambridge, MA 02139 USA. [Loike, John] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. [Means, Terry K.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Means, Terry K.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. [Means, Terry K.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Moestrup, Soren K.] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. [Post, Steven] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72211 USA. [Sawamura, Tatsuya] Res Inst, Natl Cerebral & Cardiovasc Ctr, Dept Vasc Physiol, Suita, Osaka 5658565, Japan. [Silverstein, Samuel] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. [Wang, Xiang-Yang] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Inst Mol Med,Dept Humen & Mol Genet, Richmond, VA 23298 USA. [El Khoury, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory,Infect Dis Div, Charlestown, MA 02129 USA. RP PrabhuDas, M (reprint author), NIAID, NIH, Div Allergy Immunol & Transplantat, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM mprabhudas@niaid.nih.gov; jelkhoury@mgh.harvard.edu RI Sawamura, Tatsuya/E-7103-2010; Moestrup, Soren Kragh/A-1403-2014; OI Moestrup, Soren Kragh/0000-0003-3862-2107; Post, Steven/0000-0002-4711-1723 FU NCI NIH HHS [R01 CA154708, R01 CA129111]; NHLBI NIH HHS [R37 HL063762]; NIAID NIH HHS [U24 AI082660]; NINDS NIH HHS [R01 NS059005] NR 77 TC 30 Z9 33 U1 3 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2014 VL 192 IS 5 BP 1997 EP 2006 DI 10.4049/jimmunol.1490003 PG 10 WC Immunology SC Immunology GA AC7IL UT WOS:000332701400001 PM 24563502 ER PT J AU Shenderov, K Riteau, N Yip, R Mayer-Barber, KD Oland, S Hieny, S Fitzgerald, P Oberst, A Dillon, CP Green, DR Cerundolo, V Sher, A AF Shenderov, Kevin Riteau, Nicolas Yip, Ronald Mayer-Barber, Katrin D. Oland, Sandy Hieny, Sara Fitzgerald, Pat Oberst, Andrew Dillon, Christopher P. Green, Douglas R. Cerundolo, Vincenzo Sher, Alan TI Cutting Edge: Endoplasmic Reticulum Stress Licenses Macrophages To Produce Mature IL-1 beta in Response to TLR4 Stimulation through a Caspase-8-and TRIF-Dependent Pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY RESPONSE; TRANSCRIPTION FACTOR; NLRP3 INFLAMMASOME; MATURATION; ACTIVATION; INDUCTION; SENSOR AB The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1 beta. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1 beta in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1 beta occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1 beta is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1 beta production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings. C1 [Shenderov, Kevin; Riteau, Nicolas; Mayer-Barber, Katrin D.; Oland, Sandy; Hieny, Sara; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Yip, Ronald; Cerundolo, Vincenzo] John Radcliffe Hosp, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England. [Fitzgerald, Pat; Dillon, Christopher P.; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Oberst, Andrew] Univ Washington, Dept Immunol, Seattle, WA 98109 USA. RP Shenderov, K (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenderovk@niaid.nih.gov; asher@niaid.nih.gov RI Dillon, Christopher/P-4457-2014 OI Dillon, Christopher/0000-0002-9458-0266 FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health; Medical Research Council; Cancer Research UK [C399/A2291]; Wellcome Trust; Rhodes Trust; Medical Scientist Training Program funding from the Johns Hopkins University School of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health and by grants from the Medical Research Council, Cancer Research UK (Programme Grant C399/A2291 to V. C.) and the Wellcome Trust. K. S. was supported by a scholarship from the Rhodes Trust and by Medical Scientist Training Program funding from the Johns Hopkins University School of Medicine. NR 19 TC 55 Z9 58 U1 1 U2 15 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2014 VL 192 IS 5 BP 2029 EP 2033 DI 10.4049/jimmunol.1302549 PG 5 WC Immunology SC Immunology GA AC7IL UT WOS:000332701400006 PM 24489101 ER PT J AU Nakayamada, S Poholek, AC Lu, KT Takahashi, H Kato, M Iwata, S Hirahara, K Cannons, JL Schwartzberg, PL Vahedi, G Sun, HW Kanno, Y O'Shea, JJ AF Nakayamada, Shingo Poholek, Amanda C. Lu, Kristina T. Takahashi, Hayato Kato, Masanari Iwata, Shigeru Hirahara, Kiyoshi Cannons, Jennifer L. Schwartzberg, Pamela L. Vahedi, Golnaz Sun, Hong-wei Kanno, Yuka O'Shea, John J. TI Type I IFN Induces Binding of STAT1 to Bcl6: Divergent Roles of STAT Family Transcription Factors in the T Follicular Helper Cell Genetic Program SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PERSISTENT LCMV INFECTION; GERMINAL CENTER FORMATION; CXC CHEMOKINE RECEPTOR-5; PLAQUE-FORMING CELLS; CUTTING EDGE; B-CELLS; HUMORAL IMMUNITY; IMMUNOGLOBULIN PRODUCTION; TYROSINE PHOSPHORYLATION; NEGATIVE REGULATOR AB CD4(+) T follicular helper cells (TFH) are critical for the formation and function of B cell responses to infection or immunization, but also play an important role in autoimmunity. The factors that contribute to the differentiation of this helper cell subset are incompletely understood, although several cytokines including IL-6, IL-21, and IL-12 can promote TFH cell formation. Yet, none of these factors, nor their downstream cognate STATs, have emerged as nonredundant, essential drivers of TFH cells. This suggests a model in which multiple factors can contribute to the phenotypic characteristics of TFH cells. Because type I IFNs are often generated in immune responses, we set out to investigate whether these factors are relevant to TFH cell differentiation. Type I IFNs promote Th1 responses, thus one possibility was these factors antagonized TFH-expressed genes. However, we show that type I IFNs (IFN-alpha/beta) induced B cell lymphoma 6 (Bcl6) expression, the master regulator transcription factor for TFH cells, and CXCR5 and programmed cell death-1 (encoded by Pdcd1), key surface molecules expressed by TFH cells. In contrast, type I IFNs failed to induce IL-21, the signature cytokine for TFH cells. The induction of Bcl6 was regulated directly by STAT1, which bound to the Bcl6, Cxcr5, and Pdcd1 loci. These data suggest that type I IFNs (IFN-alpha/beta) and STAT1 can contribute to some features of TFH cells but are inadequate in inducing complete programming of this subset. C1 [Nakayamada, Shingo; Poholek, Amanda C.; Takahashi, Hayato; Kato, Masanari; Iwata, Shigeru; Hirahara, Kiyoshi; Vahedi, Golnaz; Kanno, Yuka; O'Shea, John J.] NIAMSD, Lymphocyte Biol Sect, Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Lu, Kristina T.; Cannons, Jennifer L.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Sun, Hong-wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. RP Poholek, AC (reprint author), NIAMSD, NIH, 10 Ctr Dr,Room 13C120, Bethesda, MD 20892 USA. EM amanda.poholek@nih.gov RI Kanno, Yuka/B-5802-2013; Hirahara, Kiyoshi/E-2460-2017; OI Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319 FU Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Human Genome Research Institute; Postdoctoral Research Associate Program; National Institute of General Medical Sciences; National Institutes of Health; Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute, the Postdoctoral Research Associate Program, the National Institute of General Medical Sciences, the National Institutes of Health (to A. C. P. and K. T. L.), and the Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (to K.H.). NR 90 TC 25 Z9 28 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2014 VL 192 IS 5 BP 2156 EP 2166 DI 10.4049/jimmunol.1300675 PG 11 WC Immunology SC Immunology GA AC7IL UT WOS:000332701400019 PM 24489092 ER PT J AU Miranda, J Romero, R Korzeniewski, SJ Schwartz, AG Chaemsaithong, P Stampalija, T Yeo, L Dong, Z Hassan, SS Chrousos, GP Gold, P Chaiworapongsa, T AF Miranda, Jezid Romero, Roberto Korzeniewski, Steven J. Schwartz, Alyse G. Chaemsaithong, Piya Stampalija, Tamara Yeo, Lami Dong, Zhong Hassan, Sonia S. Chrousos, George P. Gold, Philip Chaiworapongsa, Tinnakorn TI The anti-aging factor alpha-klotho during human pregnancy and its expression in pregnancies complicated by small-for-gestational-age neonates and/or preeclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Fetal growth restriction; hypertension in pregnancy; lifespan; metabolism; pregnancy ID INTRAUTERINE GROWTH RESTRICTION; ENDOTHELIAL-CELL DYSFUNCTION; CHRONIC KIDNEY-DISEASE; ENDOPLASMIC-RETICULUM STRESS; LINKING PLACENTAL ISCHEMIA; FETAL-GROWTH; OXIDATIVE STRESS; SPIRAL ARTERIES; CALCIUM HOMEOSTASIS; SOLUBLE KLOTHO AB Objective: alpha-klotho, a protein with anti-aging properties, has been involved in important biological processes, such as calcium/phosphate metabolism, resistance to oxidative stress, and nitric oxide production in the endothelium. Recent studies have suggested a role of alpha-klotho in endocrine regulation of mineral metabolism and postnatal growth in infants. Yet, the role of alpha-klotho during pregnancy remains largely unknown. The aim of this study was to determine whether maternal plasma concentration of alpha-klotho changes during pregnancy and evaluate its expression in pregnancies complicated by small for gestational age (SGA) and/or preeclampsia (PE). Study design: This cross-sectional study included patients in the following groups: (1) non pregnant women (n = 37); (2) uncomplicated pregnancy (n = 130); (3) PE without an SGA neonate (PE; n = 58); (4) PE with an SGA neonate (PE and SGA; n=52); and (5) SGA neonate without PE (SGA; n = 52). Plasma concentrations of alpha-klotho were determined by ELISA. Results: The median plasma alpha-klotho concentration was higher in pregnant than in nonpregnant women. Among women with an uncomplicated pregnancy, the median plasma concentration of alpha-klotho increased as a function of gestational age (Spearman Rho = 0.2; p = 0.006). The median (interquartile range) plasma concentration of alpha-klotho in women with PE and SGA [947.6 (762-2013) pg/mL] and SGA without PE [1000 (585-1567) pg/mL] were 21% and 17% lower than that observed in women with an uncomplicated pregnancy [1206.6 (894-2012) pg/mL], (p = 0.005 and p = 0.02), respectively. Additionally, there were no significant differences in the median plasma concentration of alpha-klotho between uncomplicated pregnancies and women with PE without an SGA neonate (p = 0.5). Conclusion: Maternal plasma concentration of alpha-klotho was higher during pregnancy than in a non-pregnant state. Moreover, the median maternal plasma concentration of alpha-klotho was lower in mothers who delivered an SGA neonate than in those with an uncomplicated pregnancy regardless of the presence or absence of PE. C1 [Miranda, Jezid; Romero, Roberto; Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaemsaithong, Piya; Stampalija, Tamara; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Miranda, Jezid; Romero, Roberto; Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaemsaithong, Piya; Stampalija, Tamara; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Miranda, Jezid; Korzeniewski, Steven J.; Schwartz, Alyse G.; Chaemsaithong, Piya; Stampalija, Tamara; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Stampalija, Tamara] Univ Milan, Dept Biol & Clin Sci, Milan, Italy. [Chrousos, George P.] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp,Dept Pediat 1, Div Endocrinol Diabet & Metab, Athens, Greece. [Chrousos, George P.] Div Endocrinol & Metab, Athens, Greece. [Gold, Philip] NIMH, NIH, Bethesda, MD 20892 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov RI Stampalija, Tamara/K-4900-2014 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HSN275201300006C] 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, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HSN275201300006C. NR 123 TC 3 Z9 3 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAR PY 2014 VL 27 IS 5 BP 449 EP 457 DI 10.3109/14767058.2013.818652 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AC4YC UT WOS:000332526200004 PM 23808483 ER PT J AU Miller, DS AF Miller, David S. TI Sphingolipid Signaling Reduces Basal P-Glycoprotein Activity in Renal Proximal Tubule SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ORGANIC ANION SECRETION; SPHINGOSINE 1-PHOSPHATE; BLOOD-BRAIN; CONFOCAL MICROSCOPY; TRANSPORT; SPHINGOSINE-1-PHOSPHATE; KIDNEY; TOXICITY; PATHWAYS; MODELS AB P-glycoprotein is an ATP-driven xenobiotic export pump that is highly expressed in barrier and excretory tissues, where it greatly influences drug pharmacokinetics. Recent studies in the blood-brain and spinal cord barriers identified a sphingolipidbased signaling pathway that regulates basal activity of P-glycoprotein. Here we use an established comparative renal model that permits direct measurement of P-glycoprotein activity to determine whether such signaling occurs in another tissue, killifish renal proximal tubule. Isolated killifish tubules exposed to 0.01-1.0 mM sphingosine-1-phosphate (S1P) exhibited a profound decrease in P-glycoprotein transport activity, measured as specific accumulation of a fluorescent cyclosporine A derivative in the tubule lumen. Loss of activity had a rapid onset and was fully reversible when the S1P was removed. Transport mediated by multidrug resistance-associated protein 2 (Mrp2) or a teleost fish organic anion transporter (Oat) was not affected. S1P effects were blocked by a specific S1P receptor 1 (S1PR1) antagonist and mimicked by a S1PR agonist. Sphingosine also reduced P-glycoprotein transport activity and those effects were blocked by an inhibitor of sphingosine kinase and by the S1PR1 antagonist. These results for a comparative renal model suggest that sphingolipid signaling to P-glycoprotein is not just restricted to the blood-brain and blood-spinal cord barriers, but occurs in other excretory and barrier tissues. C1 [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Miller, David S.] Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences] FX This work was supported by the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences]. NR 26 TC 6 Z9 6 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2014 VL 348 IS 3 BP 459 EP 464 DI 10.1124/jpet.113.210641 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AC1BU UT WOS:000332230000011 PM 24385389 ER PT J AU Cheng, NQ Wu, WM Watts, NR Steven, AC AF Cheng, Naiqian Wu, Weimin Watts, Norman R. Steven, Alasdair C. TI Exploiting radiation damage to map proteins in nucleoprotein complexes: The internal structure of bacteriophage T7 SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Nucleocapsid structure; Cryo-electron microscopy; DNA ejection; Radiation biology; 3-dimensional image reconstruction; Differential mass mapping ID PHI-KZ; ANGSTROM RESOLUTION; ELECTRON-MICROSCOPY; INNER BODY; CRYO-EM; DNA; VIRUS; MATURATION; MACROMOLECULES; TEMPERATURES AB In the final stage of radiation damage in cryo-electron microscopy of proteins, bubbles of hydrogen gas are generated. Proteins embedded in DNA bubble sooner than free-standing proteins and DNA does not bubble under the same conditions. These properties make it possible to distinguish protein from DNA. Here we explored the scope of this technique ("bubblegram imaging") by applying it to bacteriophage T7, viewed as a partially defined model system. T7 has a thin-walled icosahedral capsid, 60 nm in diameter, with a barrel-shaped protein core under one of its twelve vertices (the portal vertex). The core is densely wrapped with DNA but details of their interaction and how their injection into a host bacterium is coordinated are lacking. With short (10 s) intervals between exposures of 17 electrons/angstrom(2) each, bubbling starts in the third exposure, with 1-4 bubbles nucleating in the core: in subsequent exposures, these bubbles grow and merge. A 3D reconstruction from fifth-exposure images depicts a bipartite cylindrical gas cloud in the core. In its portal-proximal half, the axial region is gaseous whereas in the portal-distal half, it is occupied by a 3 nm-wide dense rod. We propose that they respectively represent core protein and an end of the packaged genome, poised for injection into a host cell. Single bubbles at other sites may represent residual scaffolding protein. Thus, bubbling depends on dose rate, protein amount, and tightness of the DNA seal. Published by Elsevier Inc. C1 [Cheng, Naiqian; Wu, Weimin; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Watts, Norman R.] NIH, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIH, Bldg 50,Room 1517, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU NIAMS FX We thank Ms. Lili You for collecting the data on bubble sizes and Drs. L.W. Black and R.L. Duda and Mr. M.A. DiMattia for helpful discussions. This research was supported by the Intramural Research Program of NIAMS. NR 42 TC 8 Z9 8 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAR PY 2014 VL 185 IS 3 BP 250 EP 256 DI 10.1016/j.jsb.2013.12.004 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AC8WI UT WOS:000332815400002 PM 24345345 ER PT J AU Narayan, K Danielson, CM Lagarec, K Lowekamp, BC Coffman, P Laquerre, A Phaneuf, MW Hope, TJ Subramaniam, S AF Narayan, Kedar Danielson, Cindy M. Lagarec, Ken Lowekamp, Bradley C. Coffman, Phil Laquerre, Alexandre Phaneuf, Michael W. Hope, Thomas J. Subramaniam, Sriram TI Multi-resolution correlative focused ion beam scanning electron microscopy: Applications to cell biology SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Three-dimensional electron microscopy; Ion abrasion scanning electron microscopy; Correlative microscopy; HIV-1 core; 3D imaging of bacteria; Tomography; FIB-SEM AB Efficient correlative imaging of small targets within large fields is a central problem in cell biology. Here, we demonstrate a series of technical advances in focused ion beam scanning electron microscopy (FIB-SEM) to address this issue. We report increases in the speed, robustness and automation of the process, and achieve consistent z slice thickness of similar to 3 nm. We introduce "keyframe imaging" as a new approach to simultaneously image large fields of view and obtain high-resolution 3D images of targeted sub-volumes. We demonstrate application of these advances to image post-fusion cytoplasmic intermediates of the HIV core. Using fluorescently labeled cell membranes, proteins and HIV cores, we first produce a "target map" of an HIV infected cell by fluorescence microscopy. We then generate a correlated 3D EM volume of the entire cell as well as high-resolution 3D images of individual HIV cores, achieving correlative imaging across a volume scale of 10(9) in a single automated experimental run. (C) 2014 Published by Elsevier Inc. C1 [Narayan, Kedar; Coffman, Phil; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Danielson, Cindy M.; Hope, Thomas J.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Lagarec, Ken; Laquerre, Alexandre; Phaneuf, Michael W.] Fibics Inc, Ottawa, ON K1A 0G1, Canada. [Lowekamp, Bradley C.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, NIH, LCB, 50 South Dr,Bldg 50,Rm 4306, Bethesda, MD 20892 USA. EM ss1@nih.gov OI Danielson, Cindy/0000-0002-6382-7799 FU Center for Cancer Research, NCI, NIH FX We thank Kunio Nagashima for assistance with specimen preparation and Prashant Rao for assistance with image processing. Resin embedded B. subtilis samples, and resin-embedded co-cultures of plasmacytoid dendritic cells and Huh-7 cells were kind gifts from Dr. Kumaran Ramamurthi and Dr. Francis V. Chisari, respectively. This work was supported by funds from the Center for Cancer Research, NCI, NIH. NR 18 TC 24 Z9 24 U1 4 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAR PY 2014 VL 185 IS 3 BP 278 EP 284 DI 10.1016/j.jsb.2013.11.008 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AC8WI UT WOS:000332815400005 PM 24300554 ER PT J AU Bundrick, SC Thearle, MS Venti, CA Krakoff, J Votruba, SB AF Bundrick, Sarah C. Thearle, Marie S. Venti, Colleen A. Krakoff, Jonathan Votruba, Susanne B. TI Soda Consumption during Ad Libitum Food Intake Predicts Weight Change SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Soda; Food intake; Sugar-sweetened beverages; Weight change; Vending machines ID SUGAR-SWEETENED BEVERAGES; ENERGY-INTAKE; US ADULTS; OBESITY; PREVALENCE; VALIDITY; TRENDS; YOUNG; WOMEN; WATER AB Soda consumption may contribute to weight gain over time. Objective data were used to determine whether soda consumption predicts weight gain or changes in glucose regulation over time. Subjects without diabetes (128 men, 75 women; mean age 34.3 +/- 8.9 years; mean body mass index 32.5 +/- 7.4; mean percentage body fat 31.6%+/- 8.6%) self-selected their food from an ad libitum vending machine system for 3 days. Mean daily energy intake was calculated from food weight. Energy consumed from soda was recorded as were food choices that were low in fat (<20% of calories from fat) or high in simple sugars (>30%). Food choices were expressed as percentage of daily energy intake. A subset of 85 subjects had measurement of follow-up weights and oral glucose tolerance (57 men, 28 women; mean follow-up time=2.5 +/- 2.1 years, range 6 months to 9.9 years). Energy consumed from soda was negatively related to age (r=-0.27, P=0.0001) and choosing low-fat foods (r=-0.35, P<0.0001), but positively associated with choosing solid foods high in simple sugars (r=0.45, P<0.0001) and overall average daily energy intake (r=0.46, P<0.0001). Energy intake from food alone did not differ between individuals who did and did not consume beverage calories (P=0.11). Total daily energy intake had no relationship with change in weight (P=0.29) or change in glucose regulation (P=0.38) over time. However, energy consumed from soda correlated with change in weight (r=0.21, P=0.04). This relationship was unchanged after adjusting for follow-up time and initial weight. Soda consumption is a marker for excess energy consumption and is associated with weight gain. C1 [Bundrick, Sarah C.; Thearle, Marie S.; Venti, Colleen A.; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85016 USA. [Votruba, Susanne B.] NIDDK, NIH, Phoenix, AZ 85016 USA. RP Votruba, SB (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, 4212 N 16th St, Phoenix, AZ 85016 USA. EM votrubas@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases. Clinical Trial Registry: Clinicaltrials.gov Identifier NCT00342732. NR 28 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAR PY 2014 VL 114 IS 3 BP 444 EP 449 DI 10.1016/j.jand.2013.09.016 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AC4OR UT WOS:000332501100013 PM 24321742 ER PT J AU Shaw, P AF Shaw, Philip TI Emotion, Sex, and the Medial Temporal Lobe SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID DEPRESSION; DISORDER; CHILDREN; MODEL C1 [Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Shaw, Philip] NIMH, Intramural Program, Bethesda, MD USA. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Div Intramural Res Programs, Bldg 31,B1 B37, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 12 TC 0 Z9 0 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2014 VL 53 IS 3 BP 271 EP 273 DI 10.1016/j.jaac.2013.12.005 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AC3QD UT WOS:000332435400003 PM 24565355 ER PT J AU Piacentini, J Bennett, S Compton, SN Kendall, PC Birmaher, B Albano, AM March, J Sherrill, J Sakolsky, D Ginsburg, G Rynn, M Bergman, RL Gosch, E Waslick, B Iyengar, S McCracken, J Walkup, J AF Piacentini, John Bennett, Shannon Compton, Scott N. Kendall, Phillip C. Birmaher, Boris Albano, Anne Marie March, John Sherrill, Joel Sakolsky, Dara Ginsburg, Golda Rynn, Moira Bergman, R. Lindsey Gosch, Elizabeth Waslick, Bruce Iyengar, Satish McCracken, James Walkup, John TI 24-and 36-Week Outcomes for the Child/Adolescent Anxiety Multimodal Study (CAMS) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE anxiety; Child/Adolescent Anxiety Multimodal Study (CAMS); cognitive-behavioral therapy (CBT); follow-up; selective serotonin reuptake inhibitor (SSRI) ID COGNITIVE-BEHAVIORAL THERAPY; REPLICATION-ADOLESCENT SUPPLEMENT; RANDOMIZED CLINICAL-TRIAL; 7.4-YEAR FOLLOW-UP; CHILDHOOD ANXIETY; DISORDERED YOUTH; SUBSTANCE USE; DEPRESSION; PREVALENCE; COMBINATION AB Objective: We report active treatment group differences on response and remission rates and changes in anxiety severity at weeks 24 and 36 for the Child/Adolescent Anxiety Multimodal Study (CAMS). Method: CAMS youth (N = 488; 74% <= 12 years of age) with DSM-IV separation, generalized, or social anxiety disorder were randomized to 12 weeks of cognitive-behavioral therapy (CBT), sertraline (SRT), CBT+SRT (COMB), or medication management/pill placebo (PBO). Responders attended 6 monthly booster sessions in their assigned treatment arm; youth in COMB and SRT continued on their medication throughout this period. Efficacy of COMB, SRT, and CBT (n = 412) was assessed at 24 and 36 weeks postrandomization. Youth randomized to PBO (n = 76) were offered active CAMS treatment if nonresponsive at week 12 or over follow-up and were not included here. Independent evaluators blind to study condition assessed anxiety severity, functioning, and treatment response. Concomitant treatments were allowed but monitored over follow-up. Results: The majority (>80%) of acute responders maintained positive response at both weeks 24 and 36. Consistent with acute outcomes, COMB maintained advantage over CBT and SRT, which did not differ, on dimensional outcomes; the 3 treatments did not differ on most categorical outcomes over follow-up. Compared to COMB and CBT, youth in SRT obtained more concomitant psychosocial treatments, whereas those in SRT and CBT obtained more concomitant combined (medication plus psychosocial) treatment. Conclusions: COMB maintained advantage over CBT and SRT on some measures over follow-up, whereas the 2 monotherapies remained indistinguishable. The observed convergence of COMB and monotherapy may be related to greater use of concomitant treatment during follow-up among youth receiving the monotherapies, although other explanations are possible. Although outcomes were variable, most CAMS-treated youth experienced sustained treatment benefit. C1 [Piacentini, John; Bergman, R. Lindsey; McCracken, James] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Bennett, Shannon; Walkup, John] Weill Cornell Med Coll, New York, NY USA. [Compton, Scott N.; March, John] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Kendall, Phillip C.] Temple Univ, Philadelphia, PA 19122 USA. [Birmaher, Boris; Sakolsky, Dara; Iyengar, Satish] Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Birmaher, Boris; Sakolsky, Dara; Iyengar, Satish] Clin Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Albano, Anne Marie; Rynn, Moira] Columbia Univ, Med Ctr, New York State Psychiat Inst, New York, NY 10027 USA. [Sherrill, Joel] NIMH, Div Serv & Intervent Res, Bethesda, MD USA. [Ginsburg, Golda] Johns Hopkins Med Inst, Baltimore, MD USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Philadelphia, PA USA. [Waslick, Bruce] Baystate Med Ctr, Springfield, MA 01199 USA. RP Piacentini, J (reprint author), Univ Calif Los Angeles, Semel Inst, 760 Westwood Blvd,Rm 67-455, Los Angeles, CA 90024 USA. EM jpiacentini@mednet.ucla.edu FU NIMH grants [U01 MH64088, U01 MH064003, U01 MH63747, U01 MH64003, U01 MH64092, U01 MH64107, U01 MH064089] FX This research was supported by NIMH grants U01 MH64088 (J.P.), U01 MH064003 (S.C.), U01 MH63747 (P.K.), U01 MH64003 (B B.), U01 MH64092 (A.M.A), U01 MH64107 (J.M.), and U01 MH064089 (J.W). Sertraline and matching placebo were supplied Free of charge by Pfizer NR 30 TC 21 Z9 22 U1 4 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2014 VL 53 IS 3 BP 297 EP 310 DI 10.1016/j.jaac.2013.11.010 PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AC3QD UT WOS:000332435400005 PM 24565357 ER PT J AU Lee, H Abe, Y Lee, I Shrivastav, S Crusan, AP Huttemann, M Hopfer, U Felder, RA Asico, LD Armando, I Jose, PA Kopp, JB AF Lee, Hewang Abe, Yoshifusa Lee, Icksoo Shrivastav, Shashi Crusan, Annabelle P. Huettemann, Maik Hopfer, Ulrich Felder, Robin A. Asico, Laureano D. Armando, Ines Jose, Pedro A. Kopp, Jeffrey B. TI Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats SO KIDNEY INTERNATIONAL LA English DT Article DE mitochondria; oxygen consumption rate; pyruvate dehydrogenase complex; renal proximal tubule; systolic blood pressure ID PYRUVATE-DEHYDROGENASE COMPLEX; OXIDATIVE-PHOSPHORYLATION; OXIDASE ACTIVITY; BLOOD-PRESSURE; NADPH OXIDASE; KIDNEY; RECEPTORS; MEMBRANE; STRESS; SHR AB Renal proximal tubule cells from spontaneously hypertensive rats (SHR), compared with normotensive Wistar-Kyoto rats (WKY), have increased oxidative stress. The contribution of mitochondrial oxidative phosphorylation to the subsequent hypertensive phenotype remains unclear. We found that renal proximal tubule cells from SHR, relative to WKY, had significantly higher basal oxygen consumption rates, adenosine triphosphate synthesis-linked oxygen consumption rates, and maximum and reserve respiration. These bioenergetic parameters indicated increased mitochondrial function in renal proximal tubule cells from SHR compared with WKY. Pyruvate dehydrogenase complex activity was consistently higher in both renal proximal tubule cells and cortical homogenates from SHR than those from WKY. Treatment for 6 days with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, significantly increased renal pyruvate dehydrogenase complex activity and systolic blood pressure in 3-week-old WKY and SHR. Therefore, mitochondrial oxidative phosphorylation is higher in renal proximal tubule cells from SHR compared with WKY. Thus, the pyruvate dehydrogenase complex is a determinant of increased mitochondrial metabolism that could be a causal contributor to the hypertension in SHR. C1 [Lee, Hewang; Crusan, Annabelle P.; Asico, Laureano D.; Armando, Ines; Jose, Pedro A.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Bethesda, MD 20892 USA. [Lee, Hewang; Abe, Yoshifusa; Shrivastav, Shashi; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Lee, Icksoo] Dankook Univ, Coll Med, Cheonan Si, Chungcheongnam, South Korea. [Huettemann, Maik] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Huettemann, Maik] Wayne State Univ, Sch Med, Cardiovasc Res Inst, Detroit, MI USA. [Hopfer, Ulrich] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Felder, Robin A.] Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA USA. RP Lee, H (reprint author), Univ Maryland, Sch Med, Dept Med, Div Nephrol, 10 Ctr Dr,3N114, Bethesda, MD 20892 USA. EM lih14@mail.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health [R37HL023081, R01DK039308, R01HL092196, P01HL074940, P01HL068686, DK090918]; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program [Z01DK043308]; Children's National Medical Center intramural Avery Award FX We are grateful to Drs Jurgen Schnermann and Oksana Gavrilova (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD), and Dr Cinthia B Drachenberg (University of Maryland School of Medicine, Baltimore, MD) for their critical evaluation of the manuscript, Drs Hideko Takahashi, Osama Ichii, Huiyan Lu, Patrick Dummer, Taichi Murakami, Hidefumi Wakashin, Koji Okamoto, Crisanto Escano, Peiying Yu, Perry Comegys, Norma Colocho, Kevin Bittman and Margaret Finesilver for technical help. This study was supported in part by grants from the National Institutes of Health (R37HL023081, R01DK039308, R01HL092196, P01HL074940, and P01HL068686, PAJ, DK090918, IA), National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (Z01DK043308, JBK), and Children's National Medical Center intramural Avery Award (HL). NR 44 TC 4 Z9 4 U1 1 U2 6 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 MAR PY 2014 VL 85 IS 3 BP 561 EP 569 DI 10.1038/ki.2013.397 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AC1AC UT WOS:000332225600015 PM 24132210 ER PT J AU Ferguson, JF Mulvey, CK Patel, PN Shah, RY Doveikis, J Zhang, WY Tabita-Martinez, J Terembula, K Eiden, M Koulman, A Griffin, JL Mehta, NN Shah, R Propert, KJ Song, WL Reilly, MP AF Ferguson, Jane F. Mulvey, Claire K. Patel, Parth N. Shah, Rhia Y. Doveikis, Julia Zhang, Weiyu Tabita-Martinez, Jennifer Terembula, Karen Eiden, Michael Koulman, Albert Griffin, Julian L. Mehta, Nehal N. Shah, Rachana Propert, Kathleen J. Song, Wen-Liang Reilly, Muredach P. TI Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers SO MOLECULAR NUTRITION & FOOD RESEARCH LA English DT Article DE Endotoxemia; Fish oil; Inflammation; LPS; n-3 PUFA ID POLYUNSATURATED FATTY-ACIDS; INTRAVENOUS FISH-OIL; EICOSAPENTAENOIC ACID; DOCOSAHEXAENOIC ACID; INSULIN-RESISTANCE; SECONDARY-PREVENTION; CONTROLLED-TRIALS; INNATE IMMUNITY; DOUBLE-BLIND; N-3 PUFA AB ScopeFish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. Methods and resultsThe Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at low (1/day, 900 mg) or high (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor- (TNF-), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. ConclusionEPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions. C1 [Ferguson, Jane F.; Mulvey, Claire K.; Patel, Parth N.; Shah, Rhia Y.; Doveikis, Julia; Zhang, Weiyu; Tabita-Martinez, Jennifer; Terembula, Karen; Mehta, Nehal N.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Eiden, Michael; Koulman, Albert; Griffin, Julian L.] Elsie Widdowson Lab, MRC Human Nutr Res, Cambridge, England. [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Shah, Rachana] Childrens Hosp Philadelphia, Div Pediat Endocrinol, Philadelphia, PA USA. [Propert, Kathleen J.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Song, Wen-Liang] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. RP Ferguson, JF (reprint author), Univ Penn, Perelman Sch Med, Smilow Ctr Translat Res 11 130 11, 3400 Civ Ctr Blvd,Bldg 421, Philadelphia, PA 19104 USA. EM jfer@mail.med.upenn.edu RI Ferguson, Jane/C-7154-2011; OI Ferguson, Jane/0000-0001-6896-1025; Koulman, Albert/0000-0001-9998-051X; Shah, Rachana/0000-0001-7866-557X FU UPenn Investigational Drug Services; National Institutes of Health (NIH) [UL1RR024134, P20-DK 019525]; NIH-NHLBI SCCOR Project grant [P50-HL-083799]; American Heart Association [12POST11840017]; Medical Research Council, UK [UD99999906]; [RO1-HL-111694]; [RO1-HL-113147]; [RO1-DK-090505]; [UO1-HL-108636]; [K24-HL-107643] FX We would like to thank the participants of the FFAME study, the staff at the UPenn Clinical Translational Research Center, and the support of the UPenn Investigational Drug Services. Study materials (Lovaza and matching placebo) were provided to M.P.R. by GlaxoSmithKline. The project described was supported by the National Institutes of Health (NIH) through Grants UL1RR024134 and P20-DK 019525 (both to the University of Pennsylvania) as well as a NIH-NHLBI SCCOR Project grant (P50-HL-083799) to M.P.R. J.F.F. is supported by a postdoctoral fellowship grant from the American Heart Association (12POST11840017). M.P.R. is also supported by RO1-HL-111694, RO1-HL-113147, RO1-DK-090505, UO1-HL-108636, and K24-HL-107643. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. J.L.G., A.K., and M.E. are supported by the Medical Research Council, UK (UD99999906). GlaxoSmithKline had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. NR 53 TC 18 Z9 18 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1613-4125 EI 1613-4133 J9 MOL NUTR FOOD RES JI Mol. Nutr. Food Res. PD MAR PY 2014 VL 58 IS 3 BP 601 EP 613 DI 10.1002/mnfr.201300368 PG 13 WC Food Science & Technology SC Food Science & Technology GA AC2NZ UT WOS:000332339600017 PM 24190860 ER PT J AU Lauren, F Stephen, M Floeter, MK AF Lauren, Flynn Stephen, Matthew Floeter, Mary Kay TI DISEASE SPREAD THROUGH CONTIGUITY AND AXONAL TRACTS IN PRIMARY LATERAL SCLEROSIS SO MUSCLE & NERVE LA English DT Article DE chart review; disease progression; motor neuron disorder; primary lateral sclerosis; symptom spread ID PROGRESSION; PHENOTYPE; SYMPTOMS AB Our goal in this report was to determine whether symptom progression in primary lateral sclerosis (PLS) was consistent with disease spread through axonal pathways or contiguous cortical regions. The date of symptom onset in each limb and cranial region was obtained from 45 PLS patient charts. Each appearance of symptoms in a new body region was classified as axonal, contiguous, possibly contiguous, or unrelated, according to whether the somatotopic representations were adjacent in the cortex. Of 152 spread events, the first spread event was equally divided between axonal (22) and contiguous (23), but the majority of subsequent spread events were classified as contiguous. Symptom progression in PLS patients is consistent with disease spread along axonal tracts and by local cortical spread. Both were equally likely for the first spread event, but local cortical spread was predominant thereafter, suggesting that late degeneration does not advance through long axonal tracts. Muscle Nerve49:439-441, 2014 C1 [Lauren, Flynn; Stephen, Matthew; Floeter, Mary Kay] NINDS, Spast & Spinal Physiol Unit, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), NINDS, Spast & Spinal Physiol Unit, NIH, Bldg 10,CRC Room 7-5680, Bethesda, MD 20892 USA. EM floeterm@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke [NIH Z01 NS002976] FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NIH Z01 NS002976). NR 12 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD MAR PY 2014 VL 49 IS 3 BP 439 EP 441 DI 10.1002/mus.24116 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AB7VP UT WOS:000331999300019 ER PT J AU Hatfield, DL Tsuji, PA Carlson, BA Gladyshev, VN AF Hatfield, Dolph L. Tsuji, Petra A. Carlson, Bradley A. Gladyshev, Vadim N. TI Selenium and selenocysteine: roles in cancer, health, and development SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review DE cancer; selenium; selenocysteine; selenoproteins ID CHEMICALLY-INDUCED HEPATOCARCINOGENESIS; THIOREDOXIN REDUCTASE INHIBITORS; PREVENTION TRIAL SELECT; SELENOPROTEIN EXPRESSION; VITAMIN-E; GLUTATHIONE-PEROXIDASE; REDOX HOMEOSTASIS; KNOCKOUT MICE; TRANSFER-RNA; UGA CODONS AB The many biological and biomedical effects of selenium are relatively unknown outside the selenium field. This fascinating element, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid-1990s selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results. However, basic research on selenium continued to move at a rapid pace, elucidating its many roles in health, development, and in cancer prevention and promotion. Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions. C1 [Hatfield, Dolph L.; Carlson, Bradley A.] Ctr Canc Res, NIH, Mol Biol Selenium Sect, Mouse Canc Genet Program, Bethesda, MD 20892 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. [Gladyshev, Vadim N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. RP Hatfield, DL (reprint author), Ctr Canc Res, NIH, Mol Biol Selenium Sect, Mouse Canc Genet Program, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; NIH FX The authors express their sincere appreciation to Dr Vyacheslav Labunskyy for his help in designing Figure 3. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research to D.L.H., and NIH grants to V.N.G. NR 94 TC 97 Z9 105 U1 7 U2 81 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2014 VL 39 IS 3 BP 112 EP 120 DI 10.1016/j.tibs.2013.12.007 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC7ZI UT WOS:000332752400002 PM 24485058 ER PT J AU Schmidt, LS Linehan, WM AF Schmidt, Laura S. Linehan, W. Marston TI Higher Prevalence of Novel Mutations in VHL Gene in Chinese Von Hippel-Lindau Disease Patients EDITORIAL COMMENT SO UROLOGY LA English DT Editorial Material C1 [Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Schmidt, Laura S.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA. RP Schmidt, LS (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA BC011038-06]; NCI NIH HHS [HHSN261200800001E] NR 3 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 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD MAR PY 2014 VL 83 IS 3 AR 675.e5 DI 10.1016/j.urology.2013.09.070 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AC3IR UT WOS:000332411200045 PM 24581541 ER PT J AU Keck, TM Zou, MF Bi, GH Zhang, HY Wang, XF Yang, HJ Srivastava, R Gardner, EL Xi, ZX Newman, AH AF Keck, Thomas M. Zou, Mu-Fa Bi, Guo-Hua Zhang, Hai-Ying Wang, Xiao-Fei Yang, Hong-Ju Srivastava, Ratika Gardner, Eliot L. Xi, Zheng-Xiong Newman, Amy Hauck TI A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats SO ADDICTION BIOLOGY LA English DT Article DE Cocaine; cue-induced cocaine seeking; MFZ 10-7; mGluR5; MTEP; reinstatement; self-administration; sucrose ID METABOTROPIC GLUTAMATE-RECEPTOR; NEGATIVE ALLOSTERIC MODULATORS; STRESS-INDUCED RELAPSE; NUCLEUS-ACCUMBENS; IN-VIVO; INDUCED REINSTATEMENT; SUBSYNAPTIC LOCALIZATION; SQUIRREL-MONKEYS; DRUG-SEEKING; MPEP AB Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl)ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role. C1 [Keck, Thomas M.; Zou, Mu-Fa; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, NIH,DHHS, Baltimore, MD USA. [Bi, Guo-Hua; Zhang, Hai-Ying; Wang, Xiao-Fei; Yang, Hong-Ju; Srivastava, Ratika; Gardner, Eliot L.; Xi, Zheng-Xiong] NIDA, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), NIDA, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. EM zxi@mail.nih.gov; anewman@intra.nida.nih.gov RI Keck, Thomas/G-9798-2012; OI Keck, Thomas/0000-0003-1845-9373; Srivastava, Rakesh/0000-0003-3112-4252; Srivastava, Rakesh/0000-0002-0065-4069; Zhang, Haiying/0000-0003-0593-5940 FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; NIH FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. T.M.K. was supported by an NIH Postdoctoral Intramural Research Training Award (IRTA) Fellowship. mGluR5-transfected HEK 293 cells were generously provided by Dr. Karen O'Malley of Washington University in St. Louis. NR 66 TC 8 Z9 8 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1369-1600 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2014 VL 19 IS 2 BP 195 EP 209 DI 10.1111/adb.12086 PG 15 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA AB1CO UT WOS:000331529100006 PM 24001208 ER PT J AU Vishwanathan, R Iannaccone, A Scott, TM Kritchevsky, SB Jennings, BJ Carboni, G Forma, G Satterfield, S Harris, T Johnson, KC Schalch, W Renzi, LM Rosano, C Johnson, EJ AF Vishwanathan, Rohini Iannaccone, Alessandro Scott, Tammy M. Kritchevsky, Stephen B. Jennings, Barbara J. Carboni, Giovannella Forma, Gina Satterfield, Suzanne Harris, Tamara Johnson, Karen C. Schalch, Wolfgang Renzi, Lisa M. Rosano, Caterina Johnson, Elizabeth J. TI Macular pigment optical density is related to cognitive function in older people SO AGE AND AGEING LA English DT Article DE lutein; zeaxanthin; cognition; macular pigment; ageing; older people ID LUTEIN; ZEAXANTHIN; MEMORY; AGE; CONSUMPTION; CAROTENOIDS; POPULATION; DECLINE; ADULTS; FRUIT AB Background: the xanthophylls lutein (L) and zeaxanthin (Z) exist in relatively high concentration in multiple central nervous tissues (e. g. cortex and neural retina). L + Z in macula (i.e. macular pigment, MP) are thought to serve multiple functions, including protection and improvement of visual performance. Also, L + Z in the macula are related to L + Z in the cortex. Objective: to determine whether macular pigment optical density (MPOD, L + Z in the macula) is related to cognitive function in older adults. Methods: participants were older adults (n = 108, 77.6 +/- 2.7 years) sampled from the age-related maculopathy ancillary study of the Health Aging and Body Composition Study (Memphis, TN, USA). Serum carotenoids were measured using high performance liquid chromatography. MPOD was assessed using heterochromatic flicker photometry. Eight cognitive tests designed to evaluate several cognitive domains including memory and processing speed were administered. Partial correlation coefficients were computed to determine whether cognitive measures were related to serum L + Z and MPOD. Results: MPOD levels were significantly associated with better global cognition, verbal learning and fluency, recall, processing speed and perceptual speed, whereas serum L + Z was significantly related to only verbal fluency. Conclusion: MPOD is related to cognitive function in older people. Its role as a potential biomarker of cognitive function deserves further study. C1 [Vishwanathan, Rohini; Johnson, Elizabeth J.] Tufts Univ, Carotenoids & Hlth Lab, Boston, MA 02111 USA. [Iannaccone, Alessandro; Jennings, Barbara J.; Carboni, Giovannella; Forma, Gina] Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Memphis, TN 38163 USA. [Scott, Tammy M.] Tufts Univ, Nutr & Aging Lab, Boston, MA 02111 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Carboni, Giovannella; Forma, Gina] Univ Cagliari, Ist Oftalmol, Calgliari, Italy. [Satterfield, Suzanne; Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Harris, Tamara] NIA, NIH, Bethesda, MD 20892 USA. [Schalch, Wolfgang] DSM Nutr Prod, Kaiseraugst, Switzerland. [Renzi, Lisa M.] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Rosano, Caterina] Univ Piitsburgh, Dept Epidemiol, Pittsburgh, PA 15232 USA. RP Johnson, EJ (reprint author), Tufts Univ, Carotenoids & Hlth Lab, 711 Washington St, Boston, MA 02111 USA. EM elizabeth.johnson@tufts.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Renzi-Hammond, Lisa/0000-0003-4334-8202 FU NIH [K23 EY000409, N01 AG62101, N01 AG62103, N01 AG62106]; International Retinal Research Foundation; Research to Prevent Blindness; American Health Assistance Foundation; DSM FX This work was supported by NIH grant K23 EY000409 (A. I.), and by NIH contracts N01 AG62101, N01 AG62103 and N01 AG62106 (Health ABC Study); by the International Retinal Research Foundation (A. I.), by Research to Prevent Blindness (Career Development Award to A. I. and unrestricted grant to UTHSC Hamilton Eye Institute), by the American Health Assistance Foundation and by DSM. The instrument utilised to measure MPOD in this study was generously donated by Bausch and Lomb and Kemin Foods. Portions of these findings have been presented at the Association for Research in Vision and Ophthalmology Annual Meeting (2007) and at the Experimental Biology Annual Meeting (2008). NR 27 TC 28 Z9 28 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD MAR PY 2014 VL 43 IS 2 BP 271 EP 275 DI 10.1093/ageing/aft210 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AB8GP UT WOS:000332028600023 PM 24435852 ER PT J AU Abbondanzieri, EA Le Grice, SFJ AF Abbondanzieri, Elio A. Le Grice, Stuart F. J. TI Unraveling the Gymnastics of Reverse Transcription Through Single Molecule Spectroscopy SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Editorial Material C1 [Abbondanzieri, Elio A.] Delft Univ Technol, Dept Bionanosci, Delft, Netherlands. [Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM legrices@mail.nih.gov NR 3 TC 0 Z9 1 U1 2 U2 4 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 MAR 1 PY 2014 VL 30 IS 3 BP 209 EP 210 DI 10.1089/aid.2014.0023 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AB9FI UT WOS:000332095600003 PM 24588577 ER PT J AU Burns, DN DeGruttola, V Pilcher, CD Kretzschmar, M Gordon, CM Flanagan, EH Duncombe, C Cohen, MS AF Burns, David N. DeGruttola, Victor Pilcher, Christopher D. Kretzschmar, Mirjam Gordon, Christopher M. Flanagan, Elizabeth H. Duncombe, Christopher Cohen, Myron S. CA NIH-BMGF Finding Persons Unaware TI Toward an Endgame: Finding and Engaging People Unaware of Their HIV-1 Infection in Treatment and Prevention SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ANTIRETROVIRAL THERAPY INITIATION; SOCIAL NETWORKS; UNITED-STATES; NORTH-AMERICA; SOUTH-AFRICA; TRANSMISSION; MEN; SEX; BEHAVIOR; RATES AB Epidemic modeling suggests that a major scale-up in HIV treatment could have a dramatic impact on HIV incidence. This has led both researchers and policymakers to set a goal of an AIDS-Free Generation. One of the greatest obstacles to achieving this objective is the number of people with undiagnosed HIV infection. Despite recent innovations, new research strategies are needed to identify, engage, and successfully treat people who are unaware of their infection. C1 [Burns, David N.; Flanagan, Elizabeth H.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [DeGruttola, Victor] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Pilcher, Christopher D.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Kretzschmar, Mirjam] RIVM, Ctr Infect Dis Control, Bilthoven, Netherlands. [Kretzschmar, Mirjam] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Gordon, Christopher M.] NIMH, NIH, Rockville, MD 20857 USA. [Duncombe, Christopher] Bill & Melinda Gates Fdn, Seattle, WA USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. RP Burns, DN (reprint author), NIAID, Clin Prevent Res Branch, Prevent Sci Program, Div Aids, 5th Floor,Room 5121 6700B Rockledge Dr, Bethesda, MD 20892 USA. EM burnsda@niaid.nih.gov OI Burns, David/0000-0002-3362-865X FU Division of AIDS of the National Institute of Allergy and Infectious Diseases; National Institute of Mental Health, National Institutes of Health; Bill and Melinda Gates Foundation; National Institutes of Health [R34 MH096606, R37 A151164, UMI A1068619, P30 A150410] FX The Finding Persons Unaware of their HIV Infection Workshop was sponsored by the Division of AIDS of the National Institute of Allergy and Infectious Diseases, and the National Institute of Mental Health, National Institutes of Health, and the Bill and Melinda Gates Foundation. This research was supported in part by the National Institutes of Health (Christopher D. Pilcher, R34 MH096606; Victor DeGruttola, R37 A151164; and Myron S. Cohen, UMI A1068619 and P30 A150410). NR 87 TC 12 Z9 12 U1 0 U2 3 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 MAR 1 PY 2014 VL 30 IS 3 BP 217 EP 224 DI 10.1089/aid.2013.0274 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AB9FI UT WOS:000332095600006 PM 24410300 ER PT J AU Nilsson, C Godoy-Ramirez, K Hejdeman, B Brave, A Gudmundsdotter, L Hallengard, D Currier, JR Wieczorek, L Hasselrot, K Earl, PL Polonis, VR Marovich, MA Robb, ML Sandstrom, E Wahren, B Biberfeld, G AF Nilsson, Charlotta Godoy-Ramirez, Karina Hejdeman, Bo Brave, Andreas Gudmundsdotter, Lindvi Hallengard, David Currier, Jeffrey R. Wieczorek, Lindsay Hasselrot, Klara Earl, Patricia L. Polonis, Victoria R. Marovich, Mary A. Robb, Merlin L. Sandstrom, Eric Wahren, Britta Biberfeld, Gunnel TI Broad and Potent Cellular and Humoral Immune Responses After a Second Late HIV-Modified Vaccinia Virus Ankara Vaccination in HIV-DNA-Primed and HIV-Modified Vaccinia Virus Ankara-Boosted Swedish Vaccinees SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-CELL; ANTIBODY; CLADE; MVA; IMMUNOGENICITY; INDIVIDUALS; INFECTION; EPITOPES; ENVELOPE AB We have previously shown that an HIV vaccine regimen including three HIV-DNA immunizations and a single HIV-modified vaccinia virus Ankara (MVA) boost was safe and highly immunogenic in Swedish volunteers. A median 38 months after the first HIV-MVA vaccination, 24 volunteers received 10(8) plaque-forming units of HIV-MVA. The vaccine was well tolerated. Two weeks after this HIV-MVA vaccination, 18 (82%) of 22 evaluable vaccinees were interferon (IFN)- enzyme-linked immunospot (ELISpot) reactive: 18 to Gag and 10 (45%) to Env. A median minimal epitope count of 4 to Gag or Env was found in a subset of 10 vaccinees. Intracellular cytokine staining revealed CD4(+) and/or CD8(+) T cell responses in 23 (95%) of 24 vaccinees, 19 to Gag and 19 to Env. The frequency of HIV-specific CD4(+) and CD8(+) T cell responses was equally high (75%). A high proportion of CD4(+) and CD8(+) T cell responses to Gag was polyfunctional with production of three or more cytokines (40% and 60%, respectively). Of the Env-specific CD4(+) T cells 40% were polyfunctional. Strong lymphoproliferative responses to Aldrithiol-2 (AT-2)-treated subtype A, B, C, and A_E virus were demonstrable in 21 (95%) of 22 vaccinees. All vaccinees developed binding antibodies to Env and Gag. Neutralizing antibodies were detected in a peripheral blood mononuclear cell (PBMC)-based assay against subtype B and CRF01_AE viruses. The neutralizing antibody response rates were influenced by the vaccine dose and/or mode of delivery used at the previous HIV-MVA vaccination. Thus, a second late HIV-MVA boost induced strong and broad cellular immune responses and improved antibody responses. The data support further exploration of this vaccine concept. C1 [Nilsson, Charlotta; Godoy-Ramirez, Karina; Brave, Andreas; Gudmundsdotter, Lindvi; Hallengard, David; Earl, Patricia L.; Wahren, Britta; Biberfeld, Gunnel] Swedish Inst Communicable Dis Control, SE-17182 Solna, Sweden. [Nilsson, Charlotta; Brave, Andreas; Gudmundsdotter, Lindvi; Hallengard, David; Wahren, Britta; Biberfeld, Gunnel] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Nilsson, Charlotta] Karolinska Inst, Dept Lab Med, Huddinge, Sweden. [Hejdeman, Bo; Sandstrom, Eric] Karolinska Inst, Dept Educ & Clin Res, Sodersjukhuset, Stockholm, Sweden. [Currier, Jeffrey R.; Wieczorek, Lindsay; Polonis, Victoria R.; Marovich, Mary A.; Robb, Merlin L.] Walter Reed Army Inst Res, Dept Retrovirol, Rockville, MD USA. [Hasselrot, Klara] Ctr Mol Med, Infect Dis Unit, Dept Med, Solna, Sweden. [Hasselrot, Klara] Karolinska Univ Hosp, Solna, Sweden. [Earl, Patricia L.] NIAID, NIH, Bethesda, MD 20892 USA. RP Nilsson, C (reprint author), Swedish Inst Communicable Dis Control, Dept Diagnost & Vaccinol, SE-17182 Solna, Sweden. EM charlotta.nilsson@smi.se FU European Union [INCO-DEV A4 ICFP501A4PR03, AVIP 503487]; European Union (Europrise); Swedish International Development Cooperation Agency (Sida) [SWE-2004-120, HIV2004-000809, 2004:813]; Swedish Research Council (Vetenskapsradet) [K2004-16x-07743-19]; Lakare mot AIDS Forskningsfond [04-050301, 01-051101]; Vecura, Karolinska University Hospital; Division of Intramural Research, NIAID, NIH; U.S. Military HIV Research Program; U.S. Military HIV Research Program, WRAIR FX The study was funded by the European Union (INCO-DEV A4 ICFP501A4PR03 to E. S. and AVIP 503487 and Europrise to B. W. and E. S.), the Swedish International Development Cooperation Agency (Sida) (SWE-2004-120 to C.N. and HIV2004-000809 and 2004:813 to G. B.), the Swedish Research Council (Vetenskapsradet, K2004-16x-07743-19 to B. W.), and Lakare mot AIDS Forskningsfond (04-050301 and 01-051101 to E. S.). None of these institutions had any influence on the study or its analysis. Documentation and production of the HIV-DNA vaccines were supported by Vecura, Karolinska University Hospital. Construction of the HIV-1 MVA was supported by the Division of Intramural Research, NIAID, NIH and the U.S. Military HIV Research Program. The production costs were funded by the U.S. Military HIV Research Program, WRAIR. NR 35 TC 7 Z9 8 U1 1 U2 4 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 MAR 1 PY 2014 VL 30 IS 3 BP 299 EP 311 DI 10.1089/aid.2013.0149 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AB9FI UT WOS:000332095600018 PM 24090081 ER PT J AU Li, WQ Park, Y Wu, JW Goldstein, AM Taylor, PR Hollenbeck, AR Freedman, ND Abnet, CC AF Li, Wen-Qing Park, Yikyung Wu, Jennifer W. Goldstein, Alisa M. Taylor, Philip R. Hollenbeck, Albert R. Freedman, Neal D. Abnet, Christian C. TI Index-based dietary patterns and risk of head and neck cancer in a large prospective study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NIH-AARP DIET; HEALTH-AMERICAN-ASSOCIATION; EXPLORATORY FACTOR-ANALYSIS; UPPER AERODIGESTIVE TRACT; RETIRED-PERSONS DIET; HUMAN-PAPILLOMAVIRUS; NATIONAL-INSTITUTES; EPIDEMIOLOGY CONSORTIUM; INTERNATIONAL HEAD; MEDITERRANEAN DIET AB Background: Head and neck cancer (HNC) is the seventh most common cancer worldwide. Although diet has been proposed to play an important role in HNC, few associations with diet have been convincing other than alcohol intake. Studies of dietary patterns that examine overall diets may provide broader insight than studies of individual foods. Little is known about the association between dietary patterns and risk of HNC. Objective: We prospectively evaluated the association between 2 index-based dietary patterns [ie, the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet Score (aMED)] and risk of head and neck squamous cell carcinoma. Design: We included 494,967 participants from the NIH-AARP Diet and Health study (1995-2006). HRs (95% CIs) were estimated by using Cox regression. Scores for the HEI-2005 and aMED were calculated on the basis of diet assessed by using a baseline foodfrequency questionnaire. Higher scores reflected adherence to dietary recommendations for healthy eating. Our main outcome was the incidence of HNC, including cancer of the larynx, oral cavity, and orohypopharynx. Results: A total of 1868 HNC cases were identified during followup. Higher HEI-2005 scores were associated with reduced risk of HNC in men [HR: 0.74 (95% CI: 0.61, 0.89) for highest compared with lowest quintiles; P-trend = 0.00081 and women [HR: 0.48; 95% CI: 0.33, 0.70; P-trend < 0.00011. High aMED scores were also associated with lower HNC risk in men (HR: 0.80; 95% CI: 0.64, 1.01; P-trend = 0.002) and women (HR: 0.42; 95% CI: 0.24, 0.74; P-trend <0.0001). Associations were similar among subsites. We did not find significant interactions between smoking and alcohol intake and each index on HNC risk. Conclusions: HEI-2005 and aMED scores were associated inversely with risk of HNC. Large interventional studies are required to assess the causality before conveying definite public health messages. C1 [Li, Wen-Qing; Park, Yikyung; Wu, Jennifer W.; Goldstein, Alisa M.; Taylor, Philip R.; Freedman, Neal D.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Li, WQ (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM liw9@mail.nih.gov RI Li, Wenqing/N-2293-2014; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; OI Li, Wenqing/0000-0002-1283-4091; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, NIH FX Supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 47 TC 12 Z9 13 U1 0 U2 11 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 MAR PY 2014 VL 99 IS 3 BP 559 EP 566 DI 10.3945/ajcn.113.073163 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AB9VN UT WOS:000332143900019 PM 24401718 ER PT J AU Bailey, JF Duncan, AE Colman, RJ Mattison, JA Kramer, PA AF Bailey, Jeannie F. Duncan, Andrea E. Colman, Ricki J. Mattison, Julie A. Kramer, Patricia A. TI The effect of caloric restriction on the rate and severity of age-related spinal osteoarthritis SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 08-12, 2014 CL Calgary, CANADA SP Amer Assoc Phys Anthropologists C1 [Bailey, Jeannie F.; Duncan, Andrea E.; Kramer, Patricia A.] Univ Washington, Seattle, WA 98195 USA. [Colman, Ricki J.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Mattison, Julie A.] NIA, Intramural Res Program, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2014 VL 153 SU 58 SI SI BP 71 EP 71 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA AA6RH UT WOS:000331225100032 ER PT J AU Song, SS Holloway, RL Song, WC Bae, CJ AF Song, Sunbin S. Holloway, Ralph L. Song, Wu-Chul Bae, Christopher J. TI Changes in human brain morphometry following the transition to plant and animal domestication SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 08-12, 2014 CL Calgary, CANADA SP Amer Assoc Phys Anthropologists C1 [Song, Sunbin S.] NIH, Bethesda, MD USA. [Holloway, Ralph L.] Columbia Univ, New York, NY 10027 USA. [Song, Wu-Chul] Konkuk Univ, Seoul, South Korea. [Bae, Christopher J.] Univ Hawaii, Honolulu, HI 96822 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2014 VL 153 SU 58 SI SI BP 243 EP 244 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA AA6RH UT WOS:000331225100798 ER PT J AU Wildman, DE Caravas, J Agnew, D Benirschke, K Savage-Rumbaugh, S Kim, CJ Romero, R Wagner, GP Mcgowen, MR AF Wildman, Derek E. Caravas, Jason Agnew, Dalen Benirschke, Kurt Savage-Rumbaugh, Sue Kim, C. J. Romero, Roberto Wagner, Gunter P. Mcgowen, Michael R. TI Gene expression and activity during primate pregnancies SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Physical-Anthropologists CY APR 08-12, 2014 CL Calgary, CANADA SP Amer Assoc Phys Anthropologists C1 [Wildman, Derek E.; Caravas, Jason; Mcgowen, Michael R.] Wayne State Univ, Detroit, MI USA. [Wildman, Derek E.; Kim, C. J.; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Brookline, MA USA. [Agnew, Dalen] Michigan State Univ, Coll Vet Med, Diagnost Ctr Populat & Anim Hlth, E Lansing, MI 48824 USA. [Benirschke, Kurt] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Savage-Rumbaugh, Sue] Iowa Primate Learning Sanctuary, Bonobo Hope, Des Moines, IA USA. [Wagner, Gunter P.] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 EI 1096-8644 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2014 VL 153 SU 58 SI SI BP 272 EP 272 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA AA6RH UT WOS:000331225100927 ER PT J AU Shaw, P Stringaris, A Nigg, J Leibenluft, E AF Shaw, Philip Stringaris, Argyris Nigg, Joel Leibenluft, Ellen TI Emotion Dysregulation in Attention Deficit Hyperactivity Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID CHILD-BEHAVIOR CHECKLIST; PEDIATRIC BIPOLAR DISORDER; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIALS; SEVERE MOOD DYSREGULATION; FAMILY RISK ANALYSIS; DEFICIT/HYPERACTIVITY DISORDER; DELAY AVERSION; SELF-REGULATION; DOUBLE-BLIND AB Although it has long been recognized that many individuals with attention deficit hyperactivity disorder (ADHD) also have difficulties with emotion regulation, no consensus has been reached on how to conceptualize this clinically challenging domain. The authors examine the current literature using both quantitative and qualitative methods. Three key findings emerge. First, emotion dysregulation is prevalent in ADHD throughout the lifespan and is a major contributor to impairment. Second, emotion dysregulation in ADHD may arise from deficits in orienting toward, recognizing, and/or allocating attention to emotional stimuli; these deficits implicate dysfunction within a striato-amygdalo-medial prefrontal cortical network. Third, while current treatments for ADHD often also ameliorate emotion dysregulation, a focus on this combination of symptoms reframes clinical questions and could stimulate novel therapeutic approaches. The authors then consider three models to explain the overlap between emotion dysregulation and ADHD: emotion dysregulation and ADHD are correlated but distinct dimensions; emotion dysregulation is a core diagnostic feature of ADHD; and the combination constitutes a nosological entity distinct from both ADHD and emotion dysregulation alone. The differing predictions from each model can guide research on the much-neglected population of patients with ADHD and emotion dysregulation. C1 [Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. NIMH, Intramural Program, Bethesda, MD 20892 USA. Kings Coll London, Inst Psychiat, London WC2R 2LS, England. Oregon Hlth & Sci Univ, Dept Psychiat, Div Psychol, Portland, OR 97201 USA. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU U.K. Department of Health; Biomedical Research Centre of the National Institute of Health Research, U.K. FX Dr. Stringaris is a Wellcome Trust Fellow and also receives funding from the U.K. Department of Health and the Biomedical Research Centre of the National Institute of Health Research, U.K.; he receives royalties from Cambridge University Press. The other authors report no financial relationships with commercial interests. NR 149 TC 100 Z9 102 U1 8 U2 68 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 MAR PY 2014 VL 171 IS 3 BP 276 EP 293 DI 10.1176/appi.ajp.2013.13070966 PG 18 WC Psychiatry SC Psychiatry GA AC2QG UT WOS:000332348400008 PM 24480998 ER PT J AU Shrestha, SS Nelson, EE Liow, JS Gladding, R Lyoo, CH Noble, PL Morse, C Henter, ID Kruger, J Zhang, B Suomi, SJ Svenningsson, P Pike, VW Winslow, JT Leibenluft, E Pine, DS Innis, RB AF Shrestha, Stal Saurav Nelson, Eric E. Liow, Jeih-San Gladding, Robert Lyoo, Chul Hyoung Noble, Pam L. Morse, Cheryl Henter, Ioline D. Kruger, Jeremy Zhang, Bo Suomi, Stephen J. Svenningsson, Per Pike, Victor W. Winslow, James T. Leibenluft, Ellen Pine, Daniel S. Innis, Robert B. TI Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; EARLY-LIFE STRESS; 5-HT1A RECEPTORS; RHESUS-MONKEYS; BRAIN; DEPRESSION; MICE; ADULT; NEUROTRANSMISSION; PRIMATES AB Objective: This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth an animal model of human childhood stress were also studied. Method: At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. Results: Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. Conclusions: Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo. C1 [Shrestha, Stal Saurav] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Shrestha, SS (reprint author), NIMH, Intramural Res Program, Bethesda, MD 20892 USA. EM saurav.shrestha@nih.gov OI Nelson, Eric/0000-0002-3376-2453 FU Intramural Research Program of the NIMH FX The authors acknowledge the support of the Intramural Research Program of the NIMH and thank Masanori Ichise, Masahiro Fujita, Sami S. Zoghbi, Paul Cumming, Allison Nugent, Kimberly J. Jenko, David A. Luckenbaugh, George M. Anderson, Alex Cummins, and the joint National Institutes of Health-Karolinska Institutet Doctoral Program in Neuroscience. NR 44 TC 18 Z9 19 U1 0 U2 13 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 MAR PY 2014 VL 171 IS 3 BP 323 EP 331 DI 10.1176/appi.ajp.2013.13020183 PG 9 WC Psychiatry SC Psychiatry GA AC2QG UT WOS:000332348400011 PM 24480874 ER PT J AU Vieland, VJ Walters, KA Lehner, T Azaro, M Tobin, K Huang, YG Brzustowicz, LM AF Vieland, Veronica J. Walters, Kimberly A. Lehner, Thomas Azaro, Marco Tobin, Kathleen Huang, Yungui Brzustowicz, Linda M. TI Revisiting Schizophrenia Linkage Data in the NIMH Repository: Reanalysis of Regularized Data Across Multiple Studies SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID AFRICAN-AMERICAN FAMILIES; GENOME-WIDE LINKAGE; SUSCEPTIBILITY LOCI; BIPOLAR DISORDER; MILLENNIUM CONSORTIUM; HUMAN-GENETICS; SCAN; HETEROGENEITY; SAMPLE; MODEL AB Objective: The Combined Analysis of Psychiatric Studies (CAPS) project conducted extensive review and regularization across studies of all schizophrenia linkage data available as of 2011 from the National Institute of Mental Health-funded Center for Collaborative Genomic Studies on Mental Disorders, also known as the Human Genetics Initiative (HGI). The authors reanalyzed the data using statistical methods tailored to accumulation of evidence across multiple, potentially highly heterogeneous, sets of data. Method: Data were subdivided based on contributing study, major population group, and presence or absence within families of schizophrenia with a substantial affective component. The posterior probability of linkage (PPL) statistical framework was used to sequentially update linkage evidence across these data subsets (omnibus results). Results: While some loci previously implicated using the HGI data were also identified in the present omnibus analysis (2q36.1, 15q23), others were not. Several loci were found that had not previously been reported in the HGI samples but are supported by independent linkage or association studies (3q28, 12q23.1, 11p11.2, Xq26.1). Not surprisingly, differences were seen across population groups. Of particular interest are signals on 11p15.3, 11p11.2, and Xq26.1, for which data from families with a substantial affective component support linkage while data from the remaining families provide evidence against linkage. All three of these loci overlap with loci reported in independent studies of bipolar disorder or mixed bipolar-schizophrenia samples. Conclusions: Public data repositories provide the opportunity to leverage large multisite data sets for studying complex disorders. Analysis with a statistical method specifically designed for such data enables us to extract new information from an existing data resource. C1 [Vieland, Veronica J.] Nationwide Childrens Hosp, Res Inst, Battelle Ctr Math Med, Columbus, OH 43205 USA. Rutgers State Univ, Dept Genet, Piscataway, NJ USA. NIMH, Bethesda, MD 20892 USA. RP Vieland, VJ (reprint author), Nationwide Childrens Hosp, Res Inst, Battelle Ctr Math Med, Columbus, OH 43205 USA. EM veronica.vieland@nationwidechildrens.org FU NIH [R01 MH086117, U24 MH068457] FX Supported by NIH grants R01 MH086117 and U24 MH068457. NR 46 TC 3 Z9 3 U1 0 U2 0 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 MAR PY 2014 VL 171 IS 3 BP 350 EP 359 DI 10.1176/appi.ajp.2013.11121766 PG 10 WC Psychiatry SC Psychiatry GA AC2QG UT WOS:000332348400014 PM 24170318 ER PT J AU Glantz, MD Medina-Mora, ME Petukhova, M Andrade, LH Anthony, JC de Girolamo, G de Graaf, R Degenhardt, L Demyttenaere, K Florescu, S Gureje, O Haro, JM Horiguchi, I Karam, EG Kostyuchenko, S Lee, S Lepine, JP Matschinger, H Neumark, Y Posada-Villa, J Sagar, R Stein, DJ Tomov, T Wells, JE Chatterji, S Kessler, RC AF Glantz, Meyer D. Medina-Mora, Maria Elena Petukhova, Maria Andrade, Laura Helena Anthony, James C. de Girolamo, Giovanni de Graaf, Ron Degenhardt, Louisa Demyttenaere, Koen Florescu, Silvia Gureje, Oye Maria Haro, Josep Horiguchi, Itsuko Karam, Elie G. Kostyuchenko, Stanislav Lee, Sing Lepine, Jean-Pierre Matschinger, Herbert Neumark, Yehuda Posada-Villa, Jose Sagar, Rajesh Stein, Dan J. Tomov, Toma Wells, J. Elisabeth Chatterji, Somnath Kessler, Ronald C. TI Alcohol Abuse in Developed and Developing Countries in the World Mental Health Surveys: Socially Defined Consequences or Psychiatric Disorder? SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID SUBSTANCE USE DISORDERS; NATIONAL EPIDEMIOLOGIC SURVEY; ITEM RESPONSE THEORY; DSM-IV; HAZARDOUS USE; DRUG-ABUSE; DEPENDENCE; CRITERIA; PSYCHOPATHOLOGY; ADOLESCENTS AB BackgroundPrevious single country research has raised concerns that: (1) the DSM-IV diagnosis of alcohol abuse (AA) is met primarily through the hazardous use criterion related to drinking and driving and (2) that the hazardous use and social consequences AA criteria primarily reflect varying socioeconomic and cultural factors rather than psychiatric disorder. MethodsUsing representative cross-national data from the 21 countries in the World Mental Health surveys, adults meeting DSM-IV lifetime criteria for AA but not dependence from 10 developed (n=46,071) and 11 developing (n=49,761) countries were assessed as meeting AA with the hazardous use or the social consequences criteria. ResultsBetween 29.3% (developed) and 16.2% (developing) of respondents with AA met only the hazardous use criterion. AA cases with and without hazardous use were similar in age-of-onset, course, predictors, and psychopathological consequences in both developed and developing countries. Discussion and ConclusionsDespite some associations of the AA criteria with socioeconomic factors, the hazardous use and social consequences criteria were significantly associated with psychiatric predictors and sequelae. The findings indicate that these criteria reflect psychiatric disorder and are appropriate for inclusion as DSM-5 Alcohol Use Disorder criteria. Scientific SignificanceThese findings support a psychiatric rather than a sociocultural view of the hazardous use and social consequences symptoms and provide evidence that they are appropriate diagnostic criteria cross-nationally with utility in a wide range of socioeconomic environments. This suggests consideration for their adoption by ICD-11. Further research is needed on the implications of these results for prevention and treatment. (Am J Addict 2014;23:145-155) C1 [Glantz, Meyer D.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Medina-Mora, Maria Elena] Natl Inst Psychiat, Mexico City, DF, Mexico. [Petukhova, Maria; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Andrade, Laura Helena] Univ Sao Paulo, Sch Med, Dept Inst Psychiat, Sect Psychiat Epidemiol LIM 23, Sao Paulo, Brazil. [Anthony, James C.] Michigan State Univ, Coll Human Med, Dept Epidemiol, E Lansing, MI 48824 USA. [de Girolamo, Giovanni] IRCCS Ctr S Giovanni di Dio Fatebenefratelli, Bologna, Italy. [de Graaf, Ron] Netherlands Inst Mental Hlth & Addict, Utrecht, Netherlands. [Degenhardt, Louisa] Univ New S Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Demyttenaere, Koen] Univ Hosp Gasthuisberg, Dept Psychiat, B-3000 Louvain, Belgium. [Florescu, Silvia] Natl Sch Publ Hlth & Hlth Serv Management, Publ Hlth Res & Evidence Based Med Dept, Bucharest, Romania. [Gureje, Oye] Univ Coll Hosp, Dept Psychiat, Ibadan, Nigeria. [Maria Haro, Josep] CIBERSAM Dr Antoni Pujades, Parc Sanitari St Joan de Deu, Barcelona, Spain. [Horiguchi, Itsuko] Juntendo Univ, Sch Med, Dept Publ Hlth, Tokyo 113, Japan. [Karam, Elie G.] Balamand Univ, Fac Med, St George Hosp Univ Med Ctr, Dept Psychiat & Clin Psychol,IDRAAC, Beirut, Lebanon. [Kostyuchenko, Stanislav] Ukrainian Psychiat Assoc, Kiev, Ukraine. [Lee, Sing] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Psychiat, Shatin, Hong Kong, Peoples R China. [Lepine, Jean-Pierre] Univ Paris Diderot & Paris Descartes, Hop Lariboisiere Fernand Widal, AP HP, Univ Paris Diderot,INSERM U705,CNRS UMR 7157, Paris, France. [Matschinger, Herbert] Univ Leipzig, Fak Med, Inst Arbeits & Sozialmed, D-04109 Leipzig, Germany. [Neumark, Yehuda] Hebrew Univ Jerusalem Hadassah Hosp & Med Sch, Braun Sch Publ Hlth & Community Med, Jerusalem, Israel. [Posada-Villa, Jose] Saldarriaga Concha Fdn, Dev Rehabil Syst FSC, Bogata Dc, Colombia. [Sagar, Rajesh] All India Inst Med Sci, Dept Psychiat, New Delhi, India. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, ZA-7925 Cape Town, South Africa. [Tomov, Toma] New Bulgarian Univ, Inst Human Relat, Sofia, Bulgaria. [Wells, J. Elisabeth] Univ Otago, Dept Publ Hlth & Gen Practice, Christchurch, New Zealand. [Chatterji, Somnath] WHO, CH-1211 Geneva, Switzerland. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu RI Degenhardt, Louisa/D-4515-2012; Lee, Sing/O-2136-2015; Haro, Josep Maria/D-1423-2011; Stein, Dan/A-1752-2008; Andrade, Laura Helena/F-3023-2010 OI Degenhardt, Louisa/0000-0002-8513-2218; Haro, Josep Maria/0000-0002-3984-277X; Stein, Dan/0000-0001-7218-7810; Andrade, Laura Helena/0000-0002-2362-3521 FU NIMH NIH HHS [U01‐MH60220] NR 54 TC 3 Z9 3 U1 6 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD MAR PY 2014 VL 23 IS 2 BP 145 EP 155 DI 10.1111/j.1521-0391.2013.12082.x PG 11 WC Substance Abuse SC Substance Abuse GA AA9AP UT WOS:000331386400007 PM 25187050 ER PT J AU Dietzgen, RG Kuhn, JH Clawson, AN Freitas-Astua, J Goodin, MM Kitajima, EW Kondo, H Wetzel, T Whitfield, AE AF Dietzgen, Ralf G. Kuhn, Jens H. Clawson, Anna N. Freitas-Astua, Juliana Goodin, Michael M. Kitajima, Elliott W. Kondo, Hideki Wetzel, Thierry Whitfield, Anna E. TI Dichorhavirus: a proposed new genus for Brevipalpus mite-transmitted, nuclear, bacilliform, bipartite, negative-strand RNA plant viruses SO ARCHIVES OF VIROLOGY LA English DT Article ID ORCHID-FLECK-VIRUS; ORDER MONONEGAVIRALES; PHOENICIS ACARI; TENUIPALPIDAE; INFECTION; CALIFORNICUS; RHABDOVIRUS; POLYMERASE; BIOLOGY; GENOME AB Orchid fleck virus (OFV) is an unassigned negative-sense, single-stranded (-)ssRNA plant virus that was previously suggested to be included in the family Rhabdoviridae, order Mononegavirales. Although OFV shares some biological characteristics, including nuclear cytopathological effects, gene order, and sequence similarities, with nucleorhabdoviruses, its taxonomic status is unclear because unlike all mononegaviruses, OFV has a segmented genome and its particles are not enveloped. This article analyses the available biological, physico-chemical, and nucleotide sequence evidence that seems to indicate that OFV and several other Brevipalpus mite-transmitted short bacilliform (-)ssRNA viruses are likely related and may be classified taxonomically in novel species in a new free-floating genus Dichorhavirus. C1 [Dietzgen, Ralf G.] Univ Queensland, Queensland Alliance Agr & Food Innovat, St Lucia, Qld 4072, Australia. [Kuhn, Jens H.; Clawson, Anna N.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Freitas-Astua, Juliana] Embrapa Cassava & Fruits, Cruz Das Almas, BA, Brazil. [Goodin, Michael M.] Univ Kentucky, Lexington, KY USA. [Kitajima, Elliott W.] ESALQ USP, NAP MEPA, Piracicaba, SP, Brazil. [Kondo, Hideki] Okayama Univ, Inst Plant Sci & Resources, Kurashiki, Okayama, Japan. [Wetzel, Thierry] AlPlanta, RLP Agrosci, Neustadt, Germany. [Whitfield, Anna E.] Kansas State Univ, Manhattan, KS 66506 USA. RP Dietzgen, RG (reprint author), Univ Queensland, Queensland Alliance Agr & Food Innovat, St Lucia, Qld 4072, Australia. EM r.dietzgen@uq.edu.au RI Kuhn, Jens H./B-7615-2011; Freitas-Astua, Juliana/C-5833-2013 OI Kuhn, Jens H./0000-0002-7800-6045; Freitas-Astua, Juliana/0000-0002-0506-6880 FU NIAID [HHSN272200700016I] FX The taxonomic changes suggested here have not been endorsed by the ICTV Executive Committee, may differ from any new taxonomy that is ultimately approved by the ICTV, and is presented for discussion only but has no official standing. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Consulting, Inc., and ANC as the owner of Logos Consulting, Inc., both subcontractors to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200700016I. NR 54 TC 21 Z9 22 U1 0 U2 13 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD MAR PY 2014 VL 159 IS 3 BP 607 EP 619 DI 10.1007/s00705-013-1834-0 PG 13 WC Virology SC Virology GA AB8DE UT WOS:000332019500026 PM 24081823 ER PT J AU Valapala, M Wilson, C Hose, S Bhutto, IA Grebe, R Dong, AL Greenbaum, S Gu, LM Sengupta, S Cano, M Hackett, S Xu, GT Lutty, GA Dong, LJ Sergeev, Y Handa, JT Campochiaro, P Wawrousek, E Zigler, JS Sinha, D AF Valapala, Mallika Wilson, Christine Hose, Stacey Bhutto, Imran A. Grebe, Rhonda Dong, Aling Greenbaum, Seth Gu, Limin Sengupta, Samhita Cano, Marisol Hackett, Sean Xu, Guotong Lutty, Gerard A. Dong, Lijin Sergeev, Yuri Handa, James T. Campochiaro, Peter Wawrousek, Eric Zigler, J. Samuel, Jr. Sinha, Debasish TI Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/beta A3/A1-crystallin via V-ATPase-MTORC1 signaling SO AUTOPHAGY LA English DT Article DE autophagy; beta A3/A1-crystallin; lysosomes; MTORC1; phagocytosis; retinal pigment epithelium; retinal function; V-ATPase ID VACUOLAR H+-ATPASE; AMINO-ACIDS; AUTOPHAGIC DEGRADATION; DISEASE; MTORC1; PROTEIN; BETA-A3/A1-CRYSTALLIN; PHAGOCYTOSIS; MYOPATHY; DEATH AB In phagocytic cells, including the retinal pigment epithelium (RPE), acidic compartments of the endolysosomal system are regulators of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. The acidification of the endolysosomal system is modulated by a proton pump, the V-ATPase, but the mechanisms that direct the activity of the V-ATPase remain elusive. We found that in RPE cells, CRYBA1/A3/A1-crystallin, a lens protein also expressed in RPE, is localized to lysosomes, where it regulates endolysosomal acidification by modulating the V-ATPase, thereby controlling both phagocytosis and autophagy. We demonstrated that CRYBA1 coimmunoprecipitates with the ATP6V0A1/V-0-ATPase a1 subunit. Interestingly, in mice when Cryba1 (the gene encoding both the A3- and A1-crystallin forms) is knocked out specifically in RPE, V-ATPase activity is decreased and lysosomal pH is elevated, while cathepsin D (CTSD) activity is decreased. Fundus photographs of these Cryba1 conditional knockout (cKO) mice showed scattered lesions by 4 months of age that increased in older mice, with accumulation of lipid-droplets as determined by immunohistochemistry. Transmission electron microscopy (TEM) of cryba1 cKO mice revealed vacuole-like structures with partially degraded cellular organelles, undigested photoreceptor outer segments and accumulation of autophagosomes. Further, following autophagy induction both in vivo and in vitro, phospho-AKT and phospho-RPTOR/Raptor decrease, while pMTOR increases in RPE cells, inhibiting autophagy and AKT-MTORC1 signaling. Impaired lysosomal clearance in the RPE of the cryba1 cKO mice also resulted in abnormalities in retinal function that increased with age, as demonstrated by electroretinography. Our findings suggest that loss of CRYBA1 causes lysosomal dysregulation leading to the impairment of both autophagy and phagocytosis. C1 [Valapala, Mallika; Wilson, Christine; Hose, Stacey; Bhutto, Imran A.; Grebe, Rhonda; Dong, Aling; Greenbaum, Seth; Gu, Limin; Sengupta, Samhita; Cano, Marisol; Hackett, Sean; Lutty, Gerard A.; Handa, James T.; Campochiaro, Peter; Zigler, J. Samuel, Jr.; Sinha, Debasish] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Gu, Limin; Xu, Guotong] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Ophthalmol, Shanghai 200092, Peoples R China. [Gu, Limin; Xu, Guotong] Tongji Univ, Sch Med, Tongji Eye Inst, Shanghai 200092, Peoples R China. [Dong, Lijin; Sergeev, Yuri; Wawrousek, Eric] NEI, NIH, Bethesda, MD 20892 USA. RP Sinha, D (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. EM Debasish@jhmi.edu FU Research to Prevent Blindness; National Institutes of Health [EY019037-S, EY14005, EY01765] FX We thank Drs Ana Maria Cuervo and Hiroshi Koga for their advice and for providing GFP-LC3-mCherry plasmid. The mCherry-hLC3B plasmid was a kind gift from Dr. David Rubinsztein and LAMP1-YFP from Dr Jennifer Lippincott-Schwartz. Best1-Cre transgenic mouse was kindly provided by Dr Joshua Dunaief. We thank Dr Morton F Goldberg for critical reading and discussion of the manuscript. SS is in the Centennial High School Science Research Program. DS is a recipient of the Sybil B. Harrington Special Scholar award for Macular Degeneration from Research to Prevent Blindness. Supported by National Institutes of Health: EY019037-S (DS), EY14005 (JTH), EY01765 (Wilmer Imaging Core) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). NR 70 TC 33 Z9 33 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD MAR 1 PY 2014 VL 10 IS 3 BP 480 EP 496 DI 10.4161/auto.27292 PG 17 WC Cell Biology SC Cell Biology GA AC0DG UT WOS:000332164400009 PM 24468901 ER PT J AU Seo, SH Kim, BM Joe, A Han, HW Chen, XY Cheng, Z Jang, ES AF Seo, Sun-Hwa Kim, Bo-Mi Joe, Ara Han, Hyo-Won Chen, Xiaoyuan Cheng, Zhen Jang, Eue-Soon TI NIR-light-induced surface-enhanced Raman scattering for detection and photothermal/photodynamic therapy of cancer cells using methylene blue-embedded gold nanorod@SiO2 nanocomposites SO BIOMATERIALS LA English DT Article DE Methylene blue; Gold nanorod; SERS imaging; Photodynamic therapy; Photothermal therapy ID PHOTODYNAMIC THERAPY; PHOTOTHERMAL THERAPY; MESOPOROUS SILICA; SILVER ELECTRODE; REFRACTIVE-INDEX; NANORODS; SERS; NANOPARTICLES; TUNABILITY; GROWTH AB Methylene blue-loaded gold nanorod@SiO2 (MB-GNR@SiO2) core@shell nanoparticles are synthesized for use in cancer imaging and photothermal/photodynamic dual therapy. For the preparation of GNR@SiO2 nanoparticles, we found that the silica coating rate of hexadecylcetyltrimethylammonium bromide (CTAB)-capped GNRs is much slower than that of PEGylated GNRs due to the densely coated CTAB bilayer. Encapsulated MB molecules have both monomer and dimer forms that result in an increase in the photosensitizing effect through different photochemical pathways. As a consequence of the excellent plasmonic properties of GNRs at near-infrared (NIR) light, the embedded MB molecules showed NIR light-induced SERS performance with a Raman enhancement factor of 3.0 x 10(10), which is enough for the detection of a single cancer cell. Moreover, the MB-GNR@SiO2 nanoparticles exhibit a synergistic effect of photodynamic and photothermal therapies of cancer under single-wavelength NIR laser irradiation. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Seo, Sun-Hwa; Kim, Bo-Mi; Joe, Ara; Han, Hyo-Won; Jang, Eue-Soon] Kumoh Natl Inst Technol, Dept Appl Chem, Gyeongbuk 730701, South Korea. [Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Cheng, Zhen] Stanford Univ, Dept Radiol, MIPS, Stanford, CA 94305 USA. [Cheng, Zhen] Stanford Univ, Dept Radiol, BioX Program, Stanford, CA 94305 USA. RP Jang, ES (reprint author), Kumoh Natl Inst Technol, Dept Appl Chem, Gyeongbuk 730701, South Korea. EM euesoon@kumoh.ac.kr RI Cheng, Zhen/K-2843-2012 FU Korean Ministry of Education, Science Technology [2013-0024700]; Small & Medium Business Administration of Korea [S2072168] FX This work was supported by research fund of the Korean Ministry of Education, Science & Technology (2013-0024700) and Small & Medium Business Administration of Korea (S2072168). NR 41 TC 53 Z9 55 U1 48 U2 277 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD MAR PY 2014 VL 35 IS 10 BP 3309 EP 3318 DI 10.1016/j.biomaterials.2013.12.066 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AC0MC UT WOS:000332188400017 PM 24424205 ER PT J AU Kim, KI Simon, R AF Kim, Kyung In Simon, Richard TI Overfitting, generalization, and MSE in class probability estimation with high- dimensional data SO BIOMETRICAL JOURNAL LA English DT Article DE Class probability estimation; Covariance penalty; High-dimensional data; Mean square error; Overfitting ID GENE-EXPRESSION; PREDICTION ERROR; CLASSIFICATION AB Accurate class probability estimation is important for medical decision making but is challenging, particularly when the number of candidate features exceeds the number of cases. Special methods have been developed for nonprobabilistic classification, but relatively little attention has been given to class probability estimation with numerous candidate variables. In this paper, we investigate overfitting in the development of regularized class probability estimators. We investigate the relation between overfitting and accurate class probability estimation in terms of mean square error. Using simulation studies based on real datasets, we found that some degree of overfitting can be desirable for reducing mean square error. We also introduce a mean square error decomposition for class probability estimation that helps clarify the relationship between overfitting and prediction accuracy. C1 [Kim, Kyung In; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9609 Med Ctr Dr,MSC 9735, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov RI Kim, Kyung In/L-2263-2016 OI Kim, Kyung In/0000-0002-4822-8333 NR 18 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD MAR PY 2014 VL 56 IS 2 BP 256 EP 269 DI 10.1002/bimj.201300083 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AC2KX UT WOS:000332331100006 PM 24338793 ER PT J AU Paul, SM Gabor, LR Rudzinski, S Giovanni, D Boyce, AM Kelly, MRN Collins, MT AF Paul, Scott M. Gabor, Lisa R. Rudzinski, Scott Giovanni, David Boyce, Alison M. Kelly, Marilyn R. N. Collins, Michael T. TI Disease severity and functional factors associated with walking performance in polyostotic fibrous dysplasia SO BONE LA English DT Article DE Polyostotic fibrous dysplasia; McCune-Albright Syndrome; Ambulation; Functional measures ID MCCUNE-ALBRIGHT-SYNDROME; STIMULATORY G-PROTEIN; NATURAL-HISTORY; ACTIVATING MUTATIONS; 6-MINUTE WALK; BONE; GENE; GAIT; HIP; PAMIDRONATE AB The purpose of this study was to determine the association between measures of disease severity, impairment, and ambulation ability in persons with polyostotic fibrous dysplasia (PFD). A cross-sectional sample of 81 patients (ages 5-57) with polyostotic fibrous dysplasia was evaluated as part of an ongoing study. Subjects were scored on the Skeletal Disease Burden Score (SDBS), completed a 9-minute walk test (9MW), manual muscle testing (MMT), and measurements of range of motion (ROM). Correlations between continuous variables were calculated using the Pearson correlation coefficient and ordinal variables by Spearman correlation coefficient. It was found that subjects with more severe disease walked slower than those with less skeletal disease, with the exception of the youngest subjects. Walking velocity was faster in subjects with better hip strength and range Of motion and slower in those with bilateral coxa vara. Those subjects with more severe disease had less range of motion, were weaker at the hips, and more likely to have leg length discrepancy. Skeletal disease severity was associated with hip weakness, leg length discrepancy, and loss of range of motion. In most cases, findings did not differ in the presence or absence of associated endocrinopathies. Skeletal disease severity, MMT and ROM each has an impact on walking efficiency in persons with PFD. These findings suggest that treatment focused on strategies to improve or, at least, maintain hip strength and range of motion, correct leg length discrepancies and hip malalignment may help preserve ambulation ability in persons with PFD and that treatment should begin at a young age. Published by Elsevier Inc. C1 [Paul, Scott M.; Gabor, Lisa R.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Rudzinski, Scott] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Giovanni, David] PRMC Wound Care Ctr, Salisbury, MD USA. [Boyce, Alison M.; Kelly, Marilyn R. N.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Bone Hlth Program, Washington, DC 20010 USA. RP Paul, SM (reprint author), NIH, Dept Rehabil Med, Bldg 10 CRC Rm 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM spaul@cc.nih.gov; lisa.gabor@gmail.com; rudzinskism@upmc.edu; giovannidavidmd@msn.com; boyceam@nidcr.nih.gov; marilynhkelly@gmail.com; mc247k@nih.gov FU National Institutes of Health, Division of Intramural Research; NIDCR; Clinical Center Rehabilitation Medicine Department FX This research was funded entirely by the National Institutes of Health, Division of Intramural Research; the NIDCR and the Clinical Center Rehabilitation Medicine Department. NR 46 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD MAR PY 2014 VL 60 BP 41 EP 47 DI 10.1016/j.bone.2013.11.022 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB8RH UT WOS:000332057200006 PM 24316419 ER PT J AU Bonner, TI AF Bonner, T. I. TI Should pharmacologists care about alternative splicing? IUPHAR Review 4 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE alternative splicing; splice variant nomenclature; 5-HT4 receptor; PAC(1) receptor; Ca(V)1; 2; Ca(V)3; 1 ID MESSENGER-RNA ANALYSIS; HUMAN 5-HT4 RECEPTOR; SMOOTH-MUSCLE-CELLS; CALCIUM-CHANNEL; SEROTONIN 5-HT4; SIGNAL-TRANSDUCTION; ADENYLATE-CYCLASE; ALPHA(1) SUBUNIT; PHOSPHOLIPASE-C; PACAP RECEPTOR AB Alternative splicing of mRNAs occurs in the majority of human genes, and most differential splicing results in different protein isoforms with possibly different functional properties. However, there are many reported splicing variations that may be quite rare, and not all combinatorially possible variants of a given gene are expressed at significant levels. Genes of interest to pharmacologists are frequently expressed at such low levels that they are not adequately represented in genome-wide studies of transcription. In single-gene studies, data are commonly available on the relative abundance and functional significance of individual alternatively spliced exons, but there are rarely data that quantitate the relative abundance of full-length transcripts and define which combinations of exons are significant. A number of criteria for judging the significance of splice variants and suggestions for their nomenclature are discussed. C1 [Bonner, T. I.] NIMH, Bethesda, MD 20892 USA. RP Bonner, TI (reprint author), NIMH, Off Sci Director, 49 Convent Dr,Bldg 49,Rm B1B80,MSC4405, Bethesda, MD 20892 USA. EM tibonner@mail.nih.gov FU National Institutes of Health (National Institute of Mental Health) FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Mental Health). NR 40 TC 3 Z9 3 U1 0 U2 8 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 MAR PY 2014 VL 171 IS 5 SI SI BP 1231 EP 1240 DI 10.1111/bph.12526 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AB6OQ UT WOS:000331909700013 PM 24670145 ER PT J AU Al-Khodor, S Marshall-Batty, K Nair, V Ding, L Greenberg, DE Fraser, IDC AF Al-Khodor, Souhaila Marshall-Batty, Kimberly Nair, Vinod Ding, Li Greenberg, David E. Fraser, Iain D. C. TI Burkholderia cenocepacia J2315 escapes to the cytosol and actively subverts autophagy in human macrophages SO CELLULAR MICROBIOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; CYSTIC-FIBROSIS; CEPACIA COMPLEX; INTRACELLULAR SURVIVAL; SP-NOV; LEGIONELLA-PNEUMOPHILA; FRANCISELLA-TULARENSIS; CONTAINING VACUOLE; EPITHELIAL-CELLS; NADPH OXIDASE AB Selective autophagy functions to specifically degrade cellular cargo tagged by ubiquitination, including bacteria. Strains of the Burkholderia cepacia complex (Bcc) are opportunistic pathogens that cause life-threatening infections in patients with cystic fibrosis (CF) and chronic granulomatous disease (CGD). While there is evidence that defective macrophage autophagy in a mouse model of CF can influence B.cenocepacia susceptibility, there have been no comprehensive studies on how this bacterium is sensed and targeted by the host autophagy response in human macrophages. Here, we describe the intracellular life cycle of B.cenocepaciaJ2315 and its interaction with the autophagy pathway in human cells. Electron and confocal microscopy analyses demonstrate that the invading bacteria interact transiently with the endocytic pathway before escaping to the cytosol. This escape triggers theselective autophagy pathway, and the recruitment of ubiquitin, the ubiquitin-binding adaptors p62 and NDP52 and the autophagosome membrane-associated protein LC3B, to the bacterial vicinity. However, despite recruitment of these key autophagy pathway effectors, B.cenocepacia blocks autophagosome completion and replicates in the host cytosol. We find that a pre-infection increase in cellular autophagy flux can significantly inhibit B.cenocepacia replication and that lower autophagy flux in macrophages from immunocompromised CGD patients could contribute to increased B.cenocepacia susceptibility, identifying autophagy manipulation as a potential therapeutic approach to reduce bacterial burden in B.cenocepacia infections. C1 [Al-Khodor, Souhaila; Fraser, Iain D. C.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Marshall-Batty, Kimberly; Greenberg, David E.] Univ Texas SW Med Ctr Dallas, Div Infect Dis, Dept Med, Dallas, TX 75390 USA. [Nair, Vinod] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Ding, Li] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Fraser, IDC (reprint author), NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM david.greenberg@utsouthwestern.edu; fraseri@niaid.nih.gov OI Al Khodor, Souhaila/0000-0003-4858-7130 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research; UT Southwestern Medical Center FX This work was generously supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research (S.A- K., V.N., L. D. and I. D. C. F.). K.M-B. and D. E. G. were supported by UT Southwestern Medical Center. We are grateful to Dr John Kehrl for the LC3B-GFP expressing THP-1 cell line, to Dr Steve Holland for access to CGD patient blood samples and bone marrow from CGD model mice, and to David Dorward for assistance with TEM image processing. We thank colleagues in the Laboratory of Systems Biology for helpful discussions and critical reading of the manuscript. The authors declare that they have no relevant conflicts of interest. NR 64 TC 13 Z9 13 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD MAR PY 2014 VL 16 IS 3 BP 378 EP 395 DI 10.1111/cmi.12223 PG 18 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA AA4HJ UT WOS:000331056400008 PM 24119232 ER PT J AU Schiller, R Scozzafava, G Tumber, A Wickens, JR Bush, JT Rai, G Lejeune, C Choi, H Yeh, TL Chan, MC Mott, BT McCullagh, JSO Maloney, DJ Schofield, CJ Kawamura, A AF Schiller, Rachel Scozzafava, Giuseppe Tumber, Anthony Wickens, James R. Bush, Jacob T. Rai, Ganesha Lejeune, Clarisse Choi, Hwanho Yeh, Tzu-Lan Chan, Mun Chiang Mott, Bryan T. McCullagh, James S. O. Maloney, David J. Schofield, Christopher J. Kawamura, Akane TI A Cell-Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1 SO CHEMMEDCHEM LA English DT Article DE 2-oxoglutarate (2OG) oxygenases; cell permeability; epigenetics; inhibitors; jmjc histone demethylases; structure-activity relationships ID ONCOMETABOLITE 2-HYDROXYGLUTARATE; SUBSTRATE-SPECIFICITY; LYSINE DEMETHYLASES; STRUCTURAL INSIGHTS; BUTYRIC-ACID; MECHANISMS; BINDING; PROBE AB The 2-oxoglutarate (2OG)-dependent JumonjiC domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4M). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation. C1 [Schiller, Rachel; Wickens, James R.; Bush, Jacob T.; Lejeune, Clarisse; Choi, Hwanho; Yeh, Tzu-Lan; Chan, Mun Chiang; McCullagh, James S. O.; Schofield, Christopher J.; Kawamura, Akane] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England. [Scozzafava, Giuseppe; Tumber, Anthony] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Headington OX3 7DQ, England. [Rai, Ganesha; Mott, Bryan T.; Maloney, David J.] NIH, NCATS, Bethesda, MD 20892 USA. [Kawamura, Akane] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Schofield, CJ (reprint author), Univ Oxford, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England. EM christopher.schofield@chem.ox.ac.uk; akane.kawamura@chem.ox.ac.uk OI Schofield, Christopher/0000-0002-0290-6565 FU Clarendon Fund; Eli Lilly and Company; Wellcome Trust (UK); European Union (EU); British Heart Foundation; US National Center for Advancing Translational Sciences; Molecular Libraries Roadmap for Medical Research Initiative of the US National Institutes of Health [U54MH084681] FX R.S. was supported by the Clarendon Fund and Eli Lilly and Company. The authors thank the Wellcome Trust (UK), the European Union (EU) and the British Heart Foundation for funding. G. R., B. T. M. and D.J.M. were supported by the intramural research program of the US National Center for Advancing Translational Sciences and the Molecular Libraries Roadmap for Medical Research Initiative of the US National Institutes of Health (U54MH084681). The authors also thank Dr. Myung Kyu Lee (BioNanotechnology Research Centre, Korea Research Institute of Bioscience and Bio-technology (KRIBB), Republic of Korea) for the kind gift of the anti-hydroxyAsn803 (HyAsn803) antibody. The authors also thank Sander S. van Berkel for his help during manuscript preparation, Clarence Yapp for IF assay assistance, and John Richard Morphy and Paul Brennan for helpful discussions. NR 39 TC 16 Z9 16 U1 3 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD MAR PY 2014 VL 9 IS 3 SI SI BP 566 EP 571 DI 10.1002/cmdc.201300428 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AB4YI UT WOS:000331795500014 PM 24504543 ER PT J AU Grohar, PJ Segars, LE Yeung, C Pommier, Y D'Incalci, M Mendoza, A Helman, LJ AF Grohar, Patrick J. Segars, Laure E. Yeung, Choh Pommier, Yves D'Incalci, Maurizio Mendoza, Arnulfo Helman, Lee J. TI Dual Targeting of EWS-FLI1 Activity and the Associated DNA Damage Response with Trabectedin and SN38 Synergistically Inhibits Ewing Sarcoma Cell Growth SO CLINICAL CANCER RESEARCH LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; CHILDRENS ONCOLOGY GROUP; ECTEINASCIDIN-743 YONDELIS; TRANSCRIPTIONAL SIGNATURE; IN-VITRO; S-PHASE; REPLICATION; TUMORS; ET-743; RHABDOMYOSARCOMA AB Purpose: The goal of hi is study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy. Experimental Design: We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells. Results: We demonstrate by siRNA experiments that EWS-FLI1 drives the expression of the Werner syndrome protein (WRN) in Ewing sarcoma cells. Because WRN-deficient cells are known to be hypersensitive to camptothecins, we utilize trabectedin to block EWS-FLI1 activity, suppress WRN expression, and selectively sensitize Ewing sarcoma cells to the DNA-damaging effects of SN38. We show that trabectedin and SN38 are synergistic, demonstrate an increase in DNA double-strand breaks, an accumulation of cells in S-phase and a low picomolar IC50, In addition, SN38 cooperates with trabectedin to augment the suppression of EWS-FLI1. downstream targets, leading to an improved therapeutic index in vivo. These effects translate into the marked regression of two Ewing sarcoma xenografts at a fraction of the dose of camptothecin used in other xenograft studies. Conclusions: These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy. (C) 2013 AACR. C1 [Grohar, Patrick J.] Monroe Carrell Jr Childrens Hosp Vanderbilt, Nashville, TN 37232 USA. [Grohar, Patrick J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Segars, Laure E.; Yeung, Choh; Mendoza, Arnulfo; Helman, Lee J.] NCI, Mol Oncol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [D'Incalci, Maurizio] Ist Ric Farmacol Mario Negri IRCCS, Milan, Italy. RP Grohar, PJ (reprint author), Monroe Carrell Jr Childrens Hosp Vanderbilt, 2220 Pierce Ave,PRB 397, Nashville, TN 37232 USA. EM patrick.grohar@vanderbilt.edu OI D'Incalci, Maurizio/0000-0001-8784-1360 FU St. Baldrick's research foundation; Lily's Garden Foundation; Westhaven foundation; Hyundai Hope on Wheels; Sarcoma Alliance for Research through Collaboration; Monroe Carell Jr. Children's Hospital at Vanderbilt University; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This work has been supported in part by a grant from St. Baldrick's research foundation (P.J. Grohar and L.E. Segars). P.J. Grohar also receives grant support from the Lily's Garden Foundation, the Westhaven foundation, Hyundai Hope on Wheels, the Sarcoma Alliance for Research through Collaboration, and the Turner-Hazinski Award at the Monroe Carell Jr. Children's Hospital at Vanderbilt University. The intramural program at the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 (L.J. Helman), also funded this project. NR 53 TC 23 Z9 24 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2014 VL 20 IS 5 BP 1190 EP 1203 DI 10.1158/1078-0432.CCR-13-0901 PG 14 WC Oncology SC Oncology GA AC3GE UT WOS:000332403100016 PM 24277455 ER PT J AU Callejas-Diaz, A Gea-Banacloche, JC AF Callejas-Diaz, Alejandro Gea-Banacloche, Juan C. TI Clostridium difficile: Deleterious Impact on Hematopoietic Stem Cell Transplantation SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Article DE C. difficile; C difficile infection; CDI; Clostridium difficile-associated disease; Diarrhea; Hematopoietic stem cell transplant; Hematologic malignancies; Immunosuppressed; Epidemiology; Diagnosis; Treatment; Outcomes ID VERSUS-HOST-DISEASE; RISK-FACTORS; INFECTION; EPIDEMIOLOGY; RECIPIENTS; FIDAXOMICIN; VANCOMYCIN; DIARRHEA; CANCER; MULTICENTER AB C. difficile infection (CDI), the most common cause of hospital-acquired diarrhea, is very frequent after hematopoietic stem cell transplantation (HSCT). Recent publications suggest it affects between 6 % and 20 % of HSCT recipients during the first year and is more common following allogeneic transplant (allo-HSCT). The best diagnostic strategy remains to be defined, but molecular testing for the toxin genes by polymerase chain reaction (PCR) seems to be replacing the traditional enzyme immunoassays (EIA). The higher sensitivity of the PCR may result in increased measured incidence of disease. C. difficile infection typically occurs during the first month after HSCT. Although the course of CDI after HSCT does not seem to be different than in other hospitalized patients, it may result in worsening of bowel graft versus host disease (GVHD) after allo-HSCT. Current evidence suggests a reciprocal effect by which GVHD may increase the risk of CDI and C. difficile disease may increase the risk of GVHD. Metronidazole was the treatment most commonly used in all recent series, followed by the combination metronidazole and oral vancomycin. There is minimal information on the use of fidaxomicin in HSCT recipients. Regarding stool transplant, there is one case report of successful use of this modality in an HSCT recipient. These two newer approaches will certainly be investigated in the future. C1 [Callejas-Diaz, Alejandro] Hosp Univ Puerta Hierro Majadahonda, Serv Med Interna, Madrid, Spain. [Gea-Banacloche, Juan C.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Gea-Banacloche, JC (reprint author), NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. EM banacloj@mail.nih.gov NR 35 TC 7 Z9 8 U1 1 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD MAR PY 2014 VL 9 IS 1 BP 85 EP 90 DI 10.1007/s11899-013-0193-y PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AB7XM UT WOS:000332004400011 PM 24390550 ER PT J AU de Renty, C Kaneko, KJ DePamphilis, ML AF de Renty, Christelle Kaneko, Kotaro J. DePamphilis, Melvin L. TI The dual roles of geminin during trophoblast proliferation and differentiation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Geminin; Trophoblast stem cells; Trophoblast giant cells; Differentiation; Trophectoderm; Endoreplication; Endocycles; Chk1; Cdkn1a/p21/Cip1; Cdkn1c/p57/Kip2 ID PROMOTING COMPLEX/CYCLOSOME APC/C; GIANT-CELLS; STEM-CELLS; MOUSE EMBRYOS; MAMMALIAN DEVELOPMENT; PLURIPOTENT CELLS; REGULATES CHK1; S-PHASE; LINEAGE; CYCLE AB Geminin is a protein involved in both DNA replication and cell fate acquisition. Although it is essential for mammalian preimplantation development, its role remains unclear. In one study, ablation of the geminin gene (Gmnn) in mouse preimplantation embryos resulted in apoptosis, suggesting that geminin prevents DNA re-replication, whereas in another study it resulted in differentiation of blastomeres into trophoblast giant cells (TGCs), suggesting that geminin regulates trophoblast specification and differentiation. Other studies concluded that trophoblast differentiation into TGCs is regulated by fibroblast growth factor-4 (FGF4), and that geminin is required to maintain endocydes. Here we show that ablation of Gmnn in trophoblast stem cells (TSCs) proliferating in the presence of FGF4 closely mimics the events triggered by FGF4 deprivation: arrest of cell proliferation, formation of giant cells, excessive DNA replication in the absence of DNA damage and apoptosis, and changes in gene expression that include loss of Chid with up-regulation of p57 and p21. Moreover, FGF4 deprivation of TSCs reduces geminin to a basal level that is required for maintaining endocycles in TGCs. Thus, geminin acts both like a component of the FGF4 signal transduction pathway that governs trophoblast proliferation and differentiation, and geminin is required to maintain endocycles. Published by Elsevier Inc. C1 [de Renty, Christelle; Kaneko, Kotaro J.; DePamphilis, Melvin L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU NICHD intramural research program FX The authors thank Alex Vassilev and Yi-Yuan Huang for their help and advice. This work was supported by the NICHD intramural research program. NR 62 TC 8 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 1 PY 2014 VL 387 IS 1 BP 49 EP 63 DI 10.1016/j.ydbio.2013.12.034 PG 15 WC Developmental Biology SC Developmental Biology GA AB8QT UT WOS:000332055800005 PM 24412371 ER PT J AU Brite, J Shiroma, EJ Bowers, K Yeung, E Laughon, SK Grewal, JG Zhang, C AF Brite, J. Shiroma, E. J. Bowers, K. Yeung, E. Laughon, S. K. Grewal, J. G. Zhang, C. TI Height and the risk of gestational diabetes: variations by race/ethnicity SO DIABETIC MEDICINE LA English DT Article ID WEIGHT CHARACTERISTICS; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; SHORT STATURE; MELLITUS; PREGNANCY; ORIGINS; LENGTH; WOMEN; GENE AB AimsGestational diabetes is a common pregnancy complication affecting races/ethnicities disproportionally. Adult height, an indicator of both genetic and early-life factors, is inconsistently associated with gestational diabetes risk. We examined the association and whether it varies by races in a nationally representative US cohort. MethodsAnalyses were conducted among 135861 pregnancies in the Consortium on Safe Labor, 5567 of which were diagnosed with gestational diabetes based on medical records review. Generalized estimating equations were used to estimate odds ratios (95% confidence intervals) of gestational diabetes, controlling for other risk factors including body weight. Additionally, a meta-analysis of 15761 pregnancies with gestational diabetes and 205828 without gestational diabetes was conducted to estimate the pooled mean difference in height between those with gestational diabetes and control subjects. ResultsHeight was inversely associated with gestational diabetes risk across races/ethnicities, with the strongest association among Asians (P for interaction <0.01). Comparing extreme quartiles (>168 vs. <157cm), adjusted odds ratios (95% confidence intervals) were 0.18 (0.09-0.36) for Asians/Pacific Islanders, 0.33 (0.29-0.38) for non-Hispanic white women, 0.39 (0.31-0.51) for Hispanics and 0.59 (0.47-0.75) for non-Hispanic black women. Meta-analysis found women with gestational diabetes to be significantly shorter than others. ConclusionsTaller women are at lower risk of developing gestational diabetes, with the magnitude of association varying significantly across races/ethnicities. C1 [Brite, J.; Shiroma, E. J.; Bowers, K.; Yeung, E.; Laughon, S. K.; Grewal, J. G.; Zhang, C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD USA. [Brite, J.] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Shiroma, E. J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Zhang, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD USA. EM zhangcu@mail.nih.gov RI Yeung, Edwina/F-5992-2015; Bowers, Katherine/N-5226-2015; OI Yeung, Edwina/0000-0002-3851-2613; Grewal, Jagteshwar/0000-0002-0141-4876; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health [HL007575] FX JB, KB, EY, SKL, JGG and CZ were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. This research was supported by research grant HL007575 from the National Institutes of Health. NR 28 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 EI 1464-5491 J9 DIABETIC MED JI Diabetic Med. PD MAR PY 2014 VL 31 IS 3 BP 332 EP 340 DI 10.1111/dme.12355 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AA8IC UT WOS:000331338200012 PM 24308574 ER PT J AU O'Dea, EB Pepin, KM Lopman, BA Wilke, CO AF O'Dea, Eamon B. Pepin, Kim M. Lopman, Ben A. Wilke, Claus O. TI Fitting outbreak models to data from many small norovirus outbreaks SO EPIDEMICS LA English DT Article DE Stochastic epidemic model; Parameter estimation; Norovirus; Health-care-associated infection; Generalized linear model ID GENERALIZED LINEAR-MODELS; STOCHASTIC EPIDEMIC MODEL; ENVIRONMENTAL CONTAMINATION; SUSCEPTIBLE INDIVIDUALS; ASYMPTOTIC PROPERTIES; DISEASE TRANSMISSION; INITIAL NUMBER; UNITED-STATES; GASTROENTERITIS; ESTIMATOR AB Infectious disease often occurs in small, independent outbreaks in populations with varying characteristics. Each outbreak by itself may provide too little information for accurate estimation of epidemic model parameters. Here we show that using standard stochastic epidemic models for each outbreak and allowing parameters to vary between outbreaks according to a linear predictor leads to a generalized linear model that accurately estimates parameters from many small and diverse outbreaks. By estimating initial growth rates in addition to transmission rates, we are able to characterize variation in numbers of initially susceptible individuals or contact patterns between outbreaks. With simulation, we find that the estimates are fairly robust to the data being collected at discrete intervals and imputation of about half of all infectious periods. We apply the method by fitting data from 75 norovirus outbreaks in healthcare settings. Our baseline regression estimates are 0.0037 transmissions per infective-susceptible day, an initial growth rate of 0.27 transmissions per infective day, and a symptomatic period of 3.35 days. Outbreaks in long-term-care facilities had significantly higher transmission and initial growth rates than outbreaks in hospitals. (C) 2014 The Authors. Published by Elsevier B.V. All rights reserved. C1 [O'Dea, Eamon B.] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Pepin, Kim M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pepin, Kim M.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Lopman, Ben A.] Hlth Protect Agcy, Ctr Infect, Gastrointestinal Emerging & Zoonot Infect Dept, London NW9 5EQ, England. [Wilke, Claus O.] Univ Texas Austin, Ctr Computat Biol & Bioinformat, Austin, TX 78712 USA. [Wilke, Claus O.] Univ Texas Austin, Inst Cell & Mol Biol, Austin, TX 78712 USA. RP O'Dea, EB (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30030 USA. RI O'Dea, Eamon/E-6389-2016; OI O'Dea, Eamon/0000-0003-4748-683X; Wilke, Claus/0000-0002-7470-9261 FU NSF [EF-0742373]; NIH [R01 GM088344]; BEACON [61-2075UT]; RAPIDD program of the Science and Technology Directorate; U.S. Department of Homeland Security; Fogarty International Center, NIH FX This work was supported by NSF Grant EF-0742373 and NIH Grant R01 GM088344. E.B.O. was also supported by BEACON Grant 61-2075UT. K.M.P. was also supported by the RAPIDD program of the Science and Technology Directorate, U.S. Department of Homeland Security, and the Fogarty International Center, NIH. Our funding sources had no role in this study's design; in the collection, analysis, and interpretation of the analyzed data; in the writing of this paper; or in the decision to submit this paper for publication. NR 57 TC 2 Z9 2 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2014 VL 6 BP 18 EP 29 DI 10.1016/j.epidem.2013.12.002 PG 12 WC Infectious Diseases SC Infectious Diseases GA AC3HP UT WOS:000332408200003 PM 24593918 ER PT J AU Reiner, RC Stoddard, ST Scott, TW AF Reiner, Robert C., Jr. Stoddard, Steven T. Scott, Thomas W. TI Socially structured human movement shapes dengue transmission despite the diffusive effect of mosquito dispersal SO EPIDEMICS LA English DT Article DE Infectious disease; Spatial epidemiology; Social networks; Agent-based model ID AEDES-AEGYPTI DIPTERA; VIRUS TRANSMISSION; HUMAN MOBILITY; PUERTO-RICO; NETWORKS; THAILAND; DYNAMICS; VECTOR; COMMUNITIES; CULICIDAE AB For sexually and directly transmitted infectious diseases, social connections influence transmission because they determine contact between individuals. For pathogens that are indirectly transmitted by arthropod vectors, the movement of the vectors is thought to diminish the role of social connections. Results from a recent study of mosquito-borne dengue virus (DENV), however, indicate that human movement alone can explain significant spatial variation in urban transmission rates. Because movement patterns are structured by social ties, this result suggests that social proximity may be a good predictor of infection risk for DENV and other pathogens transmitted by the mosquito Aedes aegypti. Here we investigated the effect of socially structured movement on DENV transmission using a spatially explicit, agent-based transmission model. When individual movements overlap to a high degree within social groups we were able to recreate infection patterns similar to those detected in dengue-endemic, northeastern Peru. Our results are consistent with the hypothesis that social proximity drives fine-scale heterogeneity in DENV transmission rates, a result that was robust to the influence of mosquito dispersal. This heterogeneity in transmission caused by socially structured movements appeared to be hidden by the diffusive effect of mosquito dispersal in aggregated infection dynamics, which implies this heterogeneity could be present and active in real dengue systems without being easily noticed. Accounting for socially determined, overlapping human movements could substantially improve the efficiency and efficacy of dengue surveillance and disease prevention programs as well as result in more accurate estimates of important epidemiological quantities, such as R-0. (C) 2013 The Authors. Published by Elsevier BAT. All rights reserved. C1 [Reiner, Robert C., Jr.; Stoddard, Steven T.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Reiner, Robert C., Jr.; Stoddard, Steven T.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. RP Reiner, RC (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM rcreiner@ucdavis.edu FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill & Melinda Gates Foundation [OPP52250]; Innovative Vector Control Consortium; NIH [R01-AI069341, R01-AI091980, R01-GM08322] FX This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. T.W.S. acknowledges funding from the Bill & Melinda Gates Foundation (OPP52250), the Innovative Vector Control Consortium, and the NIH (R01-AI069341, R01-AI091980, and R01-GM08322). We would like to thank Alex Perkins, David Smith and Sandra Olkowski for insightful comments that greatly improved the manuscript and the figures. NR 40 TC 23 Z9 23 U1 4 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD MAR PY 2014 VL 6 BP 30 EP 36 DI 10.1016/j.epidem.2013.12.003 PG 7 WC Infectious Diseases SC Infectious Diseases GA AC3HP UT WOS:000332408200004 PM 24593919 ER PT J AU Hill, AM Stewart, PW Fung, MK Kris-Etherton, PM Ginsberg, HN Tracy, RP Pearson, TA Lefevre, M Reed, RG Elmer, PJ Holleran, S Ershow, AG AF Hill, Alison M. Stewart, Paul W. Fung, Mark K. Kris-Etherton, Penny M. Ginsberg, Henry N. Tracy, Russell P. Pearson, Thomas A. Lefevre, Michael Reed, Roberta G. Elmer, Patricia J. Holleran, Stephen Ershow, Abby G. CA DELTA Dietary Effects Lipoprot TI Monthly haemostatic factor variability in women and men SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Controlled dietary intervention; factor VII; fibrinogen; menstrual cycle; plasminogen activator inhibitor ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; SATURATED FATTY-ACIDS; MENSTRUAL-CYCLE; FACTOR-VII; MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; FIBRINOLYTIC FACTORS; LIPOPROTEINS; DIETARY; LIPIDS AB BackgroundHormonal status influences haemostatic factors including fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), and concentrations differ among men, premenopausal and postmenopausal women. This study examines how phases of the menstrual cycle influence variability of fibrinogen, factor VII and PAI-1. DesignWe studied 103 subjects (39 premenopausal women, 18 postmenopausal women and 46 men) during three, randomized, 8-week energy- and nutrient-controlled experimental diets in the Dietary Effects on Lipids and Thrombogenic Activity (DELTA) Study. Fasting blood samples were collected weekly during the last 4weeks of each diet period, and haemostatic factors were quantified. Two linear mixed-effects models were used for fibrinogen, factor VII and PAI-1: one to estimate and compare group-specific components of variance, and the other to estimate additional fixed effects representing cyclical functions of day of menstrual cycle in premenopausal women. ResultsSystematic cyclical variation with day of menstrual cycle was observed for fibrinogen (P<00001), factor VII (P=00012) and PAI-1 (P=00024) in premenopausal women. However, the amplitude of cycling was small relative to the total magnitude of intra-individual variability. In addition, the intra-individual variance and corresponding coefficient of variation observed in premenopausal women did not differ from postmenopausal women and men. ConclusionsThe variability in haemostatic factors in premenopausal women is no greater than for postmenopausal women or men. Consequently, premenopausal women can be included in studies investigating haemostatic factor responses without controlling for stage of menstrual cycle. C1 [Hill, Alison M.; Kris-Etherton, Penny M.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Stewart, Paul W.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Fung, Mark K.; Tracy, Russell P.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Ginsberg, Henry N.] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Pearson, Thomas A.; Reed, Roberta G.] Bassett Res Inst, Cooperstown, NY 13326 USA. [Lefevre, Michael] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Elmer, Patricia J.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Holleran, Stephen] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10032 USA. [Ershow, Abby G.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Kris-Etherton, PM (reprint author), Penn State Univ, Dept Nutr Sci, 110 Chandlee Bldg, University Pk, PA 16802 USA. EM pmk3@psu.edu RI Hill, Alison/E-9571-2013; Lefevre, Michael/B-5030-2014 OI Hill, Alison/0000-0002-6732-4224; Lefevre, Michael/0000-0002-2046-3593 FU NIH [5-U01-HL 049644, HL 049648, HL 049649, HL 049651, HL 049659, M01-NCRR 00645]; NIH Office for Research on Women's Health FX This work was supported by NIH grants (5-U01-HL 049644, HL 049648, HL 049649, HL 049651, and HL 049659, and M01-NCRR 00645), and the NIH Office for Research on Women's Health. The following companies made in-kind contributions of products: AARHUS, Bertoli USA, Best Foods, Campbell Soup Company, Del Monte Foods, General Mills, Hershey Foods Corporation, Institute of Shortening and Edible Oils, Kraft General Foods, Land O'Lakes, McCormick Incorporated, Nabisco Foods Group, Neomonde Baking Company, Palm Oil Research Institute, Park Corporation, Procter and Gamble, Quaker Oats, Ross Laboratories, Swift-Armour and Eckrich, Van Den Bergh Foods, Cholestech, and Lifelines Technology Incorporated. The study sponsors did not have any role in the study design, in collection, analysis and interpretation of data, or any other aspect of the manuscript. The authors have indicated that they have no conflict of interests. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 EI 1365-2362 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAR PY 2014 VL 44 IS 3 BP 309 EP 318 DI 10.1111/eci.12235 PG 10 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AA3IG UT WOS:000330985500010 PM 24382103 ER PT J AU Blanchet, EM Gabriel, S Martucci, V Fakhry, N Chen, CC Deveze, A Millo, C Barlier, A Pertuit, M Loundou, A Pacak, K Taieb, D AF Blanchet, Elise M. Gabriel, Sophie Martucci, Victoria Fakhry, Nicolas Chen, Clara C. Deveze, Arnaud Millo, Corina Barlier, Anne Pertuit, Morgane Loundou, Anderson Pacak, Karel Taieb, David TI F-18-FDG PET/CT as a predictor of hereditary head and neck paragangliomas SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Fluorodeoxyglucose; genetics; head and neck paraganglioma; hereditary cancer; PET-CT; radiopharmaceuticals ID FUNCTIONAL-CHARACTERIZATION; PHEOCHROMOCYTOMA; MUTATIONS AB Background Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that F-18-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours (F-18-FDG uptake being linked to SDHx mutations). However, the data concerning F-18-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between F-18-FDG uptake and the SDHx mutation status in HNPGL patients. Methods F-18-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies. Results Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL F-18-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%. Conclusions F-18-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of F-18-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected. C1 [Blanchet, Elise M.; Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Gabriel, Sophie; Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, Dept Nucl Med, CERIMED, Marseille, France. [Fakhry, Nicolas] Aix Marseille Univ, La Timone Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Marseille, France. [Chen, Clara C.] NIH, Dept Nucl Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Deveze, Arnaud] Aix Marseille Univ, North Hosp, Dept Otorhinolaryngol Head & Neck Surg, Marseille, France. [Millo, Corina] NIH, PET Dept, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Barlier, Anne; Pertuit, Morgane] Aix Marseille Univ, Concept Hosp, Lab Biochem & Mol Biol, Marseille, France. [Loundou, Anderson] Aix Marseille Univ, Dept Publ Hlth, Marseille, France. RP Blanchet, EM (reprint author), CRC, Program Reprod & Adult Endocrinol, NICHD, NIH Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM elise.blanchet@gmail.com OI Barlier, Anne/0000-0002-3740-6173 FU Intramural NIH HHS [ZIA HD008735-13, ZIA HD008735-12] NR 18 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 EI 1365-2362 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAR PY 2014 VL 44 IS 3 BP 325 EP 332 DI 10.1111/eci.12239 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AA3IG UT WOS:000330985500012 PM 24422786 ER PT J AU Katagiri, N Uemae, Y Sakamoto, J Hidaka, Y Susa, T Kato, Y Kimura, S Suzuki, M AF Katagiri, Nobuto Uemae, Youji Sakamoto, Joe Hidaka, Yoshie Susa, Takao Kato, Yukio Kimura, Shioko Suzuki, Masakazu TI Molecular cloning and functional characterization of two forms of Pax8 in the rainbow trout, Oncorhynchus mykiss SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE Pax8; Thyroid gland; Nkx2-1; TTF1; Thyroid transcription factor 1; Rainbow trout ID THYROID-GLAND; DEVELOPMENTAL EXPRESSION; MESSENGER-RNA; FACTOR TTF-1; TRANSCRIPTION; GENE; SALMON; HORMONE; BINDING; ENHANCER AB We have identified two distinct Pax8 (a and b) mRNAs from the thyroid gland of the rainbow trout (Oncorhynchus mykiss), which seemed to be generated by alternative splicing. Both Pax8a and Pax8b proteins were predicted to possess the paired domain, octapeptide, and partial homeodomain, while Pax8b lacked the carboxy-terminal portion due to an insertion in the coding region of the mRNA. RT-PCR analysis showed each of Pax8a and Pax8b mRNAs to be abundantly expressed in the thyroid and kidney. In situ hybridization histochemistry further detected the expression of Pax8 mRNA in the epithelial cells of the thyroid follicles of the adult trout and in the thyroid primordial cells of the embryo. The functional properties of Pax8a and Pax8b were investigated by dual luciferase assay. The transcriptional regulation by the rat thyroid peroxidase (TPO) promoter was found to be increased by Pax8a, but not by Pax8b. Pax8a further showed synergistic transcriptional activity with rat NIcx2-1 for the human TPO upstream region including the enhancer and promoter. On the other hand, Pax8b decreased the synergistic activity of Pax8a and Nkx2-1. Electrophoretic mobility shift assay additionally indicated that not only Pax8a but also Pax8b can bind to the TPO promoter and enhancer, implying that the inhibitory effect of Pax8b might result from the lack of the functional carboxy-terminal portion. Collectively, the results suggest that for the trout thyroid gland, Pax8a may directly increase TPO gene expression in cooperation with Nkx2-1 while Pax8b may work as a non-activating competitor for the TPO transcription. (C) 2014 Elsevier Inc. All rights reserved. C1 [Katagiri, Nobuto; Uemae, Youji; Sakamoto, Joe; Hidaka, Yoshie; Suzuki, Masakazu] Shizuoka Univ, Grad Sch Sci, Dept Biol Sci, Shizuoka 4228529, Japan. [Susa, Takao; Kato, Yukio] Meiji Univ, Sch Agr, Dept Life Sci, Kawasaki, Kanagawa 2148571, Japan. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Suzuki, M (reprint author), Shizuoka Univ, Grad Sch Sci, Dept Biol Sci, Ohya 836, Shizuoka 4228529, Japan. EM sbmsuzu@ipc.shizuoka.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [23570075]; Cooperative Program of Atmosphere and Ocean Research Institute, the University of Tokyo [113] FX We are grateful to the staff of Fuji Trout Hatchery for the sufficient supply of rainbow trout, and to the staff of the Fuji Branch of Shizuoka Prefectural Fisheries Experimental Station for providing a working place. We would like to thank Dr. Susumu Hyodo, Atmosphere and Ocean Research Institute, The University of Tokyo, Japan, and Mr. Rei Ohkado, Shizuoka University, for their technical assistance in this study. We are also grateful to Dr. Bridget I Baker for critical reading of the manuscript. This work was supported by Grants-in Aid for Scientific Research (23570075) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a fund from the Cooperative Program (No. 113, 2011) of Atmosphere and Ocean Research Institute, the University of Tokyo. NR 54 TC 1 Z9 1 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 EI 1095-6840 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD MAR 1 PY 2014 VL 198 BP 22 EP 31 DI 10.1016/j.ygcen.2013.12.009 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB6SY UT WOS:000331921000003 PM 24380675 ER PT J AU Tatem, AJ AF Tatem, Andrew J. TI Mapping population and pathogen movements SO INTERNATIONAL HEALTH LA English DT Review DE Disease; Migration; Mobility; Modelling; Travel ID VECTOR-BORNE DISEASE; HUMAN MOBILITY; AIR-TRAVEL; TRANSPORTATION NETWORK; PANDEMIC INFLUENZA; MALARIA; SPREAD; PREDICTABILITY; TRANSMISSION; PATTERNS AB For most of human history, populations have been relatively isolated from each other, and only recently has there been extensive contact between peoples, flora and fauna from both old and new worlds. The reach, volume and speed of modern travel are unprecedented, with human mobility increasing in high income countries by over 1000-fold since 1800. This growth is putting people at risk from the emergence of new strains of familiar diseases, and from completely new diseases, while ever more cases of the movement of both disease vectors and the diseases they carry are being seen. Pathogens and their vectors can now move further, faster and in greater numbers than ever before. Equally however, we now have access to the most detailed and comprehensive datasets on human mobility and pathogen distributions ever assembled, in order to combat these threats. This short review paper provides an overview of these datasets, with a particular focus on low income regions, and covers briefly approaches used to combine them to help us understand and control some of the negative effects of population and pathogen movements. C1 [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Tatem, AJ (reprint author), Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. EM A.J.Tatem@soton.ac.uk FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Bill and Melinda Gates Foundation [49446, 1032350] FX This work was supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID [U19AI089674] and the Bill and Melinda Gates Foundation [#49446 and #1032350]. NR 71 TC 18 Z9 20 U1 2 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD MAR PY 2014 VL 6 IS 1 BP 5 EP 11 DI 10.1093/inthealth/ihu006 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AC2OW UT WOS:000332342400003 PM 24480992 ER PT J AU Kopperdahl, DL Aspelund, T Hoffmann, PF Sigurdsson, S Siggeirsdottir, K Harris, TB Gudnason, V Keaveny, TM AF Kopperdahl, David L. Aspelund, Thor Hoffmann, Paul F. Sigurdsson, Sigurdur Siggeirsdottir, Kristin Harris, Tamara B. Gudnason, Vilmundur Keaveny, Tony M. TI Assessment of Incident Spine and Hip Fractures in Women and Men Using Finite Element Analysis of CT Scans SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOPOROSIS; FRACTURE; RISK; ASSESSMENT; BIOMECHANICS; BONE; QCT ID QUANTITATIVE COMPUTED-TOMOGRAPHY; BONE-MINERAL DENSITY; VERTEBRAL FRACTURE; PROXIMAL FEMUR; FEMORAL STRENGTH; IN-VITRO; COMPRESSIVE STRENGTH; OFFICIAL POSITIONS; REFERENCE-STANDARD; TRABECULAR BONE AB Finite element analysis of computed tomography (CT) scans provides noninvasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a 5-year case-control study of 1110 women and men over age 65 years from the AGES-Reykjavik cohort (case=incident spine or hip fracture; control=no incident spine or hip fracture). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that for incident radiographically confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% confidence interval [CI] 1.8 to 4.3) and men (2.2, 95% CI 1.5 to 3.2) and for men remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI 2.6 to 6.9) and men (3.5, 95% CI 2.3 to 5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding preestablished thresholds for fragile bone strength (spine: women 4500N, men 6500N; hip: women 3000N, men 3500N). Because it is well established that individuals over age 65 years who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have fragile bone strength at the hip or spine should also be considered at high risk of fracture. (c) 2014 American Society for Bone and Mineral Research. C1 [Kopperdahl, David L.; Hoffmann, Paul F.; Keaveny, Tony M.] ON Diagnost, Berkeley, CA USA. [Aspelund, Thor; Sigurdsson, Sigurdur; Siggeirsdottir, Kristin; Gudnason, Vilmundur] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Keaveny, Tony M.] Univ Calif Berkeley, Dept Mech Engn, Berkeley, CA 94720 USA. [Keaveny, Tony M.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. RP Kopperdahl, DL (reprint author), 2150 Shattuck Ave,Suite 610, Berkeley, CA 94703 USA. EM david.kopperdahl@ondiagnostics.com RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [AR052234, AR057616]; NIH, National Institute on Aging FX Funding for this research was provided by NIH AR052234, NIH AR057616, and the Intramural Research Program of the NIH, National Institute on Aging. The CT scans used to establish equivalence between CT and DXA-measured areal BMD were acquired as part of the Rochester Epidemiology Project at Mayo Clinic Rochester (PI: Dr Sundeep Khosla) and used here with permission. Verification of the vertebral fracture adjudication procedure at Synarc, Inc., was kindly arranged by Dr Thomas Fuerst. NR 52 TC 43 Z9 44 U1 1 U2 7 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 MAR PY 2014 VL 29 IS 3 BP 570 EP 580 DI 10.1002/jbmr.2069 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB0CF UT WOS:000331458700008 PM 23956027 ER PT J AU Turan, S Fernandez-Rebollo, E Aydin, C Zoto, T Reyes, M Bounoutas, G Chen, M Weinstein, LS Erben, RG Marshansky, V Bastepe, M AF Turan, Serap Fernandez-Rebollo, Eduardo Aydin, Cumhur Zoto, Teuta Reyes, Monica Bounoutas, George Chen, Min Weinstein, Lee S. Erben, Reinhold G. Marshansky, Vladimir Bastepe, Murat TI Postnatal Establishment of Allelic Gas Silencing as a Plausible Explanation for Delayed Onset of Parathyroid Hormone Resistance Owing to Heterozygous Gas Disruption SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE PSEUDOHYPOPARATHYROIDISM; PARATHYROID; HORMONE; STIMULATORY G PROTEIN; GNAS; IMPRINTING; RENAL; PROXIMAL; TUBULE; CYCLIC; AMP ID PROTEIN ALPHA-SUBUNIT; STIMULATORY G-PROTEIN; ALBRIGHT HEREDITARY OSTEODYSTROPHY; PSEUDOHYPOPARATHYROIDISM TYPE-IA; G(S)ALPHA GENE GNAS1; GS-ALPHA; MOUSE MODEL; TRANSIENT PSEUDOHYPOPARATHYROIDISM; PREMATURE-INFANTS; ADENYLYL-CYCLASE AB Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of -subunit of the stimulatory G protein (Gs) activity. Gs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH resistance caused by the maternal loss of Gs, ie, hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (3 weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH resistance in patients with PHP-Ia. (c) 2014 American Society for Bone and Mineral Research. C1 [Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur; Zoto, Teuta; Reyes, Monica; Bounoutas, George; Bastepe, Murat] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Turan, Serap; Fernandez-Rebollo, Eduardo; Aydin, Cumhur; Zoto, Teuta; Reyes, Monica; Bounoutas, George; Marshansky, Vladimir; Bastepe, Murat] Harvard Univ, Sch Med, Boston, MA USA. [Turan, Serap] Marmara Univ Sch Med Hosp, Istanbul, Turkey. [Fernandez-Rebollo, Eduardo] Hosp Clin Barcelona, Endocrinol & Nutr Unit, Diabet & Obes Lab, IDIBAPS, Barcelona, Spain. [Aydin, Cumhur] Gulhane Mil Med Acad, Dept Endodont, Ctr Dent Sci, Ankara, Turkey. [Chen, Min; Weinstein, Lee S.] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD USA. [Erben, Reinhold G.] Univ Vet Med, Dept Biomed Sci, Vienna, Austria. [Marshansky, Vladimir] Massachusetts Gen Hosp, Program Membrane Biol, Ctr Syst Biol, Boston, MA 02114 USA. [Marshansky, Vladimir] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP Bastepe, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 10, Boston, MA 02114 USA. EM bastepe@helix.mgh.harvard.edu FU NIH/NIDDK [RO1DK073911]; NIDDK Division of Intramural Research; European Society for Paediatric Endocrinology through Lilly USA, LLC; Turkish Society of Pediatric Endocrinology and Diabetes FX We thank Drs Harald Juppner and Henry Kronenberg for insightful discussions and critically reviewing the manuscript. This study was funded in part by NIH/NIDDK grant RO1DK073911 to MB and by the NIDDK Division of Intramural Research. ST was supported by a Sabbatical Leave Programme grant from the European Society for Paediatric Endocrinology through an educational grant from Lilly USA, LLC, and Turkish Society of Pediatric Endocrinology and Diabetes. NR 76 TC 18 Z9 18 U1 0 U2 1 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 MAR PY 2014 VL 29 IS 3 BP 749 EP 760 DI 10.1002/jbmr.2070 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB0CF UT WOS:000331458700026 PM 23956044 ER PT J AU Suh, M Barksdale, DJ Logan, JG AF Suh, Minhee Barksdale, Debra J. Logan, Jeongok G. TI Morning Blood Pressure Surge and Nighttime Blood Pressure in Relation to Nocturnal Sleep Pattern and Arterial Stiffness SO JOURNAL OF CARDIOVASCULAR NURSING LA English DT Article DE ambulatory blood pressure monitoring; sleep; vascular stiffness ID PULSE-WAVE VELOCITY; INTIMA-MEDIA THICKNESS; HYPERTENSIVE PATIENTS; CEREBROVASCULAR-DISEASE; CARDIOVASCULAR RISK; CIRCADIAN VARIATION; TIME RATE; INDIVIDUALS; SENSITIVITY; MODULATION AB Objective: The phenomenon of morning blood pressure (BP) surge (MBPS) is known to increase the risk for cardiovascular events and stroke. The purposes of this study were to explore associations between MBPS and nighttime BP and to examine arterial stiffness and sleep pattern in association with MBPS. Methods: This study included 30 healthy Korean American women aged 25 to 60 years. Ambulatory BP was monitored for 24 hours. To evaluate MBPS, maximum morning BPpower was calculated. Arterial stiffness was measured by carotid-femoral pulse wave velocity, and sleep pattern was evaluated using an actigraphy. Results: The participants (n = 8) in the upper quartile of MBPS had higher morning systolic BPs (SBPs; P = 0.015) and lower nighttime diastolic BPs (P = 0.031). The MBPS in SBP was significantly increased in the participants who had a more wakeful night (P = 0.038) and who slept longer at night (P = 0.041). Although MBPS was not significantly related to arterial stiffness, higher morning SBP (P = 0.005), morning diastolic BP (P = 0.048), and prewake SBP (P = 0.005) were associated with arterial stiffness. Conclusions: Our findings imply a possible link between disturbed sleep and MBPS. Clinicians should understand the importance of the modification of altered sleep pattern for reducing MBPS in nonhypertensive participants. C1 [Suh, Minhee; Barksdale, Debra J.] Univ N Carolina, Sch Nursing, Chapel Hill, NC USA. [Logan, Jeongok G.] NINR, NIH, Washington, DC USA. RP Suh, M (reprint author), Seoul Natl Univ, Res Inst Nursing Sci, Coll Nursing, 410 Annex,28 Yeongeon Dong, Seoul 110799, South Korea. EM mini-bee@hanmail.net NR 46 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0889-4655 EI 1550-5049 J9 J CARDIOVASC NURS JI J. Cardiovasc. Nurs. PD MAR-APR PY 2014 VL 29 IS 2 BP E10 EP E17 DI 10.1097/JCN.0b013e318291ee43 PG 8 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA AB2UX UT WOS:000331648700002 PM 23612041 ER PT J AU Redd, AD Mullis, CE Wendel, SK Sheward, D Martens, C Bruno, D Werner, L Garrett, NJ Karim, QA Williamson, C Porcella, SF Quinn, TC Karim, SSA AF Redd, Andrew D. Mullis, Caroline E. Wendel, Sarah K. Sheward, Daniel Martens, Craig Bruno, Daniel Werner, Lise Garrett, Nigel J. Karim, Quarraisha Abdool Williamson, Carolyn Porcella, Stephen F. Quinn, Thomas C. Karim, Salim S. Abdool TI Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTION; COHORT; UGANDA; RAKAI; RISK AB HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P = 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P < 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research. C1 [Redd, Andrew D.; Wendel, Sarah K.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Redd, Andrew D.; Mullis, Caroline E.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sheward, Daniel; Williamson, Carolyn] Univ Cape Town, Div Med Virol, ZA-7925 Cape Town, South Africa. [Martens, Craig; Bruno, Daniel; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. [Werner, Lise; Garrett, Nigel J.; Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Durban, South Africa. RP Redd, AD (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM aredd2@jhmi.edu OI , Carolyn/0000-0003-0125-1226; Abdool Karim, Salim/0000-0002-4986-2133 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of Allergy and Infectious Disease, National Institutes of Health; U.S. Department of Health and Human Services [AI51794]; National Research Foundation, South Africa [67385]; CONRAD [PPA-09-046, GPO-A-00-08-00005-00]; U.S. Agency for International Development (USAID); USAID; LIFELab, a biotechnology agency of the South African government's Department of Science and Technology FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. CAPRISA is part of the Comprehensive International Program of Research on AIDS (CIPRA), which is funded by the National Institute of Allergy and Infectious Disease, National Institutes of Health, the U.S. Department of Health and Human Services (grant AI51794), and the National Research Foundation, South Africa (grant 67385). The TRAPS (Tenofovir gel Research for AIDS Prevention Science) Program is funded in part by CONRAD subproject agreement PPA-09-046, under a Cooperative Agreement (GPO-A-00-08-00005-00) with the U.S. Agency for International Development (USAID). The CAPRISA 004 trial was funded by the USAID and LIFELab, a biotechnology agency of the South African government's Department of Science and Technology. NR 16 TC 4 Z9 5 U1 0 U2 2 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 MAR PY 2014 VL 52 IS 3 BP 844 EP 848 DI 10.1128/JCM.03143-13 PG 5 WC Microbiology SC Microbiology GA AC0DE UT WOS:000332164200019 PM 24371237 ER PT J AU Gordon, SE AF Gordon, Sharona E. TI Introducing the new members of the JGP Editorial Advisory Board SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Editorial Material C1 [Gordon, Sharona E.] NHLBI, Lab Kidney & Elect Metab, NIH, Bethesda, MD 20892 USA. [Gordon, Sharona E.] Int Soc Magnet Resonance Med, MRI, Bethesda, MD USA. [Gordon, Sharona E.] Soc Cardiovasc Magnet Resonance, Bethesda, MD USA. [Gordon, Sharona E.] NIH, Basic Lab Programs, Bethesda, MD USA. RP Gordon, SE (reprint author), NHLBI, Lab Kidney & Elect Metab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD MAR PY 2014 VL 143 IS 3 BP 309 EP 309 DI 10.1085/jgp.201411177 PG 1 WC Physiology SC Physiology GA AB8GQ UT WOS:000332028700001 ER PT J AU Pike, ER AF Pike, Elizabeth R. TI In need of remedy: US policy for compensating injured research participants SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID LITIGATION AB There is an emerging ethical consensus that injured research participants should receive medical care and compensation for their research-related injuries. This consensus is premised on notions of beneficence, distributive justice, compensatory justice and reciprocity. In response, countries around the world have implemented no-fault compensation systems to ensure that research participants are adequately protected in the event of injury. The United States, the world's leading sponsor of research, has chosen instead to rely on its legal system to provide injured research participants with medical care and compensation. This article argues that US reliance on its legal system leaves injured research participants unprotected in the event of injury. Nearly every injured research participant will have difficulty receiving compensation in court, and certain classes of research participants will be barred from receiving compensation altogether. The United States' outlier status also threatens to impede US-sponsored multinational research, potentially delaying important biomedical advances. To rectify this injustice, researchers, Institutional Review Boards, sponsors and research institutions should advocate systematic no-fault compensation in the United States to bring US law into accord with global ethical norms and ensure that injured research participants are adequately protected. C1 [Pike, Elizabeth R.] NIH, CC Dept Bioeth, Bethesda, MD 20892 USA. RP Pike, ER (reprint author), 1425 New York Ave,NW Suite C-100, Washington, DC 20005 USA. EM elizabeth.pike@hhs.gov FU NIH, out of the Warren G Magnussen Clinical Center FX This research was supported by the Intramural Research Program of the NIH, out of the Warren G Magnussen Clinical Center. NR 21 TC 4 Z9 4 U1 0 U2 3 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 MAR PY 2014 VL 40 IS 3 BP 182 EP 185 DI 10.1136/medethics-2012-100771 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AB2HG UT WOS:000331613200011 PM 23572565 ER PT J AU Kalman, LV Tarleton, JC Percy, AK Aradhya, S Bale, S Barker, SD Bayrak-Toydemir, P Bridges, C Buller-Burckle, AM Das, S Iyer, RK Vo, TD Zvereff, VV Toji, LH AF Kalman, Lisa V. Tarleton, Jack C. Percy, Alan K. Aradhya, Swaroop Bale, Sherri Barker, Shannon D. Bayrak-Toydemir, Pinar Bridges, Christina Buller-Burckle, Arlene M. Das, Soma Iyer, Ramaswamy K. Vo, Timothy D. Zvereff, Val V. Toji, Lorraine H. TI Development of a Genomic DNA Reference Material Panel for Rett Syndrome (MECP2-Related Disorders) Genetic Testing SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID MUTATIONS AB Rett syndrome is a dominant X-Linked disorder caused by point mutations (approximately 80%) or by deletions or insertions (approximately 15% to 18%) in the MECP2 gene. It is most common in females but Lethal in males, with a distinctly different phenotype. Rett syndrome patients have severe neurological and behavioral problems. Clinical genetic testing Laboratories commonly use characterized genomic DNA reference materials to assure the quality of the testing process; however, none are commercially available for MECP2 genetic testing. The Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with the genetic testing community and the Coriell Cell Repositories, established 27 new cell lines and characterized the MECP2 mutations in these and in 8 previously available cell lines. DNA samples from the 35 cell lines were tested by eight clinical genetic testing laboratories using DNA sequence analysis and methods to assess copy number (multiplex Ligation-dependent probe amplification, semiquantitative PCR, or array-based comparative genomic hybridization). The eight common point mutations known to cause approximately 60% of Rett syndrome cases were identified, as were other MECP2 variants, including deletions, duplications, and frame shift and splice-site mutations. Two of the 35 samples were from males with MECP2 duplications. These MECP2 and other characterized genomic DNA samples are publicly available from the NIGMS Repository at the Coriell Cell Repositories. C1 [Kalman, Lisa V.] Ctr Dis Control & Prevent, Lab Res & Evaluat Branch, Atlanta, GA 30333 USA. [Tarleton, Jack C.; Bridges, Christina] Mission Hlth Syst, Fullerton Genet Ctr, Fullerton Genet Lab, Asheville, NC USA. [Percy, Alan K.] Univ Alabama Birmingham, Intellectual & Dev Disabil Res Ctr, Birmingham, AL USA. [Aradhya, Swaroop; Bale, Sherri] GeneDx, Neurogenet, Gaithersburg, MD USA. [Barker, Shannon D.] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Bayrak-Toydemir, Pinar] ARUP Labs, Mol Genet & Genom Lab, Salt Lake City, UT USA. [Buller-Burckle, Arlene M.] Quest Diagnost Nichols Inst, San Juan Capistrano, CA USA. [Das, Soma] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Iyer, Ramaswamy K.] Univ Michigan, Med Ctr, Michigan Med Genet Labs, Ann Arbor, MI USA. [Vo, Timothy D.] Ambry Genet, Aliso Viejo, CA USA. [Zvereff, Val V.] Lab Corp America, Mol Genet & Genom, Res Triangle Pk, NC USA. [Toji, Lorraine H.] Coriell Inst Med Res, NIGMS Human Genet Cell Repository, Camden, NJ USA. RP Kalman, LV (reprint author), Ctr Dis Control & Prevent, CDC, Ctr Surveillance Epidemiol & Lab Serv, Div Lab Programs Stand & Serv,Lab Res & Evalut Br, 1600 Clifton Rd,Mailstop G23, Atlanta, GA 30333 USA. EM lkalman@cdc.gov FU NIH-NICHD grant [U54-61222] FX Supported in part by NIH-NICHD grant U54-61222 (A.K.P.). NR 18 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2014 VL 16 IS 2 BP 273 EP 279 DI 10.1016/j.jmoldx.2013.11.004 PG 7 WC Pathology SC Pathology GA AC0NZ UT WOS:000332193300015 PM 24508304 ER PT J AU Chittiboina, P Lonser, RR AF Chittiboina, Prashant Lonser, Russell R. TI Convection-enhanced delivery for diffuse intrinsic pontine glioma Response SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Editorial Material ID BRAIN-STEM; TRACER C1 [Chittiboina, Prashant; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. RP Chittiboina, P (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD MAR PY 2014 VL 13 IS 3 BP 274 EP 275 PG 2 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AB8OC UT WOS:000332048900007 PM 24724188 ER PT J AU Chittiboina, P Heiss, JD Warren, KE Lonser, RR AF Chittiboina, Prashant Heiss, John D. Warren, Katherine E. Lonser, Russell R. TI Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE convection-enhanced delivery; brainstem glioma; imaging; gadolinium; magnetic resonance imaging; oncology ID DIRECT INTERSTITIAL INFUSION; RAT-BRAIN STEM; ENHANCED DELIVERY; PRIMATE BRAIN; SPINAL-CORD; COMPUTATIONAL MODEL; MACROMOLECULES; PERFUSION; TIME; GLUCOCEREBROSIDASE AB Object. Coinfused surrogate imaging tracers can provide direct insight into the properties of convection-enhanced delivery (CED) in the nervous system. To better understand the distributive properties of CED in a clinical circumstance, the authors analyzed the imaging findings in pediatric diffuse intrinsic pontine glioma (DIPG) patients undergoing coinfusion of Gd-DTPA and interleukin-13-Pseudomonas exotoxin (IL13-PE). Methods. Consecutive patients undergoing CED (maximal rates of 5 or 10 mu l/minute) of Gd-DTPA (1 or 5 mM) and IL13-PE (0.125 mu g/ml or 0.25 mu g/ml) for DIPG were included. Real-time MRI was performed during infusions, and imaging results were analyzed. Results. Four patients (2 males, 2 females; mean age at initial infusion 13.0 +/- 5.3 years; range 5-17 years) underwent 5 infusions into DIPGs. Brainstem infusions were clearly identified on Ti-weighted MR images at 1-mM (1 infusion) and 5-mM (4 infusions) coinfused Gd-DTPA concentrations. While the volume of distribution (Vd) increased progressively with volume of infusion (Vi) (mean volume 2.5 +/- 0.9 ml; range 1.1-3.7 ml), final Vd:Vi ratios were significantly reduced with lower Gd-DTPA concentration (Vd:Vi for 1 mM of 1.6 compared with a mean Vd:Vi ratio for 5 mM of 3.3 +/- 1.0) (p = 0.04). Similarly, anatomical distribution patterns were affected by preferential flow along parallel axial fiber tracts, into prior infusion cannula tracts and intraparenchymal air pockets, and leak back around the infusion cannula at the highest rate of infusion. Conclusions. Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. C1 [Chittiboina, Prashant; Heiss, John D.; Lonser, Russell R.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Warren, Katherine E.] NCI, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. RP Lonser, RR (reprint author), Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Doan Hall,Rm 1047, Columbus, OH 43210 USA. EM russell.lonser@osumc.edu OI Heiss, John/0000-0002-3890-0165 FU intramural program of the NINDS at the NIH FX This work was support by the intramural program of the NINDS at the NIH. The IL13-PE was provided by InSys Therapeutics, Inc., under a cooperative research and development agreement with NINDS. The Smart Flow cannula and Clear Point system were provided by MIRE Interventions Inc., under a clinical trial agreement with NINDS. NR 35 TC 14 Z9 14 U1 0 U2 8 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD MAR PY 2014 VL 13 IS 3 BP 276 EP 282 DI 10.3171/2013.11.PEDS136 PG 7 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AB8OC UT WOS:000332048900008 PM 24410126 ER PT J AU Kang, F Ma, WH Ma, XW Shao, YH Yang, WD Chen, XY Li, LW Wang, J AF Kang, Fei Ma, Wenhui Ma, Xiaowei Shao, Yahui Yang, Weidong Chen, Xiaoyuan Li, Liwen Wang, Jing TI Propranolol Inhibits Glucose Metabolism and F-18-FDG Uptake of Breast Cancer Through Posttranscriptional Downregulation of Hexokinase-2 SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE propranolol; glucose metabolism; F-18-FDG PET imaging; ADRB; hexokinase 2 ID POSITRON-EMISSION-TOMOGRAPHY; PROMOTES TUMOR-GROWTH; BROWN ADIPOSE-TISSUE; OVARIAN-CARCINOMA; CELLS; THERAPY; SURVIVAL; METASTASIS; GLYCOLYSIS; ACTIVATION AB The advancement of breast cancer therapy is limited by the biologic behaviors of cancer cells, such as metastasis and recurrence. beta-adrenoceptors (ADRB) are reported to be associated with the biologic behaviors of breast cancer and may influence glucose metabolism. Here, we sought to investigate the relationship between the activation of ADRB and the expression of glucose transporter (GLUT)-1 and hexokinase (HK)-2 and to clarify the impact of ADRB on F-18-FDG PET imaging in breast cancer. Methods: ADRB1/2 expression in 4T1, MDA-MB-231, and MCF-7 breast cancer cell lines was detected by Western blotting and immunofluorescence. ADRB-dependent regulation of GLUT-1 and HK-2 was determined by in vitro pharmacologic intervention. 4T1 breast cancer cells were treated with phosphate-buffered saline, isoproterenol, or propranolol, and the transcription and expression of GLUT-1 and HK-2 were measured by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. ADRB1/2 was, respectively, blocked by small-interfering RNA to investigate the direct relationship between ADRB1/2 and HK-2. To evaluate the impact of ADRB on F-18-FDG PET imaging, BALB/c mice bearing 4T1 tumors were injected with phosphate-buffered saline, isoproterenol, or propranolol, and F-18-FDG PET imaging was performed. The tumor-to-nontumor (TINT) values of tumors and brown adipose tissue were calculated by defining the liver as a reference. The in vivo expression of GLUT-1 and HK-2 was observed by immunohistochemical analysis and Western blotting. Results: MDA-MB-231, MCF-7, and 4T1 breast cancer cells were positive for ADRB1/2 expression. The protein expression and posttranscriptional level of HK-2 were significantly decreased by treatment with propranolol in vitro, whereas GLUT-1 expression was not significantly altered by pharmacologic intervention. The expression of HK-2 could be reduced in ADRB2-blocked 4T1 cells. Mice in the propranolol-treated group exhibited lower TINT values for the tumors and brown adipose tissue than the control group. Immunohistochemical analysis and Western blotting revealed reduced HK-2 expression in the tumors of propranolol-treated mice. Conclusion: The expression of HK-2 was regulated by the activation of ADRB2 in 4T1 breast cancer cells primarily at the posttranscriptional level. Additionally, propranolol prevented glucose metabolism and F-18-FDG PET imaging of 4T1 breast cancer tumors. C1 [Kang, Fei; Ma, Wenhui; Ma, Xiaowei; Shao, Yahui; Yang, Weidong; Li, Liwen; Wang, Jing] Fourth Mil Med Univ, Xijing Hosp, Dept Nucl Med, Xian 710032, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD USA. [Li, Liwen] NW Univ Xian, Coll Life Sci, Xian 710069, Peoples R China. RP Wang, J (reprint author), Fourth Mil Med Univ, Xijing Hosp, Dept Nucl Med, 127 West Changle Rd, Xian 710032, Peoples R China. EM liven@nwu.edu.cn; wangjing@fmmu.edu.cn FU National Natural Science Foundation of China [81230033, 81227901]; National Basic Research Program of China (973 Program) [2011CB707704] 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 work was supported by the National Natural Science Foundation of China under grant nos. 81230033 and 81227901 and the National Basic Research Program of China (973 Program) under grant no. 2011CB707704. No other potential conflict of interest relevant to this article was reported. NR 41 TC 9 Z9 10 U1 2 U2 12 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 MAR PY 2014 VL 55 IS 3 BP 439 EP 445 DI 10.2967/jnumed.113.121327 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AC2RQ UT WOS:000332352100025 PM 24504055 ER PT J AU Mumford, SL Sundaram, R Schisterman, EF Sweeney, AM Barr, DB Rybak, ME Maisog, JM Parker, DL Pfeiffer, CM Louis, GMB AF Mumford, Sunni L. Sundaram, Rajeshwari Schisterman, Enrique F. Sweeney, Anne M. Barr, Dana Boyd Rybak, Michael E. Maisog, Jose M. Parker, Daniel L. Pfeiffer, Christine M. Louis, Germaine M. Buck TI Higher Urinary Lignan Concentrations in Women but Not Men Are Positively Associated with Shorter Time to Pregnancy SO JOURNAL OF NUTRITION LA English DT Article ID SERUM ENTEROLACTONE CONCENTRATION; BREAST-CANCER RISK; REGRESSION-MODELS; RANDOMIZED-TRIAL; PHYTOESTROGENS; INFERTILITY; SOY; BIOMARKERS; HEALTH; LIMIT AB Phytoestrogens have been associated with subtle hormonal changes, although effects on fecundity are unknown. Our objective was to evaluate the association between male and female urinary phytoestrogen (isoflavone and lignan) concentrations and time to pregnancy (TIP) in a population-based cohort of 501 couples desiring pregnancy and discontinuing contraception. Couples were followed for 12 moor until pregnancy. Fecundability ORs (FORs) and 95% CIs were estimated after adjusting for age, body mass index, race, site, creatinine, supplement use, and physical activity in relation to female, male, and joint couple concentrations. Models included the phytoestrogen of interest and the sum of the remaining individual phytoestrogens. FORs <1 denote a longer UP and FORs >1 a shorter TIP. Urinary lignan concentrations were higher, on average, among female partners of couples who became pregnant during the study compared with women who did not become pregnant (median enterodiol: 118 vs. 80 nmol/L; P < 0.10; median enterolactone: 990 vs. 412 nmol/L; P < 0.05) and were associated with significantly shorter UP in models based on both individual and couples' concentrations (couples' models: enterodiol FOR, 1.13; 95% Cl: 1.02, 1.26; enterolactone FOR, 1.11; 95% Cl: 1.01, 1.21). Male lignan concentrations were not associated with HP, nor were isoflavone concentrations. Sensitivity analyses showed that associations observed are unlikely to be explained by potential unmeasured confounding by lifestyle or other nutrients. Our results suggest that female urinary lignan concentrations at levels characteristic of the U.S. population are associated with a shorter TIP among couples who are attempting to conceive, highlighting the importance of dietary influences on fecundity. C1 [Mumford, Sunni L.; Sundaram, Rajeshwari; Schisterman, Enrique F.; Maisog, Jose M.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Sweeney, Anne M.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Rybak, Michael E.; Parker, Daniel L.; Pfeiffer, Christine M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. EM mumfords@mail.nih.gov OI Rybak, Michael/0000-0003-1650-8581; Sundaram, Rajeshwari/0000-0002-6918-5002; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX Supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355, N01-HD-3-3356, and N01-HD-3-3358) NR 39 TC 10 Z9 10 U1 2 U2 5 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 MAR PY 2014 VL 144 IS 3 BP 352 EP 358 DI 10.3945/jn.113.184820 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AB8QE UT WOS:000332054300016 PM 24401816 ER PT J AU Guenther, PM Kirkpatrick, SI Reedy, J Krebs-Smith, SM Buckman, DW Dodd, KW Casavale, KO Carroll, RJ AF Guenther, Patricia M. Kirkpatrick, Sharon I. Reedy, Jill Krebs-Smith, Susan M. Buckman, Dennis W. Dodd, Kevin W. Casavale, Kellie O. Carroll, Raymond J. TI The Healthy Eating Index-2010 Is a Valid and Reliable Measure of Diet Quality According to the 2010 Dietary Guidelines for Americans SO JOURNAL OF NUTRITION LA English DT Article ID EPISODICALLY CONSUMED FOODS; DISEASE; RECOMMENDATIONS; RACE/ETHNICITY; REDUCTION; PATTERNS; ADULTS; INCOME; GOALS; MODEL AB The Healthy Eating Index (HEI), a measure of diet quality, was updated to reflect the 2010 Dietary Guidelines for Americans and the accompanying USDA Food Patterns. To assess the validity and reliability of the HEI-2010, exemplary menus were scored and 2 24-h dietary recalls from individuals aged >= 2 y from the 2003-2004 NHANES were used to estimate multivariate usual intake distributions and assess whether the HEI-2010 1) has a distribution wide enough to detect meaningful differences in diet quality among individuals, 2) distinguishes between groups with known differences in diet quality by using t tests, 3) measures diet quality independently of energy intake by using Pearson correlation coefficients, 4) has >1 underlying dimension by using principal components analysis (PCA), and 5) is internally consistent by calculating Cronbach's coefficient alpha. HEI-2010 scores were at or near the maximum levels for the exemplary menus. The distribution of scores among the population was wide (5th percentile = 31.7; 95th percentile = 70.4). As predicted, men's diet quality (mean HEI-2010 total score = 49.8) was poorer than women's (52.7), younger adults' diet quality (45.4) was poorer than older adults' (56.1), and smokers' diet quality (45.7) was poorer than nonsmokers' (53.3) (P < 0.01). Low correlations with energy were observed for HEI-2010 total and component scores (vertical bar r vertical bar <= 0.21). Cronbach's coefficient a was 0.68, supporting the reliability of the HEI-2010 total score as an indicator of overall diet quality. Nonetheless, PCA indicated multiple underlying dimensions, highlighting the fact that the component scores are equally as important as the total. A comparable reevaluation of the HEI-2005 yielded similar results. This study supports the validity and the reliability of both versions of the HEI. C1 [Guenther, Patricia M.; Casavale, Kellie O.] USDA, Ctr Nutr Policy & Promot, Alexandria, VA USA. [Kirkpatrick, Sharon I.; Reedy, Jill; Krebs-Smith, Susan M.; Dodd, Kevin W.] NCI, Bethesda, MD 20892 USA. [Buckman, Dennis W.] Informat Management Serv Inc, Rockville, MD USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Guenther, PM (reprint author), Univ Utah, Div Nutr, Salt Lake City, UT 84112 USA. EM PMGuenther@outlook.com OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU National Cancer Institute [R37-CA057030] FX This research was supported by National Cancer Institute grant R37-CA057030 (to R.J.C). NR 35 TC 79 Z9 80 U1 3 U2 35 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 MAR PY 2014 VL 144 IS 3 BP 399 EP 407 DI 10.3945/jn.113.183079 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AB8QE UT WOS:000332054300022 PM 24453128 ER PT J AU Davis, AS Hintz, SR Goldstein, RF Ambalavanan, N Bann, CM Stoll, BJ Bell, EF Shankaran, S Laptook, AR Walsh, MC Hale, EC Newman, NS Das, A Higgins, RD AF Davis, A. S. Hintz, S. R. Goldstein, R. F. Ambalavanan, N. Bann, C. M. Stoll, B. J. Bell, E. F. Shankaran, S. Laptook, A. R. Walsh, M. C. Hale, E. C. Newman, N. S. Das, A. Higgins, R. D. CA Eunice Kennedy Shriver Natl Inst C Human Dev Neonatal Res Network TI Outcomes of extremely preterm infants following severe intracranial hemorrhage SO JOURNAL OF PERINATOLOGY LA English DT Article DE intraventricular hemorrhage; neurodevelopmental impairment; extremely low birth weight; cranial ultrasound ID BIRTH-WEIGHT INFANTS; GESTATIONAL-AGE; CEREBRAL-PALSY; NEURODEVELOPMENTAL OUTCOMES; INTRAVENTRICULAR HEMORRHAGE; NECROTIZING ENTEROCOLITIS; INTENSIVE-CARE; EPIPAGE COHORT; RISK-FACTORS; INFARCTION AB OBJECTIVE: Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH. STUDY DESIGN: Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: (i) unilateral vs bilateral ICH; and (ii) presence vs absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI). RESULT: Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI. CONCLUSION: Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks. C1 [Davis, A. S.; Hintz, S. R.] Stanford Univ, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Goldstein, R. F.] Duke Univ, Med Ctr, Dept Pediat, Div Neonatal Perinatal Med, Durham, NC 27710 USA. [Ambalavanan, N.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Bann, C. M.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Stoll, B. J.; Hale, E. C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Bell, E. F.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Shankaran, S.] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Laptook, A. R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Walsh, M. C.; Newman, N. S.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Das, A.] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, R. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. RP Davis, AS (reprint author), Stanford Univ, Dept Pediat, Div Neonatal & Dev Med, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM alexis.davis@stanford.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. Investigators, in addition to those listed as authors, who participated in this study are listed in the Appendix. The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development provided grant support for the Neonatal Research Network's Generic Database Study and Follow-up Study. NR 27 TC 7 Z9 7 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 EI 1476-5543 J9 J PERINATOL JI J. Perinatol. PD MAR PY 2014 VL 34 IS 3 BP 203 EP 208 DI 10.1038/jp.2013.162 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA AB8YF UT WOS:000332075200009 PM 24370654 ER PT J AU Hripcsak, G Bloomrosen, M FlatelyBrennan, P Chute, CG Cimino, J Detmer, DE Edmunds, M Embi, PJ Goldstein, MM Hammond, WE Keenan, GM Labkoff, S Murphy, S Safran, C Speedie, S Strasberg, H Temple, F Wilcox, AB AF Hripcsak, George Bloomrosen, Meryl FlatelyBrennan, Patti Chute, Christopher G. Cimino, Jim Detmer, Don E. Edmunds, Margo Embi, Peter J. Goldstein, Melissa M. Hammond, William Ed Keenan, Gail M. Labkoff, Steve Murphy, Shawn Safran, Charlie Speedie, Stuart Strasberg, Howard Temple, Freda Wilcox, Adam B. TI Health data use, stewardship, and governance: ongoing gaps and challenges: a report from AMIA's 2012 Health Policy Meeting SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE public policy; health data use; data governance; stewardship; data quality; data use principles ID MEDICAL INFORMATICS ASSOCIATION; SECONDARY USE; CARE; FRAMEWORK; REPRESENTATIVENESS; PRIVACY; RECORDS; ACCESS AB Large amounts of personal health data are being collected and made available through existing and emerging technological media and tools. While use of these data has significant potential to facilitate research, improve quality of care for individuals and populations, and reduce healthcare costs, many policy-related issues must be addressed before their full value can be realized. These include the need for widely agreed-on data stewardship principles and effective approaches to reduce or eliminate data silos and protect patient privacy. AMIA's 2012 Health Policy Meeting brought together healthcare academics, policy makers, and system stakeholders (including representatives of patient groups) to consider these topics and formulate recommendations. A review of a set of Proposed Principles of Health Data Use led to a set of findings and recommendations, including the assertions that the use of health data should be viewed as a public good and that achieving the broad benefits of this use will require understanding and support from patients. C1 [Hripcsak, George; Wilcox, Adam B.] Columbia Univ, Dept Bioinformat, New York, NY USA. [Bloomrosen, Meryl] AHIMA, Chicago, IL 60601 USA. [FlatelyBrennan, Patti] Univ Wisconsin, Madison, WI USA. [Chute, Christopher G.] Mayo Clin, Div Biomed Informat, Rochester, MN USA. [Cimino, Jim] NIH, Bethesda, MD 20892 USA. [Detmer, Don E.] Univ Virginia, Charlottesville, VA USA. [Edmunds, Margo] AcademyHealth, Washington, DC USA. [Embi, Peter J.] Ohio State Univ, Biomed Informat Columbus, Div Rheumatol & Immunol, Columbus, OH 43210 USA. [Goldstein, Melissa M.] GW Univ, Dept Hlth Policy, Washington, DC USA. [Hammond, William Ed] Duke Ctr Hlth Informat, Durham, NC USA. [Keenan, Gail M.] Univ Illinois, Chicago, IL USA. [Labkoff, Steve] Astra Zeneca, Wilmington, DE USA. [Murphy, Shawn] Partners HealthCare, Boston, MA USA. [Safran, Charlie] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Safran, Charlie] Harvard Univ, Sch Med, Boston, MA USA. [Speedie, Stuart] Univ Minnesota, Minneapolis, MN USA. [Strasberg, Howard] Wolters Kluwer Hlth, Philadelphia, PA USA. [Temple, Freda] AMIA, Bethesda, MD USA. RP Bloomrosen, M (reprint author), AHIMA, 233 North Michigan Ave, Chicago, IL 60601 USA. EM Meryl.bloomrosen@ahima.org RI Embi, Peter/E-3030-2011; OI Cimino, James/0000-0003-4101-1622 FU Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services [R13 HS 1R13HS021825-01] FX This project was funded in part under grant no. R13 HS 1R13HS021825-01 from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services. NR 75 TC 10 Z9 10 U1 4 U2 34 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2014 VL 21 IS 2 BP 204 EP 211 DI 10.1136/amiajnl-2013-002117 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AA7FT UT WOS:000331263600005 PM 24169275 ER PT J AU Tsang, SH Wang, X Li, J Buck, CB You, JX AF Tsang, Sabrina H. Wang, Xin Li, Jing Buck, Christopher B. You, Jianxin TI Host DNA Damage Response Factors Localize to Merkel Cell Polyomavirus DNA Replication Sites To Support Efficient Viral DNA Replication SO JOURNAL OF VIROLOGY LA English DT Article ID LARGE T-ANTIGEN; MRE11-RAD50-NBS1 COMPLEX; GENOME INTEGRITY; REQUIRES ATM; ACTIVATION; CARCINOMA; KINASE; CANCER; REPAIR; PHOSPHORYLATION AB Accumulating evidence indicates a role for Merkel cell polyomavirus (MCPyV) in the development of Merkel cell carcinoma (MCC), making MCPyV the first polyomavirus to be clearly associated with human cancer. With the high prevalence of MCPyV infection and the increasing amount of MCC diagnosis, there is a need to better understand the virus and its oncogenic potential. In this study, we examined the relationship between the host DNA damage response (DDR) and MCPyV replication. We found that components of the ATM- and ATR-mediated DDR pathways accumulate in MCPyV large T antigen (LT)-positive nuclear foci in cells infected with native MCPyV virions. To further study MCPyV replication, we employed our previously established system, in which recombinant MCPyV episomal DNA is autonomously replicated in cultured cells. Similar to native MCPyV infection, where both MCPyV origin and LT are present, the host DDR machinery colocalized with LT in distinct nuclear foci. Immunofluorescence in situ hybridization and bromodeoxyuridine (BrdU) incorporation analysis showed that these DDR proteins and MCPyV LT in fact colocalized at the actively replicating MCPyV replication complexes, which were absent when a replication-defective LT mutant or an MCPyV-origin mutant was introduced in place of wild-type LT or wild-type viral origin. Inhibition of DDR kinases using chemical inhibitors and ATR/ATM small interfering RNA (siRNA) knockdown reduced MCPyV DNA replication without significantly affecting LT expression or the host cell cycle. This study demonstrates that these host DDR factors are important for MCPyV DNA replication, providing new insight into the host machinery involved in the MCPyV life cycle. C1 [Tsang, Sabrina H.; Wang, Xin; Li, Jing; You, Jianxin] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP You, JX (reprint author), Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jianyou@mail.med.upenn.edu OI Buck, Christopher/0000-0003-3165-8094 FU HIV-Associated Malignancies Pilot Project Award (National Cancer Institute); National Institutes of Health (NIH) [R01CA148768, R01CA142723]; tumor virology training [2-T32-CA-115299-07]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the HIV-Associated Malignancies Pilot Project Award (National Cancer Institute), National Institutes of Health (NIH) grants R01CA148768 and R01CA142723, tumor virology training grant 2-T32-CA-115299-07, and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 55 TC 16 Z9 16 U1 0 U2 8 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 MAR PY 2014 VL 88 IS 6 BP 3285 EP 3297 DI 10.1128/JVI.03656-13 PG 13 WC Virology SC Virology GA AB9PA UT WOS:000332126000021 PM 24390338 ER PT J AU May, NA Wang, QH Balbo, A Konrad, SL Buchli, R Hildebrand, WH Schuck, P Hudson, AW AF May, Nathan A. Wang, Qiuhong Balbo, Andrea Konrad, Sheryl L. Buchli, Rico Hildebrand, William H. Schuck, Peter Hudson, Amy W. TI Human Herpesvirus 7 U21 Tetramerizes To Associate with Class I Major Histocompatibility Complex Molecules SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-STRUCTURE PREDICTION; NATURAL-KILLER-CELLS; MHC MOLECULES; ANALYTICAL ULTRACENTRIFUGATION; MONOCLONAL-ANTIBODIES; CYTOMEGALOVIRUS; GLYCOPROTEIN; LYSOSOMES; HOMOLOG; RECOGNITION AB The U21 gene product from human herpesvirus 7 binds to and redirects class I major histocompatibility complex (MHC) molecules to a lysosomal compartment. The molecular mechanism by which U21 reroutes class I MHC molecules to lysosomes is not known. Here, we have reconstituted the interaction between purified soluble U21 and class I MHC molecules, suggesting that U21 does not require additional cellular proteins to interact with class I MHC molecules. Our results demonstrate that U21, itself predicted to contain an MHC class I-like protein fold, interacts tightly with class I MHC molecules as a tetramer, in a 4:2 stoichiometry. These observations have helped to elucidate a refined model describing the mechanism by which U21 escorts class I MHC molecules to the lysosomal compartment. C1 [May, Nathan A.; Wang, Qiuhong; Konrad, Sheryl L.; Hudson, Amy W.] Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. [Balbo, Andrea] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Buchli, Rico] Pure Prot LLC, Oklahoma City, OK USA. [Hildebrand, William H.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Hudson, AW (reprint author), Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. EM ahudson@mcw.edu OI Schuck, Peter/0000-0002-8859-6966 FU Public Health Service from National Institute for Allergy and Infectious Disease [R01-AI069099]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by Public Health Service Grant R01-AI069099 from National Institute for Allergy and Infectious Disease (A.W.H.) and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 57 TC 2 Z9 3 U1 0 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 MAR PY 2014 VL 88 IS 6 BP 3298 EP 3308 DI 10.1128/JVI.02639-13 PG 11 WC Virology SC Virology GA AB9PA UT WOS:000332126000022 PM 24390327 ER PT J AU Moody, MA Santra, S Vandergrift, NA Sutherland, LL Gurley, TC Drinker, MS Allen, AA Xia, SM Meyerhoff, RR Parks, R Lloyd, KE Easterhoff, D Alam, SM Liao, HX Ward, BM Ferrari, G Montefiori, DC Tomaras, GD Seder, RA Letvin, NL Haynes, BF AF Moody, M. Anthony Santra, Sampa Vandergrift, Nathan A. Sutherland, Laura L. Gurley, Thaddeus C. Drinker, Mark S. Allen, Ashley A. Xia, Shi-Mao Meyerhoff, R. Ryan Parks, Robert Lloyd, Krissey E. Easterhoff, David Alam, S. Munir Liao, Hua-Xin Ward, Brandy M. Ferrari, Guido Montefiori, David C. Tomaras, Georgia D. Seder, Robert A. Letvin, Norman L. Haynes, Barton F. TI Toll-Like Receptor 7/8 (TLR7/8) and TLR9 Agonists Cooperate To Enhance HIV-1 Envelope Antibody Responses in Rhesus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID RECOMBINANT GLYCOPROTEIN-120 VACCINE; CELL-MEDIATED-IMMUNITY; EFFICACY TRIAL; DENDRITIC CELLS; INNATE IMMUNITY; NONHUMAN-PRIMATES; INFLUENZA VACCINE; DOUBLE-BLIND; INFECTION; ADJUVANTS AB The development of a vaccine that can induce high titers of functional antibodies against HIV-1 remains a high priority. We have developed an adjuvant based on an oil-in-water emulsion that incorporates Toll-like receptor (TLR) ligands to test whether triggering multiple pathogen-associated molecular pattern receptors could enhance immunogenicity. Compared to single TLR agonists or other pairwise combinations, TLR7/8 and TLR9 agonists combined were able to elicit the highest titers of binding, neutralizing, and antibody-dependent cellular cytotoxicity-mediating antibodies against the protein immunogen, transmitted/founder HIV-1 envelope gp140 (B.63521). We further found that the combination of TLR7/8 and TLR9 agonists was associated with the release of CXCL10 (IP-10), suggesting that this adjuvant formulation may have optimally stimulated innate and adaptive immunity to elicit high titers of antibodies. IMPORTANCE Combining TLR agonists in an adjuvant formulation resulted in higher antibody levels compared to an adjuvant without TLR agonists. Adjuvants that combine TLR agonists may be useful for enhancing antibody responses to HIV-1 vaccines. C1 [Moody, M. Anthony; Vandergrift, Nathan A.; Sutherland, Laura L.; Gurley, Thaddeus C.; Drinker, Mark S.; Allen, Ashley A.; Xia, Shi-Mao; Meyerhoff, R. Ryan; Parks, Robert; Lloyd, Krissey E.; Easterhoff, David; Alam, S. Munir; Liao, Hua-Xin; Ferrari, Guido; Tomaras, Georgia D.; Haynes, Barton F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27708 USA. [Moody, M. Anthony] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Vandergrift, Nathan A.; Alam, S. Munir; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Alam, S. Munir] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Ward, Brandy M.; Ferrari, Guido; Montefiori, David C.; Tomaras, Georgia D.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Tomaras, Georgia D.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC USA. [Santra, Sampa; Letvin, Norman L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Seder, Robert A.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Moody, MA (reprint author), Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27708 USA. EM moody007@mc.duke.edu RI Ferrari, Guido/A-6088-2015; Tomaras, Georgia/J-5041-2016 FU Collaboration for AIDS Vaccine Discovery grant; Bill and Melinda Gates Foundation; Center For HIV/AIDS Vaccine Immunology (CHAVI) [U19 AI067854]; Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID) [UM1 AI100645]; CAVD funding for the CTVIMC, grant [OPP1032325]; Duke University Center for AIDS Research Flow Cytometry and Virology cores (CFAR) [P30-AI-64518] FX Support for this work was provided by a Collaboration for AIDS Vaccine Discovery grant to B.F. Haynes from the Bill and Melinda Gates Foundation, by the Center For HIV/AIDS Vaccine Immunology (CHAVI; grant U19 AI067854), and by the Center For HIV/AIDS Vaccine Immunology-Immunogen Discovery grant (CHAVI-ID; grant UM1 AI100645). This study was further supported by CAVD funding for the CTVIMC, grant OPP1032325, and also by the Duke University Center for AIDS Research Flow Cytometry and Virology cores (CFAR; P30-AI-64518). NR 57 TC 22 Z9 22 U1 1 U2 5 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 MAR PY 2014 VL 88 IS 6 BP 3329 EP 3339 DI 10.1128/JVI.03309-13 PG 11 WC Virology SC Virology GA AB9PA UT WOS:000332126000025 PM 24390332 ER PT J AU Munro, JB Nath, A Farber, M Datta, SAK Rein, A Rhoades, E Mothes, W AF Munro, James B. Nath, Abhinav Faerber, Michael Datta, Siddhartha A. K. Rein, Alan Rhoades, Elizabeth Mothes, Walther TI A Conformational Transition Observed in Single HIV-1 Gag Molecules during In Vitro Assembly of Virus-Like Particles SO JOURNAL OF VIROLOGY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; PLASMA-MEMBRANE; PROTEIN; BINDING; DETERMINANTS; DOMAIN; SWITCH; SFP AB The conformational changes within single HIV-1 Gag molecules that occur during assembly into immature viruses are poorly understood. Using an in vitro assembly assay, it has been proposed that HIV-1 Gag undergoes a conformational transition from a compact conformation in solution to an extended rod-like conformation in virus-like particles (VLPs). Here we used single-molecule Fiirster resonance energy transfer (smFRET) to test this model by directly probing the conformation of single HIV-1 Gag molecules. We demonstrate that monomeric HIV-1 Gag lacking the p6 domain and the N-terminal myristoyl moiety is found in solution predominantly in a compact conformation. Gag in this conformation, and in the presence of nucleic acid, assembles into 30-nm-diameter particles. However, with the addition of inositol hexakisphosphate, Gag adopts a linear conformation and assembles into full-sized similar to 100-to-150-nm-diameter VLPs. Parallel fluorescence correlation spectroscopy measurements show that this conformational transition occurs early in the assembly process when Gag oligomers are small, perhaps as early as upon dimerization. Thus, smFRET measurements confirm that HIV-1 Gag transitions from a compact to a linear conformation during the formation of VLPs. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid. C1 [Munro, James B.; Faerber, Michael; Mothes, Walther] Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA. [Nath, Abhinav; Rhoades, Elizabeth] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. [Datta, Siddhartha A. K.; Rein, Alan] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. RP Munro, JB (reprint author), Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA. EM james.munro@yale.edu; walther.mothes@yale.edu OI Datta, Siddhartha/0000-0002-4098-7490 FU intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH [R21AI096999]; Irvington Fellowship Program of the Cancer Research Institute FX This work was supported in part by the intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, to A.R., by NIH grant R21AI096999 to W.M. and E.R., and by a grant from the Irvington Fellowship Program of the Cancer Research Institute to J.B.M. NR 36 TC 14 Z9 14 U1 0 U2 13 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 MAR PY 2014 VL 88 IS 6 BP 3577 EP 3585 DI 10.1128/JVI.03353-13 PG 9 WC Virology SC Virology GA AB9PA UT WOS:000332126000047 PM 24403576 ER PT J AU Low, PA Robertson, D Gilman, S Kaufmann, H Singer, W Biaggioni, I Freeman, R Perlman, S Hauser, RA Cheshire, W Lessig, S Vernino, S Mandrekar, J Dupont, WD Chelimsky, T Galpern, WR AF Low, Phillip A. Robertson, David Gilman, Sid Kaufmann, Horacio Singer, Wolfgang Biaggioni, Italo Freeman, Roy Perlman, Susan Hauser, Robert A. Cheshire, William Lessig, Stephanie Vernino, Steven Mandrekar, Jay Dupont, William D. Chelimsky, Thomas Galpern, Wendy R. TI Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial SO LANCET NEUROLOGY LA English DT Article ID CEREBRAL EXTRACELLULAR-SPACE; ALPHA-SYNUCLEIN PATHOLOGY; TRANSGENIC MOUSE MODEL; MESENCHYMAL STEM-CELLS; PARKINSONS-DISEASE; SYMPTOMS; THERAPY; BRAIN; DISORDERS; RILUZOLE AB Background No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of alpha-synudein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. Methods In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings Between April 22,2011, and April 19,2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0-85] per month in the rifampicin group vs 0-47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0,95% CI -0.24 to 0.24; p=0-82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. C1 [Low, Phillip A.; Singer, Wolfgang; Mandrekar, Jay] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Robertson, David; Biaggioni, Italo; Dupont, William D.] Vanderbilt Univ, Nashville, TN 37235 USA. [Gilman, Sid] Univ Michigan, Ann Arbor, MI 48109 USA. [Kaufmann, Horacio] NYU Med Ctr, New York, NY 10016 USA. [Freeman, Roy] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Perlman, Susan] Univ Calif Los Angeles, Los Angeles Med Ctr, Los Angeles, CA USA. [Hauser, Robert A.] Univ S Florida, Tampa, FL USA. [Cheshire, William] Mayo Clin, Jacksonville, FL 32224 USA. [Lessig, Stephanie] Univ Calif San Diego, La Jolla, CA 92093 USA. [Vernino, Steven] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Chelimsky, Thomas] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Galpern, Wendy R.] NIH, Bethesda, MD 20892 USA. RP Low, PA (reprint author), Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. EM low@mayo.edu OI Cheshire, William/0000-0002-6364-5362; Kaufmann, Horacio/0000-0002-1851-9981 FU National Institutes of Health; Mayo Clinic Center for Translational Science Activities; Mayo Funds FX National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds. NR 42 TC 33 Z9 33 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2014 VL 13 IS 3 BP 268 EP 275 DI 10.1016/S1474-4422(13)70301-6 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AC1NW UT WOS:000332264300010 PM 24507091 ER PT J AU Wentzensen, N Schiffman, M AF Wentzensen, Nicolas Schiffman, Mark TI Filling a gap in cervical cancer screening programmes SO LANCET ONCOLOGY LA English DT Editorial Material ID INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; METAANALYSIS; METHYLATION; WOMEN C1 [Wentzensen, Nicolas; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. EM wentzenn@mail.nih.gov FU Intramural NIH HHS [ZIA CP010124-18] NR 10 TC 4 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2014 VL 15 IS 3 BP 249 EP 251 DI 10.1016/S1470-2045(14)70073-7 PG 4 WC Oncology SC Oncology GA AC3FF UT WOS:000332399900027 PM 24529698 ER PT J AU Thomas, B Stedman, M Davies, L AF Thomas, Brian Stedman, Margaret Davies, Louise TI Grade as a Prognostic Factor in Oral Squamous Cell Carcinoma: A Population-Based Analysis of the Data SO LARYNGOSCOPE LA English DT Article DE Oral cavity; squamous cell carcinoma; prognosis; grade; pathology; survival; SEER; survival epidemiology; and end results database ID HISTOLOGIC GRADE; INVASIVE FRONT; CAVITY CANCER; NECK; HEAD; TONGUE; PARAMETERS; RISK AB Objectives/HypothesisHistorically, histologic grade has not been considered a useful prognostic factor in head and neck squamous cell carcinoma (SCC). However, in other solid tumors, grade is known to affect prognosis. We test the hypothesis that histologic grade is an independent predictor of prognosis in oral cavity SCC. Study DesignPopulation-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. MethodsFifteen year cause-specific survival. Multivariate analysis was performed on a subset of patients diagnosed between 2004 and 2008. ResultsAmong patients 20 to 65 years of age with American Joint Committee on Cancer (AJCC) stage I or II cancer, the adjusted risk of death is 2.7 times greater (95% CI 1.72-4.11) if the tumor is poorly differentiated or undifferentiated than it is if the tumor is well differentiated. Among patients 66 to 94 years of age, the risk of death is 3.0 (95% CI 2.02-4.54) times greater. For those over age 65, moderately differentiated tumors also confer an estimated 42% increased risk of death, but this estimate is only borderline significant (P=0.05). ConclusionsThere is a strong association between histologic grade and survival in patients with AJCC stage I or II oral cavity SCC. High histologic grade in early stage oral cavity cancer is associated with poorer survival and carries independent prognostic value in addition to tumor size, node status, and presence of distant metastasis (TNM) stage. Thus, histologic grade should be considered clinically when making treatment decisions, and multivariable models of survival should include grade as a covariate to improve prognostic accuracy. Level of Evidence2b Laryngoscope, 124:688-694, 2014 C1 [Thomas, Brian; Davies, Louise] Dartmouth Hitchcock Med Ctr, Dept Surg, Div Otolaryngol Head & Neck Surg, Lebanon, NH 03766 USA. [Davies, Louise] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. [Davies, Louise] Dept Vet Affairs Med Ctr, VA Outcomes Grp, White River Jct, VT USA. [Stedman, Margaret] NCI, Data Modeling Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Davies, L (reprint author), VA Outcomes Group 111B, 215 North Main St, White River Jct, VT 05009 USA. EM louise.davies@dartmouth.edu OI Stedman, Margaret/0000-0001-9271-8332 FU Department of Veterans Affairs, National Cancer Institute FX Sources of support: Department of Veterans Affairs, National Cancer Institute. NR 29 TC 10 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD MAR PY 2014 VL 124 IS 3 BP 688 EP 694 DI 10.1002/lary.24357 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AA8VY UT WOS:000331374300028 PM 23945976 ER PT J AU Avram, AV Guidon, A Truong, TK Liu, CL Song, AW AF Avram, Alexandru V. Guidon, Arnaud Trong-Kha Truong Liu, Chunlei Song, Allen W. TI Dynamic and Inherent B-0 Correction for DTI Using Stimulated Echo Spiral Imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion tensor imaging; stimulated echo; off-resonance correction; eddy current correction; magnetic field inhomogeneities ID DIFFUSION-WEIGHTED MRI; MAGNETIC-RESONANCE; HUMAN BRAIN; FAT-SUPPRESSION; MYELIN WATER; SPIN-ECHO; TENSOR; DISTORTIONS; ANISOTROPY; SENSITIVITY AB PurposeTo present a novel technique for high-resolution stimulated echo diffusion tensor imaging with self-navigated interleaved spirals readout trajectories that can inherently and dynamically correct for image artifacts due to spatial and temporal variations in the static magnetic field (B-0) resulting from eddy currents, tissue susceptibilities, subject/physiological motion, and hardware instabilities. MethodsThe Hahn spin echo formed by the first two 90 degrees radiofrequency pulses is balanced to consecutively acquire two additional images with different echo times and generate an inherent field map, while the diffusion-prepared stimulated echo signal remains unaffected. For every diffusion-encoding direction, an intrinsically registered field map is estimated dynamically and used to effectively and inherently correct for off-resonance artifacts in the reconstruction of the corresponding diffusion-weighted image. ResultsAfter correction with the dynamically acquired field maps, local blurring artifacts are specifically removed from individual stimulated echo diffusion-weighted images and the estimated diffusion tensors have significantly improved spatial accuracy and larger fractional anisotropy. ConclusionCombined with the self-navigated interleaved spirals acquisition scheme, our new method provides an integrated high-resolution short-echo time diffusion tensor imaging solution with inherent and dynamic correction for both motion-induced phase errors and off-resonance effects. Magn Reson Med 71:1044-1053, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Avram, Alexandru V.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Guidon, Arnaud] Duke Univ, Dept Biomed Engn, Pratt Sch Engn, Durham, NC 27706 USA. [Guidon, Arnaud; Trong-Kha Truong; Liu, Chunlei; Song, Allen W.] Duke Univ, Sch Med, Brain Imaging & Anal Ctr, Durham, NC USA. RP Avram, AV (reprint author), NICHD, NICHHD, NIH, 13 South Dr,Rm 3W16, Bethesda, MD 20892 USA. EM alexandru.avram@nih.gov RI Truong, Trong-Kha/S-3089-2016; OI Truong, Trong-Kha/0000-0003-2699-1554; Liu, Chunlei/0000-0001-8816-4832 FU National Institutes of Health [R00EB007182, EB009483, NS075017, EB012586]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX Grant sponsor: National Institutes of Health; Grant numbers: R00EB007182; EB009483; NS075017; EB012586, Grant sponsor: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 33 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAR PY 2014 VL 71 IS 3 BP 1044 EP 1053 DI 10.1002/mrm.24767 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AB2HU UT WOS:000331614600016 PM 23630029 ER PT J AU Ponce, IP Blaimer, M Breuer, FA Griswold, MA Jakob, PM Kellman, P AF Ponce, Irene P. Blaimer, Martin Breuer, Felix A. Griswold, Mark A. Jakob, Peter M. Kellman, Peter TI Auto-Calibration Approach for k-t SENSE SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE dynamic magnetic resonance imaging; parallel imaging; k-t SENSE; auto-calibration; temporal filtering ID BLAST; MRI AB PurposeThe goal of this work is to increase the spatial resolution of training data, used by reconstruction methods such as k-t SENSE in order to calculate the missing data in a series of dynamic images, without compromising their temporal resolution or acquisition time. TheoryThe k-t SENSE method allows dynamic imaging at high acceleration factors with high reconstruction quality. However, the low resolution training data required by k-t SENSE may cause undesired temporal filtering effects in the reconstructed images. MethodsIn this work, a feedback regularization approach is applied to realize auto-calibration of the k-t SENSE algorithm. To that end, a full resolution training data set is calculated from the accelerated data itself using a TSENSE reconstruction. The reconstructed training data are then fed back for the actual k-t SENSE reconstruction. For evaluation of our approach, temporal filtering effects are quantified by calculating the modulation transfer function and noise measurements are done by Monte-Carlo simulations. ResultsComputer simulations and cardiac imaging experiments demonstrate an improved temporal fidelity of auto-calibrated k-t SENSE compared to standard k-t SENSE. ConclusionAuto-calibrated k-t SENSE provides high quality reconstructions for dynamic imaging applications. Magn Reson Med 71:1123-1129, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Ponce, Irene P.; Jakob, Peter M.] Univ Wurzburg, Dept Expt Phys 5, D-97074 Wurzburg, Germany. [Blaimer, Martin; Breuer, Felix A.; Jakob, Peter M.] Res Ctr Magnet Resonance Bavaria MRB, Dept Diagnost Imaging, Wurzburg, Germany. [Griswold, Mark A.] Univ Hosp Cleveland, Dept Radiol, Cleveland, OH 44106 USA. [Griswold, Mark A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Ponce, IP (reprint author), Univ Wurzburg, Dept Expt Phys 5, Hubland, D-97074 Wurzburg, Germany. EM pponce@physik.uni-wuerzburg.de OI Jakob, Peter/0000-0002-3481-5545 FU CONACyT-DAAD; Siemens Medical, Erlangen, Germany FX Grant sponsor: CONACyT-DAAD and Siemens Medical, Erlangen, Germany. NR 15 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAR PY 2014 VL 71 IS 3 BP 1123 EP 1129 DI 10.1002/mrm.24738 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AB2HU UT WOS:000331614600025 PM 23554094 ER PT J AU Goddings, AL Mills, KL Clasen, LS Giedd, JN Viner, RM Blakemore, SJ AF Goddings, Anne-Lise Mills, Kathryn L. Clasen, Liv S. Giedd, Jay N. Viner, Russell M. Blakemore, Sarah-Jayne TI The influence of puberty on subcortical brain development SO NEUROIMAGE LA English DT Article DE Puberty; Adolescence; MRI; Subcortex ID MAJOR DEPRESSIVE DISORDER; RHESUS-MONKEY; ANDROGEN RECEPTOR; STEROID-HORMONES; SEX STEROIDS; ADOLESCENCE; MATURATION; CHILDHOOD; VOLUMES; HIPPOCAMPAL AB Puberty is characterized by hormonal, physical and psychological transformation. The human brain undergoes significant changes between childhood and adulthood, but little is known about how puberty influences its structural development. Using a longitudinal sample of 711 magnetic resonance imaging scans from 275 individuals aged 7-20 years, we examined how subcortical brain regions change in relation to puberty. Our regions of interest included the amygdala, hippocampus and corpus striatum including the nucleus accumbens (NA), caudate, putamen and globus pallidus (GP). Pubertal development was significantly related to structural volume in all six regions in both sexes. Pubertal development and age had both independent and interactive influences on volume for the amygdala, hippocampus and putamen in both sexes, and the caudate in females. There was an interactive puberty-by-age effect on volume for the NA and GP in both sexes, and the caudate in males. These findings suggest a significant role for puberty in structural brain development. (C) 2013 Published by Elsevier Inc. C1 [Goddings, Anne-Lise; Viner, Russell M.] UCL, UCL Inst Child Hlth, London WC1N 1EH, England. [Goddings, Anne-Lise; Mills, Kathryn L.; Blakemore, Sarah-Jayne] UCL, UCL Inst Cognit Neurosci, London WC1N 3AR, England. [Mills, Kathryn L.; Clasen, Liv S.; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Goddings, AL (reprint author), UCL Inst Child Hlth, Gen & Adolescent Paediat Unit, 30 Guilford St, London WC1N 1EH, England. EM anne-lise.goddings@ucl.ac.uk RI Giedd, Jay/J-9644-2015; Viner, Russell/A-1441-2009 OI Giedd, Jay/0000-0003-2002-8978; Viner, Russell/0000-0003-3047-2247 FU MRC; Royal Society; National Institutes of Health FX The authors gratefully acknowledge the continued participation of all families and individuals involved in this longitudinal study. We thank F Lalonde for his valuable contribution in processing the imaging data for this analysis. The authors of this study are funded by grants from the MRC (AG: Clinical Training Research Fellowship), the Royal Society (SJB: University Research Fellowship) and the National Institutes of Health (JNG: Intramural Research Program; KLM: Graduate Partnership Program). NR 53 TC 64 Z9 65 U1 4 U2 45 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2014 VL 88 BP 242 EP 251 DI 10.1016/j.neuroimage.2013.09.073 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AB8PH UT WOS:000332052000025 PM 24121203 ER PT J AU Artornsombudh, P Pistilli, M Foster, CS Pujari, SS Gangaputra, SS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Kempen, JH AF Artornsombudh, Pichaporn Pistilli, Maxwell Foster, C. Stephen Pujari, Siddharth S. Gangaputra, Sapna S. Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Kempen, John H. TI Factors Predictive of Remission of New-Onset Anterior Uveitis SO OPHTHALMOLOGY LA English DT Article ID JUVENILE IDIOPATHIC ARTHRITIS; INTRAOCULAR INFLAMMATORY DISEASE; INTERMEDIATE UVEITIS; CLINICAL-COURSE; PREVALENCE; EPIDEMIOLOGY; CHILDHOOD; BLINDNESS; FRAGMENT AB Purpose: To identify factors predictive of remission of inflammation in new-onset anterior uveitis cases treated at tertiary uveitis care facilities. Design: Retrospective cohort study. Participants: Patients seeking treatment at participating academic uveitis clinics within 90 days of initial diagnosis of anterior uveitis. Methods: Retrospective cohort study based on standardized chart review. Main Outcome Measures: Factors predictive of remission (no disease activity without corticosteroid or immunosuppressive treatments at all visits during a 90-day period). Results: Nine hundred ninety eyes (687 patients) had a first-ever diagnosis of anterior uveitis within 90 days before initial presentation and had follow-up visits thereafter. The median follow-up time was 160 days. Systemic diagnoses with juvenile idiopathic arthritis (JIA; adjusted hazard ratio [aHR], 0.38; 95% confidence interval [CI], 0.19-0.74) and Behcet's disease (aHR, 0.10; 95% CI, 0.01-0.85) were associated with a lower incidence of uveitis remission. Cases of bilateral uveitis (aHR, 0.68; 95% CI, 0.54-0.87) and those with a history of cataract surgery before presentation (aHR, 0.51; 95% CI, 0.29-0.87) also had a lower incidence of remission. Regarding clinical findings at the initial visit, a high degree of vitreous cells at initial presentation was associated with a lower incidence of remission (for 1+ or more vs. none: aHR, 0.72; 95% CI, 0.55-0.95). An initial visual acuity of 20/200 or worse, with respect to 20/40 or better, also was predictive of a lower incidence of remission (aHR, 0.52; 95% CI, 0.32-0.86). Conclusions: Factors associated with a lower incidence of remission among new-onset anterior uveitis cases included diagnosis with JIA, Behcet's disease, bilateral uveitis, history of cataract surgery, findings of 1+ or more vitreous cells at presentation, and an initial visual acuity of 20/200 or worse. Patients with these risk factors seem to be at higher risk of persistent inflammation; reciprocally, patients lacking these factors would be more likely to experience remission. Patients with risk factors for nonremission of uveitis should be managed taking into account the higher probability of a chronic inflammatory course. (C) 2014 by the American Academy of Ophthalmology. C1 [Artornsombudh, Pichaporn; Foster, C. Stephen; Pujari, Siddharth S.] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Artornsombudh, Pichaporn; Pistilli, Maxwell; Kempen, John H.] Univ Penn, Dept Ophthalmol, Scheie Eye Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Pujari, Siddharth S.] Om Eye Care Hosp, Belgaum, Karnataka, India. [Gangaputra, Sapna S.] Duke Univ, Sch Med, Dept Surg, Durham, NC USA. [Gangaputra, Sapna S.] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Fundus Photograph Reading Ctr, Madison, WI USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. [Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Pistilli, Maxwell/0000-0002-4266-4150 FU National Eye Institute, National Institutes of Health, Bethesda, Maryland [EY014943]; Research to Prevent Blindness, Inc., New York, New York; Paul and Evanina Mackall Foundation, New York, New York; Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts; Research to Prevent Blindness; National Eye Institute; United States Department of Veterans' Affairs FX Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: EY014943 [J.H.K.]); Research to Prevent Blindness, Inc., New York, New York; the Paul and Evanina Mackall Foundation, New York, New York; and the Ocular Immunology and Uveitis Foundation, Cambridge, Massachusetts. During the time of data collection, J.H.K. was an Research to Prevent Blindness James S. Adams Special Scholar Award recipient, J.E.T. was a Research to Prevent Blindness Harrington Special Scholar Award recipient, and D.A.J. and J.T.R. were Research to Prevent Blindness Senior Scientific Investigator Award recipients. G.A.L-C. is an employee of Johnson & Johnson and was previously supported by the National Eye Institute, and R.B.N. continues to be supported by intramural funds of the National Eye Institute. E.B.S. receives support from the United States Department of Veterans' Affairs. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; or in the preparation, review, and approval of this manuscript. NR 31 TC 4 Z9 4 U1 0 U2 9 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 MAR PY 2014 VL 121 IS 3 BP 778 EP 784 DI 10.1016/j.ophtha.2013.09.041 PG 7 WC Ophthalmology SC Ophthalmology GA AC3FT UT WOS:000332401800030 PM 24342020 ER PT J AU Cotten, CM Goldstein, RF McDonald, SA Goldberg, RN Salhab, WA Carlo, WA Tyson, JE Finer, NN Walsh, MC Ehrenkranz, RA Laptook, AR Guillet, R Schibler, K Van Meurs, KP Poindexter, BB Stoll, BJ O'Shea, TM Duara, S Das, A Higgins, RD Shankaran, S AF Cotten, C. Michael Goldstein, Ricki F. McDonald, Scott A. Goldberg, Ronald N. Salhab, Walid A. Carlo, Waldemar A. Tyson, Jon E. Finer, Neil N. Walsh, Michele C. Ehrenkranz, Richard A. Laptook, Abbot R. Guillet, Ronnie Schibler, Kurt Van Meurs, Krisa P. Poindexter, Brenda B. Stoll, Barbara J. O'Shea, T. Michael Duara, Shahnaz Das, Abhik Higgins, Rosemary D. Shankaran, Seetha CA Eunice Kennedy Shriver Natl Inst TI Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy SO PEDIATRIC RESEARCH LA English DT Article ID GENETIC ASSOCIATION; ALZHEIMERS-DISEASE; CEREBRAL-PALSY; NORTHEAST BRAZIL; CARDIAC-SURGERY; E POLYMORPHISMS; BRAIN-INJURY; CHILDREN; ALLELE; RISK AB BACKGROUND: Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE). METHODS: We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-. RESULTS: A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. CONCLUSION: Disability was not associated with the APOE genotype in this cohort of HIE survivors. C1 [Cotten, C. Michael; Goldstein, Ricki F.; Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [McDonald, Scott A.] RTI Int, Social Stat & Environm Sci, Res Triangle Pk, NC USA. [Salhab, Walid A.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Tyson, Jon E.] Univ Texas Med Sch Houston, Dept Pediat, Houston, TX USA. [Finer, Neil N.] Univ Calif San Diego, Div Neonatol, San Diego, CA 92103 USA. [Walsh, Michele C.] Case Western Reserve, Dept Pediat, Rainbow Babies & Childrens Hosp, Cleveland, OH USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Guillet, Ronnie] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Schibler, Kurt] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Cincinnati, OH 45229 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [O'Shea, T. Michael] Wake Forest Sch Med, Winston Salem, NC USA. [Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. RP Cotten, CM (reprint author), Duke Univ, Dept Pediat, Durham, NC 27706 USA. EM michael.cotten@duke.edu FU National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) FX The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) funded this trial. Principal Investigators and Research Coordinators received salary support as part of the Network grants at each site, and grant numbers are individually listed in the Supplemental Appendix online. No authors have financial ties to products used in the study or potential/perceived conflicts of interest to disclose. NR 40 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2014 VL 75 IS 3 BP 424 EP 430 DI 10.1038/pr.2013.235 PG 7 WC Pediatrics SC Pediatrics GA AC3PK UT WOS:000332433500008 PM 24322171 ER PT J AU Wei, W Kim, JM Medina, D Lakatta, EG Lin, L AF Wei, Wen Kim, Ji Min Medina, Danny Lakatta, Edward G. Lin, Li TI GeneOptimizer program-assisted cDNA reengineering enhances sRAGE autologous expression in Chinese hamster ovary cells SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE GeneOptimizer program; sRAGE; Protein expression; CHO ID ADVANCED GLYCATION ENDPRODUCTS; RAGE; RECEPTOR; PROTEIN; ATHEROSCLEROSIS; INFLAMMATION; DISEASE; BINDING; INJURY; MICE AB Soluble receptor for advanced glycation end products (sRAGE) is a secreted mammalian protein that functions as a decoy to counter-react RAGE signaling-resultant pathological conditions, and has high therapeutic potentials. Our prior studies showed that recombinant human sRAGE expressed in Chinese hamster, Ceanothus griseus, ovary (CHO) cells is modified by specific N-glycosylation, and exhibits higher bioactivity than that expressed in other host systems including insect Spodoptera frugiperda cells. Here, we show that GeneOptimizer software program-assisted, reengineered sRAGE cDNA enhances the recombinant protein expression in CHO cells. The cDNA sequence encoding human sRAGE was optimized for RNA structure, stability, and codon usages in CHO cells. We found that such optimization augmented sRAGE expression over 2 folds of its wild-type counterpart. We also studied how individual parameter impacted sRAGE autologous expression in CHO cells, and whether sRAGE bioactivity was compromised. We found that the enhanced expression appeared not to affect sRAGE N-glycosylation and bioactivity. Optimization of sRAGE expression provides a basis for future large-scale production of this protein to meet medical needs. Published by Elsevier Inc. C1 [Wei, Wen; Kim, Ji Min; Lakatta, Edward G.; Lin, Li] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Medina, Danny] Life Technol Invitrogen Inc, GeneArt Div, Carlsbad, CA 92008 USA. RP Lin, L (reprint author), NIA, Cardiovasc Sci Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM linli@mail.nih.gov FU National institute on Aging, NIH FX The work is supported in part by the intramural research program of the National institute on Aging, NIH. We thank Veena Shetty for the advice on statistic analysis, Jade Scheers and Dr. Robert Wersto (NIA flow cytometry core facility) for GFP analyses. NR 35 TC 3 Z9 3 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2014 VL 95 BP 143 EP 148 DI 10.1016/j.pep.2013.12.006 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AC0NV UT WOS:000332192900020 PM 24373844 ER PT J AU Costello, EJ He, JP Sampson, NA Kessler, RC Merikangas, KR AF Costello, E. Jane He, Jian-ping Sampson, Nancy A. Kessler, Ronald C. Merikangas, Kathleen Ries TI Services for Adolescents With Psychiatric Disorders: 12-Month Data From the National Comorbidity Survey-Adolescent SO PSYCHIATRIC SERVICES LA English DT Article ID MENTAL-HEALTH-SERVICES; SUPPLEMENT NCS-A; PEDIATRIC PRIMARY-CARE; SURVEY REPLICATION; MAJOR DEPRESSION; RECALL BIAS; CHILDREN; PREVALENCE; IDENTIFICATION; COMMUNITY AB Objective: This study examined 12-month rates of service use for mental, emotional, and behavioral disorders among adolescents. Methods: Data were from the National Comorbidity Survey Adolescent Supplement (NCS-A), a survey of DSM-IV mental, emotional, and behavioral disorders and service use. Results: In the past 12 months, 45.0% of adolescents with psychiatric disorders received some form of service. The most likely were those with ADHD (73.8%), conduct disorder (73.4%), or oppositional defiant disorder (71.0%). Least likely were those with specific phobias (40.7%) and any anxiety disorder (41.4%). Among those with any disorder, services were more likely to be received in a school setting (23.6%) or in a specialty mental health setting (22.8%) than in a general medical setting (10.1%). Youths with any disorder also received services in juvenile justice settings (4.5%), complementary and alternative medicine (5.3%), and human services settings (7.9%). Although general medical providers treated a larger proportion of youths with mood disorders than with behavior disorders, they were more likely to treat youths with behavior disorders because of the larger number of the latter (11.5% of 1,465 versus 13.9% of 820). Black youths were significantly less likely than white youths to receive specialty mental health or general medical services for mental disorders. Conclusions: Findings from this analysis of NCS-A data confirm those of earlier, smaller studies, that only a minority of youths with psychiatric disorders receive treatment of any sort. Much of this treatment was provided in service settings in which few providers were likely to have specialist mental health training. C1 [Costello, E. Jane] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. [He, Jian-ping] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Merikangas, Kathleen Ries] NIMH, Mood & Anxiety Disorders Program, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. [Sampson, Nancy A.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Costello, EJ (reprint author), Duke Univ, Dept Psychiat, Durham, NC 27706 USA. EM elizabeth.costello@duke.edu FU National Institute of Mental Health (NIMH) [U01-MH60220, R01-MH66627, U01-MH060220-09S]; National Institute on Drug Abuse (NIDA); Substance Abuse and Mental Health Services Administration (SAMHSA); Robert Wood Johnson Foundation [044780]; John W. Alden Trust; NIDA [U0I-DA024413, DA011301, DA022308]; NIMH [MH083964]; NIMH Intramural Research Program FX The NCS-A was supported by the National Institute of Mental Health (NIMH) (grants U01-MH60220, R01-MH66627, and U01-MH060220-09S), with supplemental support from the National Institute on Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (grant 044780), and the John W. Alden Trust. The NCS-A is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. This study was supported by NIDA (grants U0I-DA024413, DA011301, and DA022308), NIMH (grant MH083964), and the NIMH Intramural Research Program. The authors thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation and field work and consultation on data analysis. The sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, or approval of the manuscript. The views and opinions expressed are those of the authors and should not be construed to represent the views of any of the sponsoring organizations or agencies or the U.S. government. NR 46 TC 37 Z9 37 U1 6 U2 22 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD MAR PY 2014 VL 65 IS 3 BP 359 EP 366 DI 10.1176/appi.ps.201100518 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA AB8NY UT WOS:000332048500014 PM 24233052 ER PT J AU Lakshminarayan, K Larson, JC Virnig, B Fuller, C Allen, NB Limacher, M Winkelmayer, WC Safford, MM Burwen, DR AF Lakshminarayan, Kamakshi Larson, Joseph C. Virnig, Beth Fuller, Candace Allen, Norrina Bai Limacher, Marian Winkelmayer, Wolfgang C. Safford, Monika M. Burwen, Dale R. TI Comparison of Medicare Claims Versus Physician Adjudication for Identifying Stroke Outcomes in the Women's Health Initiative SO STROKE LA English DT Article DE Medicare; stroke; validation studies ID ISCHEMIC CEREBROVASCULAR-DISEASE; ADMINISTRATIVE DATA; ICD-9-CM; INACCURACY; DIAGNOSIS; ACCURACY; CODES AB Background and Purpose Many studies use medical record review for ascertaining outcomes. One large, longitudinal study, the Women's Health Initiative (WHI), ascertains strokes using participant self-report and subsequent physician review of medical records. This is resource-intensive. Herein, we assess whether Medicare data can reliably assess stroke events in the WHI. Methods Subjects were WHI participants with fee-for-service Medicare. Four stroke definitions were created for Medicare data using discharge diagnoses in hospitalization claims: definition 1, stroke codes in any position; definition 2, primary position stroke codes; and definitions 3 and 4, hemorrhagic and ischemic stroke codes, respectively. WHI data were randomly split into training (50%) and test sets. A concordance matrix was used to examine the agreement between WHI and Medicare stroke diagnosis. A WHI stroke and a Medicare stroke were considered a match if they occurred within 7 days of each other. Refined analyses excluded Medicare events when medical records were unavailable for comparison. Results Training data consisted of 24 428 randomly selected participants. There were 577 WHI strokes and 557 Medicare strokes using definition 1. Of these, 478 were a match. With regard to algorithm performance, specificity was 99.7%, negative predictive value was 99.7%, sensitivity was 82.8%, positive predictive value was 85.8%, and =0.84. Performance was similar for test data. Whereas specificity and negative predictive value exceeded 99%, sensitivity ranged from 75% to 88% and positive predictive value ranged from 80% to 90% across stroke definitions. Conclusions Medicare data seem useful for population-based stroke research; however, performance characteristics depend on the definition selected. C1 [Lakshminarayan, Kamakshi; Fuller, Candace] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Virnig, Beth] Univ Minnesota, Sch Publ Hlth, Div Hlth Serv Res & Policy, Minneapolis, MN 55454 USA. [Larson, Joseph C.] Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat Clin Coordinating Ctr, Seattle, WA 98104 USA. [Allen, Norrina Bai] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Limacher, Marian] Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. [Winkelmayer, Wolfgang C.] Stanford Univ, Sch Med, Dept Med, Div Nephrol, Palo Alto, CA 94304 USA. [Safford, Monika M.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Burwen, Dale R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Lakshminarayan, K (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM laksh004@umn.edu FU National Heart, Lung, and Blood Institute/National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN268201100004C, HHSN271201100004C]; [K24 HL111154] FX The WHI program is funded by the National Heart, Lung, and Blood Institute/National Institutes of Health, US Department of Health and Human Services, through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN2682011 00003C, HHSN268201100004C, and HHSN271201100004C. Dr Safford was supported by K24 HL111154 for this work. NR 11 TC 14 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2014 VL 45 IS 3 BP 815 EP 821 DI 10.1161/STROKEAHA.113.003408 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AB6DC UT WOS:000331876800044 PM 24525955 ER PT J AU Hinkle, JL AF Hinkle, Janice L. TI Reliability and Validity of the National Institutes of Health Stroke Scale for Neuroscience Nurses SO STROKE LA English DT Article DE reliability and validity ID ACUTE ISCHEMIC-STROKE; PLASMINOGEN ACTIVATOR THERAPY; NEUROLOGIC DETERIORATION; HOSPITAL DISPOSITION; CARE; ASSOCIATION; PREDICTION; SCORE C1 NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Hinkle, JL (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, 10 Ctr Dr,Bldg 10,Room B1D-733,MSC 1063, Bethesda, MD 20892 USA. EM Janice.hinkle@nih.gov NR 26 TC 4 Z9 7 U1 3 U2 9 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 MAR PY 2014 VL 45 IS 3 BP E32 EP E34 DI 10.1161/STROKEAHA.113.004243 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AB6DC UT WOS:000331876800001 PM 24496393 ER PT J AU Pahigiannis, K Kaufmann, P Koroshetz, W AF Pahigiannis, Katherine Kaufmann, Petra Koroshetz, Walter TI Carotid Intervention Is It Warranted in Asymptomatic Individuals if Risk Factors Are Aggressively Managed? SO STROKE LA English DT Editorial Material DE carotid stenosis; endarterectomy; carotid; risk factors C1 [Pahigiannis, Katherine] NINDS, Off Sci Policy & Planning, NIH, Bethesda, MD 20892 USA. [Kaufmann, Petra] NINDS, Off Clin Res, NIH, Bethesda, MD 20892 USA. [Koroshetz, Walter] NINDS, Off Director, NIH, Bethesda, MD 20892 USA. RP Koroshetz, W (reprint author), NINDS, NIH, Bldg 31,Room 8A52,31 Ctr Dr,MSC 2540, Bethesda, MD 20892 USA. EM koroshetzw@mail.nih.gov NR 0 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2014 VL 45 IS 3 BP E40 EP E41 DI 10.1161/STROKEAHA.114.003891 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AB6DC UT WOS:000331876800004 PM 24503669 ER PT J AU Pliner, HA Mann, DM Traynor, BJ AF Pliner, Hannah A. Mann, David M. Traynor, Bryan J. TI Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion SO ACTA NEUROPATHOLOGICA LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; GGGGCC HEXANUCLEOTIDE REPEAT; MYOTONIC-DYSTROPHY MUTATION; FRONTOTEMPORAL DEMENTIA; ALS; POPULATION; GENETICS; HAPLOTYPE; FAMILIES; FINLAND AB Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects similar to 6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent. C1 [Pliner, Hannah A.; Traynor, Bryan J.] NCI, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mann, David M.] Univ Manchester, Salford Royal Fdn NHS Trust, Fac Med & Human Sci, Clin & Cognit Sci Res Grp,Inst Brain Behav & Ment, Salford M6 8HD, Lancs, England. [Traynor, Bryan J.] Johns Hopkins Univ Hosp, Dept Neurol, Brain Sci Inst, Baltimore, MD 21205 USA. RP Traynor, BJ (reprint author), NCI, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Traynor, Bryan/G-5690-2010; Pliner, Hannah/F-3608-2015 OI Pliner, Hannah/0000-0003-1484-6501 FU NIH; National Institute on Aging [Z01-AG000949-02]; NINDS FX This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02), and NINDS. Bryan Traynor has a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9ORF72. NR 38 TC 9 Z9 9 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD MAR PY 2014 VL 127 IS 3 BP 391 EP 396 DI 10.1007/s00401-014-1250-x PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AB4ER UT WOS:000331742800007 PM 24496499 ER PT J AU Kershaw, KN Hankinson, AL Liu, K Reis, JP Lewis, CE Loria, CM Carnethon, MR AF Kershaw, Kiarri N. Hankinson, Arlene L. Liu, Kiang Reis, Jared P. Lewis, Cora E. Loria, Catherine M. Carnethon, Mercedes R. TI Social Relationships and Longitudinal Changes in Body Mass Index and Waist Circumference: The Coronary Artery Risk Development in Young Adults Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; longitudinal study; social relationships; waist circumference ID VISCERAL FAT; PSYCHOSOCIAL STRESS; WHITEHALL-II; SUPPORT; CARDIA; DISEASE; WEIGHT; HEALTH; WOMEN; RECRUITMENT AB Few studies have examined longitudinal associations between close social relationships and weight change. Using data from 3,074 participants in the Coronary Artery Risk Development in Young Adults Study who were examined in 2000, 2005, and 2010 (at ages 33-45 years in 2000), we estimated separate logistic regression random-effects models to assess whether patterns of exposure to supportive and negative relationships were associated with 10% or greater increases in body mass index (BMI) (weight (kg)/height (m) 2) and waist circumference. Linear regression random-effects modeling was used to examine associations of social relationships with mean changes in BMI and waist circumference. Participants with persistently high supportive relationships were significantly less likely to increase their BMI values and waist circumference by 10% or greater compared with those with persistently low supportive relationships after adjustment for sociodemographic characteristics, baseline BMI/waist circumference, depressive symptoms, and health behaviors. Persistently high negative relationships were associated with higher likelihood of 10% or greater increases in waist circumference (odds ratio = 1.62, 95% confidence interval: 1.15, 2.29) and marginally higher BMI increases (odds ratio = 1.50, 95% confidence interval: 1.00, 2.24) compared with participants with persistently low negative relationships. Increasingly negative relationships were associated with increases in waist circumference only. These findings suggest that supportive relationships may minimize weight gain, and that adverse relationships may contribute to weight gain, particularly via central fat accumulation. C1 [Kershaw, Kiarri N.; Hankinson, Arlene L.; Liu, Kiang; Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Reis, Jared P.; Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. RP Kershaw, KN (reprint author), Dept Prevent Med, 680 North Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM k-kershaw@northwestern.edu FU National Institutes of Health [N01-HC-95164]; National Heart, Lung, and Blood Institute [HHSN268201300025C, HHSN268201300026C, HHSN 268201300027C, HHSN268201300028C, HHSN268201 300029C, HHSN268200900041C, AG0005]; National Institute on Aging FX K.N.K. is funded by the National Institutes of Health (grant N01-HC-95164). The Coronary Artery Risk Development in Young Adults Study is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN 268201300027C, HHSN268201300028C, HHSN268201 300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute, the Intramural Research Program of the National Institute on Aging, and an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG0005). NR 27 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2014 VL 179 IS 5 BP 567 EP 575 DI 10.1093/aje/kwt311 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AB8HB UT WOS:000332029800007 PM 24389018 ER PT J AU Beydoun, HA Beydoun, MA AF Beydoun, Hind A. Beydoun, May A. TI Invited Commentary: Disclosure of Gender-Based Violence in Developing Countries SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE disclosure; gender; public health; survey; violence ID INTIMATE PARTNER VIOLENCE; STRESS-DISORDER SYMPTOMS; ADVERSE PREGNANCY OUTCOMES; PRACTICE-BASED PREVALENCE; 18 US STATES/TERRITORIES; AFRICAN-AMERICAN WOMEN; PRIMARY-CARE CLINICS; DOMESTIC VIOLENCE; PHYSICAL ABUSE; EMOTIONAL VIOLENCE AB The evolving concept of gender-based violence (GBV) is a multifaceted issue of public health significance. Until recently, most studies examining GBV have been conducted in North America. In this issue of the Journal, Palermo et al. (Am J Epidemiol. 2014; 179(5): 602-612) report their secondary analyses involving approximately 300,000 women from 24 developing countries who participated in Demographic and Health Surveys between 2004 and 2011. The focus of their article is on the prevalence and determinants of disclosure of GBV to formal authorities, including health care or legal professionals, police, and nongovernmental organizations. Their results indicate a wide gap between prevalence of GBV (40%) and GBV disclosure (7%), implying an underestimation of GBV that ranges from 11- to 128-fold, depending on the region and type of reporting. The extent of underreporting of GBV also varied according to personal characteristics such as age, marital status and urban or rural residence. GBV has been linked to a myriad of health problems, and it has been shown that health care utilization is considerably higher among women who have experienced GBV. Primary and secondary prevention efforts should continue to target GBV, and creative ways of addressing GBV nondisclosure should take into account regional variations and personal characteristics of affected women. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Beydoun, May A.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Baltimore, MD 21224 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 651 Colley Ave,Room 401, Norfolk, VA 23501 USA. EM baydouha@evms.edu FU Intramural NIH HHS NR 104 TC 1 Z9 1 U1 6 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2014 VL 179 IS 5 BP 613 EP 618 DI 10.1093/aje/kwt296 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AB8HB UT WOS:000332029800012 PM 24318280 ER PT J AU Weinberg, I Gona, P O'Donnell, CJ Jaff, MR Murabito, JM AF Weinberg, Ido Gona, Philimon O'Donnell, Christopher J. Jaff, Michael R. Murabito, Joanne M. TI The Systolic Blood Pressure Difference Between Arms and Cardiovascular Disease in the Framingham Heart Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiovascular disease; Cardiovascular risk; Interarm blood pressure difference ID SUBCLAVIAN ARTERY-STENOSIS; PRIMARY-CARE; BILATERAL INDIRECT; VASCULAR-DISEASE; RISK-FACTOR; PREVALENCE; METAANALYSIS; ASSOCIATION; MANAGEMENT; COHORT AB BACKGROUND: An increased interarm systolic blood pressure difference is an easily determined physical examination finding. The relationship between interarm systolic blood pressure difference and risk of future cardiovascular disease is uncertain. We described the prevalence and risk factor correlates of interarm systolic blood pressure difference in the Framingham Heart Study (FHS) original and offspring cohorts and examined the association between interarm systolic blood pressure difference and incident cardiovascular disease and all-cause mortality. METHODS: An increased interarm systolic blood pressure difference was defined as >= 10 mm Hg using the average of initial and repeat blood pressure measurements obtained in both arms. Participants were followed through 2010 for incident cardiovascular disease events. Multivariable Cox proportional hazards regression analyses were performed to investigate the effect of interarm systolic blood pressure difference on incident cardiovascular disease. RESULTS: We examined 3390 (56.3% female) participants aged 40 years and older, free of cardiovascular disease at baseline, mean age of 61.1 years, who attended a FHS examination between 1991 and 1994 (original cohort) and from 1995 to 1998 (offspring cohort). The mean absolute interarm systolic blood pressure difference was 4.6 mm Hg (range 0-78). Increased interarm systolic blood pressure difference was present in 317 (9.4%) participants. The median follow-up time was 13.3 years, during which time 598 participants (17.6%) experienced a first cardiovascular event, including 83 (26.2%) participants with interarm systolic blood pressure difference >= 10 mm Hg. Compared with those with normal interarm systolic blood pressure difference, participants with an elevated interarm systolic blood pressure difference were older (63.0 years vs 60.9 years), had a greater prevalence of diabetes mellitus (13.3% vs 7.5%,), higher systolic blood pressure (136.3 mm Hg vs 129.3 mm Hg), and a higher total cholesterol level (212.1 mg/dL vs 206.5 mg/dL). Interarm systolic blood pressure difference was associated with a significantly increased hazard of incident cardiovascular events in the multivariable adjusted model (hazard ratio 1.38; 95% CI, 1.09-1.75). For each 1-SD-unit increase in absolute interarm systolic blood pressure difference, the hazard ratio for incident cardiovascular events was 1.07 (95% CI, 1.00-1.14) in the fully adjusted model. There was no such association with mortality (hazard ratio 1.02; 95% CI 0.76-1.38). CONCLUSIONS: In this community-based cohort, an interarm systolic blood pressure difference is common and associated with a significant increased risk for future cardiovascular events, even when the absolute difference in arm systolic blood pressure is modest. These findings support research to expand clinical use of this simple measurement. (C) 2014 Elsevier Inc. All rights reserved. C1 [Weinberg, Ido; O'Donnell, Christopher J.; Jaff, Michael R.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Gona, Philimon; O'Donnell, Christopher J.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Biostat & Hlth Serv Res, Worcester, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, 55 Fruit St,Warren 905, Boston, MA 02114 USA. EM mjaff@partners.org FU NHLBI Framingham Heart Study [N01-HC-25195]; NHLBI Division of Intramural Research FX The Framingham Heart Study is supported by the NHLBI Framingham Heart Study (contract N01-HC-25195). Analysis for this project was supported by the NHLBI Division of Intramural Research. NR 39 TC 22 Z9 23 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAR PY 2014 VL 127 IS 3 BP 209 EP 215 DI 10.1016/j.amjmed.2013.10.027 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AB3YD UT WOS:000331725200024 PM 24287007 ER PT J AU Prasad, V Kim, J Rho, J AF Prasad, Vinay Kim, Julie Rho, Jason TI Pocket Ready to Eat at Home in Primary Care Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Prasad, Vinay] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Kim, Julie; Rho, Jason] Northwestern Univ, Chicago, IL 60611 USA. RP Prasad, V (reprint author), NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAR PY 2014 VL 127 IS 3 BP E21 EP E21 DI 10.1016/j.amjmed.2013.11.005 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB3YD UT WOS:000331725200011 PM 24291600 ER PT J AU Prasad, V AF Prasad, Vinay TI Observational Studies Cannot Justify the Inferior Vena Cava Filter SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter ID PULMONARY-EMBOLISM C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAR PY 2014 VL 127 IS 3 BP E15 EP E15 DI 10.1016/j.amjmed.2013.10.010 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB3YD UT WOS:000331725200008 PM 24560327 ER PT J AU Klein, WMP Bloch, M Hesse, BW McDonald, PG Nebeling, L O'Connell, ME Riley, WT Taplin, SH Tesauro, G AF Klein, William M. P. Bloch, Michele Hesse, Bradford W. McDonald, Paige G. Nebeling, Linda O'Connell, Mary E. Riley, William T. Taplin, Stephen H. Tesauro, Gina TI Behavioral Research in Cancer Prevention and Control A Look to the Future SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FORCE RECOMMENDATION STATEMENT; INTENSIVE LONGITUDINAL DATA; OF-THE-LITERATURE; HEALTH-CARE; UNITED-STATES; INFORMATION-TECHNOLOGY; PHYSICAL-ACTIVITY; SOCIAL SUPPORT; PUBLIC-HEALTH; US AB Human behavior is central to the etiology and management of cancer outcomes and presents several avenues for targeted and sustained intervention. Psychosocial experiences such as stress and health behaviors including tobacco use, sun exposure, poor diet, and a sedentary lifestyle increase the risk of some cancers yet are often quite resistant to change. Cancer screening and other health services are misunderstood and over-utilized, and vaccination underutilized, in part because of the avalanche of information about cancer prevention. Coordination of cancer care is suboptimal, and only a small fraction of cancer patients enroll in clinical trials essential to the development of new cancer treatments. A growing population of cancer survivors has necessitated a fresh view of cancer as a chronic rather than acute disease. Fortunately, behavioral research can address a wide variety of key processes and outcomes across the cancer control continuum from prevention to end-of-life care. Here we consider effects at the biobehavioral and psychological, social and organizational, and environmental levels. We challenge the research community to address key behavioral targets across all levels of influence, while taking into account the many new methodological tools that can facilitate this important work. C1 [Klein, William M. P.; Bloch, Michele; Hesse, Bradford W.; McDonald, Paige G.; Nebeling, Linda; O'Connell, Mary E.; Riley, William T.; Taplin, Stephen H.; Tesauro, Gina] NCI, Behav Res Program, Bethesda, MD 20892 USA. RP Klein, WMP (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH,DHHS, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 110 TC 10 Z9 10 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2014 VL 46 IS 3 BP 303 EP 311 DI 10.1016/j.amepre.2013.10.004 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AB1ZB UT WOS:000331591700012 PM 24512871 ER PT J AU Zonderman, AB Ejiogu, N Norbeck, J Evans, MK AF Zonderman, Alan B. Ejiogu, Ngozi Norbeck, Jennifer Evans, Michele K. TI The Influence of Health Disparities on Targeting Cancer Prevention Efforts SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; UNITED-STATES; CULTURAL COMPETENCE; MINORITY COMMUNITIES; AFRICAN-AMERICANS; LIMITED LITERACY; MENTAL-DISORDERS; LOW-INCOME; WOMEN; CARE AB Despite the advances in cancer medicine and the resultant 20% decline in cancer death rates for Americans since 1991, there remain distinct cancer health disparities among African Americans, Hispanics, Native Americans, and the those living in poverty. Minorities and the poor continue to bear the disproportionate burden of cancer, especially in terms of stage at diagnosis, incidence, and mortality. Cancer health disparities are persistent reminders that state-of-the-art cancer prevention, diagnosis, and treatment are not equally effective for and accessible to all Americans. The cancer prevention model must take into account the phenotype of accelerated aging associated with health disparities as well as the important interplay of biological and sociocultural factors that lead to disparate health outcomes. The building blocks of this prevention model will include interdisciplinary prevention modalities that encourage partnerships across medical and nonmedical entities, community-based participatory research, development of ethnically and racially diverse research cohorts, and full actualization of the prevention benefits outlined in the 2010 Patient Protection and Affordable Care Act. However, the most essential facet should be a thoughtful integration of cancer prevention and screening into prevention, screening, and disease management activities for hypertension and diabetes mellitus because these chronic medical illnesses have a substantial prevalence in populations at risk for cancer disparities and cause considerable comorbidity and likely complicate effective treatment and contribute to disproportionate cancer death rates. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Zonderman, Alan B.; Ejiogu, Ngozi; Norbeck, Jennifer; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIH, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, Biomed Res Ctr, 251 Bayview Blvd,Suite 100 Room 4C-222, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging Intramural Research Program, NIH [ZIA AG000513-13] FX This work was supported by the National Institute on Aging Intramural Research Program, NIH project number ZIA AG000513-13. NR 91 TC 13 Z9 13 U1 1 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2014 VL 46 IS 3 SU 1 BP S87 EP S97 DI 10.1016/j.amepre.2013.10.026 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AB2AU UT WOS:000331596200011 PM 24512936 ER PT J AU Huppmann, AR Nicolae, A Slack, GW Pittaluga, S Davies-Hill, T Ferry, JA Harris, NL Jaffe, ES Hasserjian, RP AF Huppmann, Alison R. Nicolae, Alina Slack, Graham W. Pittaluga, Stefania Davies-Hill, Theresa Ferry, Judith A. Harris, Nancy Lee Jaffe, Elaine S. Hasserjian, Robert P. TI EBV May Be Expressed in the LP Cells of Nodular Lymphocyte-predominant Hodgkin Lymphoma (NLPHL) in Both Children and Adults SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE nodular lymphocyte-predominant Hodgkin lymphoma; immunohistochemistry; epidemiology; Epstein-Barr virus; Hodgkin lymphoma ID EPSTEIN-BARR-VIRUS; LATENT MEMBRANE-PROTEIN; POLYMERASE-CHAIN-REACTION; EUROPEAN TASK-FORCE; TUMOR-CELLS; UNITED-STATES; H-CELLS; DISEASE; ASSOCIATION; CHILDHOOD AB Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and classical Hodgkin lymphoma (CHL) are classified separately because of their distinct clinical and pathologic features. Whereas Epstein-Barr virus (EBV) is detected in the neoplastic cells of 25% to 70% of CHL, NLPHL is generally considered to be EBV-. We assessed EBV status in 302 pediatric and adult cases of NLPHL. A total of 145 pediatric (age 18 y or younger) and 157 adult cases of NLPHL were retrieved from 3 North American centers and tested for EBV by in situ hybridization (EBV-encoded small RNA). Clinical and pathologic features were analyzed. Five (3.4%) pediatric and 7 (4.5%) adult NLPHL cases contained EBV+ lymphocyte-predominant (LP) cells. Although all 12 cases met the criteria for diagnosis of NLPHL, atypical features were present, including capsular fibrosis, atrophic germinal centers, and pleomorphic or atypical LP cells. CD20 and OCT-2 were strongly and diffusely positive in all except 1 case. However, PAX5 and CD79a were weak and/or variable in 7/8 and 6/6 cases tested, respectively. EBV+ cases were more likely to be CD30(+) (75%) compared with EBV- cases (25%) (P=0.0007); CD15 was negative in all cases. Our results show that EBV+ LP cells may occur in NLPHL. Distinguishing EBV+ NLPHL from CHL can be challenging, as EBV+ NLPHL can have partial expression of CD30 and weak PAX5 staining as well as pleomorphic-appearing LP cells. However, the overall appearance and maintenance of B-cell phenotype, with strong and diffuse CD20 and OCT-2 expression, support the diagnosis of NLPHL in these cases. C1 [Huppmann, Alison R.; Nicolae, Alina; Pittaluga, Stefania; Davies-Hill, Theresa; Jaffe, Elaine S.] NCI, Bethesda, MD 20892 USA. [Ferry, Judith A.; Harris, Nancy Lee; Hasserjian, Robert P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Slack, Graham W.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. RP Jaffe, ES (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 FU Intramural NIH HHS [ZIA SC000550-33] NR 36 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2014 VL 38 IS 3 BP 316 EP 324 DI 10.1097/PAS.0000000000000107 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA AB2XQ UT WOS:000331655900004 PM 24525501 ER PT J AU Miettinen, M Wang, ZF McCue, PA Sarlomo-Rikala, M Rys, J Biernat, W Lasota, J Lee, YS AF Miettinen, Markku Wang, Zengfeng McCue, Peter A. Sarlomo-Rikala, Maarit Rys, Janusz Biernat, Wojciech Lasota, Jerzy Lee, Yi-Shan TI SALL4 Expression in Germ Cell and Non-Germ Cell Tumors A Systematic Immunohistochemical Study of 3215 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE serous carcinoma; SALL4; gastric adenocarcinoma; germ cell tumor; urothelial carcinoma; NANOG; OCT4; cholangiocarcinoma; small cell carcinoma; immunohistochemistry ID EMBRYONIC STEM-CELLS; YOLK-SAC TUMORS; MALIGNANT RHABDOID TUMORS; IMMUNOHISTOCHEMICAL EXPRESSION; HEPATOCELLULAR-CARCINOMA; GASTRIC-CARCINOMA; ALPHA-FETOPROTEIN; OKIHIRO-SYNDROME; BREAST-CANCER; MARKER AB The SALL4 transcription factor is associated with embryonic cell pluripotency and has been shown as a useful immunohistochemical marker for germ cell tumors. However, information of SALL4 distribution in normal human tissues and non-germ cell tumors is limited. In this study we examined normal human tissues and 3215 tumors for SALL4 expression using a monoclonal antibody 6E3 and automated immunohistochemistry. In a 10-week embryo, SALL4 was expressed in ovocytes, intestine, kidney, and some hepatocytes. In adult tissues, it was only detected in germ cells. SALL4 was consistently expressed in all germ cell tumors except some trophoblastic tumors and mature components of teratomas, in which it was selectively expressed in intestinal-like and some squamous epithelia. In non-germ cell carcinomas, SALL4 was detected in 20% of cases or more of serous carcinoma of the ovary, urothelial high-grade carcinoma, and gastric adenocarcinoma (especially the intestinal type). SALL4 was only rarely (<= 5%) expressed in mammary, colorectal, prostatic, and squamous cell carcinomas. Many SALL4-positive carcinomas showed poorly differentiated patterns, and some showed positivity in most tumor cells mimicking the expression in germ cell tumors. SALL4 was commonly expressed in rhabdoid tumors of the kidney and extrarenal sites and in the Wilms tumor. Expression of SALL4 was rare in other mesenchymal and neuroendocrine tumors but was occasionally detected in melanoma, desmoplastic small round cell tumor, epithelioid sarcoma, and rhabdomyosarcoma. All hematopoietic tumors were negative. SALL4 is an excellent marker of nonteratomatous germ cell tumors, but it is also expressed in other tumors, sometimes extensively. Such expression may reflect stem cell-like differentiation and must be considered when using SALL4 as a marker for germ cell tumors. Observed lack of other pluripotency factors, OCT4 and NANOG, in SALL4-positive non-germ cell tumors can also be diagnostically helpful. C1 [Miettinen, Markku; Wang, Zengfeng; Lasota, Jerzy; Lee, Yi-Shan] NCI, Pathol Lab, Bethesda, MD 20892 USA. [McCue, Peter A.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Cell Biol & Anat, Philadelphia, PA 19107 USA. [McCue, Peter A.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, Haartman Inst, Dept Pathol, Helsinki, Finland. [Sarlomo-Rikala, Maarit] Helsinki Univ Hosp, HusLab, Helsinki, Finland. [Rys, Janusz] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Dept Tumor Pathol, Krakow, Poland. [Biernat, Wojciech] Med Univ Gdansk, Dept Pathomorphol, Gdansk, Poland. RP Miettinen, M (reprint author), NCI, Lab Surg Pathol, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NCI's intramural research program FX Conflicts of Interest and Source of Funding: Supported as a part of NCI's intramural research program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 29 TC 31 Z9 31 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2014 VL 38 IS 3 BP 410 EP 420 DI 10.1097/PAS.0000000000000116 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA AB2XQ UT WOS:000331655900018 PM 24525512 ER PT J AU Neufeld, EB Zadrozny, LM Phillips, D Aponte, A Yu, ZX Balaban, RS AF Neufeld, Edward B. Zadrozny, Leah M. Phillips, Darci Aponte, Angel Yu, Zu-Xi Balaban, Robert S. TI Decorin and biglycan retain LDL in disease-prone valvular and aortic subendothelial intimal matrix SO ATHEROSCLEROSIS LA English DT Article DE LDL retention; Decorin; Biglycan; Aortic valve; Renal ostia; Collagen; Elastin; Two photon microscopy ID LOW-DENSITY LIPOPROTEINS; HUMAN SERUM-ALBUMIN; COLLAGEN TYPE-I; VALVE DISEASE; ARTERIAL PROTEOGLYCANS; SULFATE PROTEOGLYCAN; CHONDROITIN SULFATE; TENASCIN-X; ATHEROSCLEROSIS; BINDING AB Objective: Subendothelial LDL retention by intimal matrix proteoglycans is an initial step in atherosclerosis and calcific aortic valve disease. Herein, we identify decorin and biglycan as the proteoglycans that preferentially retain LDL in intimal matrix at disease-prone sites in normal valve and vessel wall. Methods: The porcine aortic valve and renal artery ostial diverter, initiation sites of calcific valve disease and renal atherosclerosis, respectively, from normal non-diseased animals were used as models in these studies. Results: Fluorescent human LDL was selectively retained on the lesion-prone collagen/proteoglycan-enriched aortic surface of the valve, where the elastic lamina is depleted, as previously observed in lesion-prone sites in the renal ostium. iTRAQ mass spectrometry of valve and diverter protein extracts identified decorin and biglycan as the major subendothelial intimal matrix proteoglycans electrostatically retained on human LDL affinity columns. Decorin levels correlated with LDL binding in lesion-prone sites in both tissues. Collagen binding to LDL was shown to be proteoglycan-mediated. All known basement membrane proteoglycans bound LDL suggesting they may modulate LDL uptake into the subendothelial matrix. The association of purified decorin with human LDL in an in vitro microassay was blocked by serum albumin and heparin suggesting anti-atherogenic roles for these proteins in vivo. Conclusions: LDL electrostatic interactions with decorin and biglycan in the valve leaflets and vascular wall is a major source of LDL retention. The complementary electrostatic sites on LDL or these proteoglycans may provide a novel therapeutic target for preventing one of the earliest events in these cardiovascular diseases. Published by Elsevier Ireland Ltd. C1 [Neufeld, Edward B.; Zadrozny, Leah M.; Phillips, Darci; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Aponte, Angel] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. RP Neufeld, EB (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM neufelde@mail.nih.gov FU NIH DIR FX NIH DIR. NR 45 TC 11 Z9 11 U1 1 U2 6 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 MAR PY 2014 VL 233 IS 1 BP 113 EP 121 DI 10.1016/j.atherosclerosis.2013.12.038 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB1OZ UT WOS:000331563400019 PM 24529131 ER PT J AU Murphy, KE Gysbers, AM Abbott, SK Tayebi, N Kim, WS Sidransky, E Cooper, A Garner, B Halliday, GM AF Murphy, Karen E. Gysbers, Amanda M. Abbott, Sarah K. Tayebi, Nahid Kim, Woojin S. Sidransky, Ellen Cooper, Antony Garner, Brett Halliday, Glenda M. TI Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease SO BRAIN LA English DT Article DE Parkinson's disease; glucocerebrosidase; alpha-synuclein; chaperone-mediated autophagy; ceramide ID CHAPERONE-MEDIATED AUTOPHAGY; LEWY BODY DISEASE; TYPE-1 GAUCHER-DISEASE; BETA-GLUCOCEREBROSIDASE; CATHEPSIN-D; LYSOSOMAL HYDROLASES; CERAMIDE METABOLISM; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; ENZYME-ACTIVITY AB Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinson's disease. Reduced glucocerebrosidase and alpha-synuclein accumulation are directly related in cell models of Parkinson's disease. We investigated relationships between Parkinson's disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and alpha-synuclein levels in brain tissue from subjects with sporadic Parkinson's disease without GBA1 mutations. Brain regions with and without a Parkinson's disease-related increase in alpha-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinson's disease (n = 19) and age-and post-mortem delay-matched controls (n = 10). Levels of glucocerebrosidase, alpha-synuclein and related lysosomal and autophagic proteins were assessed by western blotting. Glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and alpha-synuclein messenger RNA expression determined by quantitative polymerase chain reaction. Related sphingolipids were analysed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. Glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinson's disease in regions with increased alpha-synuclein levels although limited inclusion formation, whereas GBA1 messenger RNA expression was non-selectively reduced in Parkinson's disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased alpha-synuclein and decreased ceramide. Glucocerebrosidase deficits in sporadic Parkinson's disease are related to the abnormal accumulation of alpha-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinson's disease changes are likely a result of the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinson's disease pathology. C1 [Murphy, Karen E.; Gysbers, Amanda M.; Kim, Woojin S.; Halliday, Glenda M.] Neurosci Res Australia, Sydney, NSW 2031, Australia. [Murphy, Karen E.; Kim, Woojin S.; Halliday, Glenda M.] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW 2052, Australia. [Abbott, Sarah K.; Garner, Brett] Illawarra Hlth & Med Res Inst, Wollongong, NSW 2522, Australia. [Abbott, Sarah K.; Garner, Brett] Univ Wollongong, Fac Sci, Sch Biol Sci, Wollongong, NSW 2522, Australia. [Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Cooper, Antony] Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Cooper, Antony] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2052, Australia. [Cooper, Antony] Univ New S Wales, Fac Sci, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia. RP Halliday, GM (reprint author), Neurosci Res Australia, Barker St, Randwick, NSW 2031, Australia. EM g.halliday@neura.edu.au RI Halliday, Glenda/E-8555-2011 OI Halliday, Glenda/0000-0003-0422-8398 FU National Health and Medical Research Council of Australia (NHMRC) [1008307, 1010839]; National Human Genome Research Institute; National Institutes of Health FX This work was supported by the National Health and Medical Research Council of Australia (NHMRC) project grants (#1008307 to G. M. H. and B. G., and #1010839 to A. A. C.). K. E. M. is a NHMRC Postgraduate Biomedical Scholar (#630752) and a Hicksons Lawyer Neuroscience Research Australia Postgraduate Scholar. G. M. H. is a NHMRC Senior Principal Research Fellow (#630434). B. G. is an ARC Future Fellow (#FT0991986) and NHMRC Senior Research Fellow (Hon, #630445). Contributions of E. S. and N.T. were supported by the intramural research programs of the National Human Genome Research Institute and the National Institutes of Health. NR 84 TC 98 Z9 100 U1 9 U2 39 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 MAR PY 2014 VL 137 BP 834 EP 848 DI 10.1093/brain/awt367 PN 3 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AB8JN UT WOS:000332036300019 PM 24477431 ER PT J AU Saito, M Matsuzaki, M Sakuma, T Katagata, N Watanabe, F Yamaguchi, Y Schetter, AJ Takenoshita, S Nomizu, T AF Saito, Motonobu Matsuzaki, Masami Sakuma, Takeshi Katagata, Naoto Watanabe, Fumiaki Yamaguchi, Yoshiko Schetter, Aaron J. Takenoshita, Seiichi Nomizu, Tadashi TI Clinicopathological study of non-palpable familial breast cancer detected by screening mammography and diagnosed as DCIS SO BREAST CANCER LA English DT Article DE Familial breast cancer; Hereditary breast-ovarian cancer (HBOC); Non-palpable breast cancer; Ductal carcinoma in situ (DCIS); BRCA gene ID BRCA MUTATION CARRIERS; CARCINOMA IN-SITU; OVARIAN-CANCER; WOMEN; RISK; RADIOTHERAPY; MANAGEMENT; SURGERY AB Recent widespread use of screening mammography has led to increased detection rates of non-palpable breast cancer. This study aimed to evaluate the clinicopathological features of non-palpable ductal carcinomas in situ of the breast that were detected by screening mammography of patients with a family history of breast cancer. We selected 6 Japanese patients diagnosed with non-palpable breast cancer with self-reported family history of breast cancer. Mutations in BRCA1 and BRCA2 were evaluated with germ line genetic testing and immunohistochemistry (IHC) using resected specimens. Pathological features, such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, were also evaluated. The patients (ages 41-67 years; mean 53.5) had 7 tumors with one patient having synchronous bilateral breast cancer. Breast cancer was suspected from the microcalcification in 5 tumors and the distortion in 2 tumors by mammography and diagnosed by biopsy. Breast-conserving surgery was performed in 2 patients and mastectomy was performed in 4 patients. Genetic testing revealed BRCA2 gene germ line mutation in three patients. IHC of BRCA was consistent with BRCA2 mutation status. The family history of breast cancer patients may lead one to suspect familial breast cancer and screening mammography is useful for the early detection of these cancers. IHC of BRCA showed staining results that were consistent with BRCA genetic testing, suggesting that it has the potential to be a useful tool in clinical practice. C1 [Saito, Motonobu; Matsuzaki, Masami; Sakuma, Takeshi; Katagata, Naoto; Watanabe, Fumiaki; Nomizu, Tadashi] Hoshi Gen Hosp, Dept Surg & Breast Surg, Koriyama, Fukushima 9638501, Japan. [Saito, Motonobu; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Organ Regulatory Surg, Fukushima, Japan. [Yamaguchi, Yoshiko] Hoshi Gen Hosp, Dept Pathol, Koriyama, Fukushima 9638501, Japan. [Schetter, Aaron J.] NCI, Ctr Canc Res, NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Nomizu, T (reprint author), Hoshi Gen Hosp, Dept Surg & Breast Surg, 2-1-16 Omachi, Koriyama, Fukushima 9638501, Japan. EM nomizu@hoshipital.or.jp NR 18 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 1340-6868 EI 1880-4233 J9 BREAST CANCER-TOKYO JI Beast Cancer PD MAR PY 2014 VL 21 IS 2 BP 140 EP 145 DI 10.1007/s12282-012-0389-3 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AB7QG UT WOS:000331985200004 PM 22875640 ER PT J AU Terabe, M Berzofsky, JA AF Terabe, Masaki Berzofsky, Jay A. TI The immunoregulatory role of type I and type II NKT cells in cancer and other diseases SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Review DE Tumor immunity; NKT cells; Regulatory T cells (Treg); Interaction among regulatory cells ID KILLER-T-CELLS; VERSUS-HOST-DISEASE; TUMOR-IMMUNITY; DENDRITIC CELLS; SUPPRESSOR-CELLS; BONE-MARROW; PHASE-I; AIRWAY HYPERREACTIVITY; ANTITUMOR IMMUNITY; CROSS-PRESENTATION AB NKT cells are CD1d-restricted T cells that recognize lipid antigens. They also have been shown to play critical roles in the regulation of immune responses. In the immune responses against tumors, two subsets of NKT cells, type I and type II, play opposing roles and cross-regulate each other. As members of both the innate and adaptive immune systems, which form a network of multiple components, they also interact with other immune components. Here, we discuss the function of NKT cells in tumor immunity and their interaction with other regulatory cells, especially CD4(+)CD25(+)Foxp3(+) regulatory T cells. C1 [Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Terabe, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 41,Room D702,41 Medlars Dr, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov FU National Cancer Institute, NIH; Gui Foundation FX This research was supported by the intramural research program of the National Cancer Institute, NIH and the Gui Foundation. NR 122 TC 17 Z9 20 U1 1 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2014 VL 63 IS 3 BP 199 EP 213 DI 10.1007/s00262-013-1509-4 PG 15 WC Oncology; Immunology SC Oncology; Immunology GA AB2SW UT WOS:000331643400001 PM 24384834 ER PT J AU Bilusic, M Heery, CR Arlen, PM Rauckhorst, M Apelian, D Tsang, KY Tucker, JA Jochems, C Schlom, J Gulley, JL Madan, RA AF Bilusic, Marijo Heery, Christopher R. Arlen, Philip M. Rauckhorst, Myrna Apelian, David Tsang, Kwong Y. Tucker, Jo A. Jochems, Caroline Schlom, Jeffrey Gulley, James L. Madan, Ravi A. TI Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Yeast-CEA vaccine; Immunity; Medullary thyroid cancer; ELISPOT; Immunotherapy ID HUMAN CARCINOEMBRYONIC ANTIGEN; INDEPENDENT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; DENDRITIC CELLS; ANTITUMOR RESPONSES; COLORECTAL-CANCER; IMMUNE-RESPONSE; SIPULEUCEL-T; HUMAN BREAST; IMMUNOTHERAPY AB Yeast-CEA (GI-6207) is a therapeutic cancer vaccine genetically modified to express recombinant carcinoembryonic antigen (CEA) protein, using heat-killed yeast (Saccharomyces cerevisiae) as a vector. In preclinical studies, yeast-CEA induced a strong immune response to CEA and antitumor responses. Patients received subcutaneous vaccines every 2 weeks for 3 months and then monthly. Patients were enrolled at 3 sequential dose levels: 4, 16, and 40 yeast units (10(7) yeast particles/unit). Eligible patients were required to have serum CEA > 5 ng/mL or > 20 % CEA(+) tumor block, ECOG PS 0-2, and no history of autoimmunity. Restaging scans were performed at 3 months and then bimonthly. Peripheral blood was collected for the analysis of immune response (e.g., by ELISPOT assay). Twenty-five patients with metastatic CEA-expressing carcinomas were enrolled. Median patient age was 52 (range 39-81). A total of 135 vaccines were administered. The vaccine was well tolerated, and the most common adverse event was grade 1/2 injection-site reaction. Five patients had stable disease beyond 3 months (range 3.5-18 months), and each had CEA stabilization while on-study. Some patients showed evidence post-vaccination of increases in antigen-specific CD8(+) T cells and CD4(+) T lymphocytes and decreases in regulatory T cells. Of note, a patient with medullary thyroid cancer had substantial T cell responses and a vigorous inflammatory reaction at sites of metastatic disease. Yeast-CEA vaccination had minimal toxicity and induced some antigen-specific T cell responses and CEA stabilization in a heterogeneous, heavily pre-treated patient population. Further studies are required to determine the clinical benefit of yeast-CEA vaccination. C1 [Bilusic, Marijo; Arlen, Philip M.; Gulley, James L.; Madan, Ravi A.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Heery, Christopher R.; Arlen, Philip M.; Rauckhorst, Myrna; Tsang, Kwong Y.; Tucker, Jo A.; Jochems, Caroline; Schlom, Jeffrey; Gulley, James L.; Madan, Ravi A.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apelian, David] GlobeImmune Inc, Louisville, CO USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Diane J. Poole for her technical assistance and Zhimin Guo, who was involved in early preclinical development of the vaccine. The authors also thank Bonnie L. Casey and Debra Weingarten for their editorial assistance in the preparation of this manuscript. NR 43 TC 24 Z9 24 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2014 VL 63 IS 3 BP 225 EP 234 DI 10.1007/s00262-013-1505-8 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA AB2SW UT WOS:000331643400003 PM 24327292 ER PT J AU Moeller, SJ Honorio, J Tomasi, D Parvaz, MA Woicik, PA Volkow, ND Goldstein, RZ AF Moeller, Scott J. Honorio, Jean Tomasi, Dardo Parvaz, Muhammad A. Woicik, Patricia A. Volkow, Nora D. Goldstein, Rita Z. TI Methylphenidate Enhances Executive Function and Optimizes Prefrontal Function in Both Health and Cocaine Addiction SO CEREBRAL CORTEX LA English DT Article DE anterior cingulate cortex; cerebellum; cocaine addiction; dopamine; dorsolateral prefrontal cortex; executive function; fMRI; methylphenidate; norepinephrine; Stroop ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ANTERIOR CINGULATE CORTEX; ERROR-RELATED NEGATIVITY; WORKING-MEMORY TASK; ORAL METHYLPHENIDATE; BRAIN ACTIVATION; STROOP TASK; DEPENDENT PATIENTS; NEURAL SYSTEMS AB Previous studies have suggested dopamine to be involved in error monitoring/processing, possibly through impact on reinforcement learning. The current study tested whether methylphenidate (MPH), an indirect dopamine agonist, modulates brain and behavioral responses to error, and whether such modulation is more pronounced in cocaine-addicted individuals, in whom dopamine neurotransmission is disrupted. After receiving oral MPH (20 mg) or placebo (counterbalanced), 15 healthy human volunteers and 16 cocaine-addicted individuals completed a task of executive function (the Stroop color word) during functional magnetic resonance imaging (fMRI). During MPH, despite not showing differences on percent accuracy and reaction time, all subjects committed fewer total errors and slowed down more after committing errors, suggestive of more careful responding. In parallel, during MPH all subjects showed reduced dorsal anterior cingulate cortex response to the fMRI contrast errorcorrect. In the cocaine subjects only, MPH also reduced errorcorrect activity in the dorsolateral prefrontal cortex (controls instead showed lower errorcorrect response in this region during placebo). Taken together, MPH modulated dopaminergically innervated prefrontal cortical areas involved in error-related processing, and such modulation was accentuated in the cocaine subjects. These results are consistent with a dopaminergic contribution to error-related processing during a cognitive control task. C1 [Moeller, Scott J.; Parvaz, Muhammad A.; Woicik, Patricia A.; Goldstein, Rita Z.] Brookhaven Natl Lab, Upton, NY 11973 USA. [Honorio, Jean] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Tomasi, Dardo; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, 30 Bell Ave,Bldg 490, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015; Moeller, Scott/L-5549-2016; OI Moeller, Scott/0000-0002-4449-0844; Parvaz, Muhammad/0000-0002-2671-2327 FU National Institute on Drug Abuse [1R01DA023579, 1F32DA030017-01]; US Department of Energy [DE-AC02-98CHI-886] FX This study was supported by grants from the National Institute on Drug Abuse (to R.Z.G.: 1R01DA023579; to S.J.M.: 1F32DA030017-01). This manuscript has been authored by Brookhaven Science Associates, LLC under Contract No. DE-AC02-98CHI-886 with the US Department of Energy. The United States Government retains, and the publisher, by accepting the article for publication, acknowledges, a worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for the US Government purposes. NR 84 TC 18 Z9 18 U1 2 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD MAR PY 2014 VL 24 IS 3 BP 643 EP 653 DI 10.1093/cercor/bhs345 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AB5RI UT WOS:000331845700008 PM 23162047 ER PT J AU Penezina, O Krueger, NX Rodriguez-Chavez, IR Busch, MP Hural, J Kim, JH O'Connell, RJ Hunter, E Aboud, S Higgins, K Kovalenko, V Clapham, D Crane, D Levin, AE AF Penezina, Oksana Krueger, Neil X. Rodriguez-Chavez, Isaac R. Busch, Michael P. Hural, John Kim, Jerome H. O'Connell, Robert J. Hunter, Eric Aboud, Said Higgins, Keith Kovalenko, Victor Clapham, David Crane, David Levin, Andrew E. CA HIV Selectest Study Grp TI Performance of a Redesigned HIV Selectest Enzyme-Linked Immunosorbent Assay Optimized To Minimize Vaccine-Induced Seropositivity in HIV Vaccine Trial Participants SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID T-CELL RESPONSES; EFFICACY TRIAL; DIFFERENTIAL-DIAGNOSIS; GENERATED ANTIBODIES; INFECTION; VOLUNTEERS; IMMUNOGENICITY; COMBINATION; RECIPIENTS; THAILAND AB Vaccine-induced seropositivity (VISP) or seroreactivity (VISR), defined as the reaction of antibodies elicited by HIV vaccines with antigens used in HIV diagnostic immunoassays, can result in reactive assay results for vaccinated but uninfected individuals, with subsequent misclassification of their infection status. The eventual licensure of a vaccine will magnify this issue and calls for the development of mitigating solutions in advance. An immunoassay that discriminates between antibodies elicited by vaccine antigens and those elicited by infection has been developed to address this laboratory testing need. The HIV Selectest is based on consensus and clade-specific HIV peptides that are omitted in many HIV vaccine constructs. The assay was redesigned to enhance performance across worldwide clades and to simplify routine use via a standard kit format. The redesigned assay was evaluated with sera from vaccine trial participants, HIV-infected and uninfected individuals, and healthy controls. The HIV Selectest exhibited specificities of 99.5% with sera from uninfected recipients of 6 different HIV vaccines and 100% with sera from normal donors, while detecting HIV-1 infections, including intercurrent infections, with 95 to 100% sensitivity depending on the clade, with the highest sensitivities for clades A and C. HIV Selectest sensitivity decreased in very early seroconversion specimens, which possibly explains the slightly lower sensitivity observed for asymptomatic blood donors than for clinical HIV cases. Thus, the HIV Selectest provides a new laboratory tool for use in vaccine settings to distinguish the immune response to HIV vaccine antigens from that due to true infection. C1 [Penezina, Oksana; Krueger, Neil X.; Kovalenko, Victor; Clapham, David; Crane, David; Levin, Andrew E.] Immunetics Inc, Boston, MA 02210 USA. [Rodriguez-Chavez, Isaac R.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Hural, John] HIV Vaccine Trials Network, Seattle, WA USA. [Hural, John] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Kim, Jerome H.; O'Connell, Robert J.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [O'Connell, Robert J.] USAMC AFRIMS, Bangkok, Thailand. [Hunter, Eric] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Aboud, Said] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Higgins, Keith] Global Solut Infect Dis, San Francisco, CA USA. RP Levin, AE (reprint author), Immunetics Inc, Boston, MA 02210 USA. EM alevin@immunetics.com FU Westat, Inc. [8067-S04]; National Heart, Lung, and Blood Institute [HHSN268200417175C] FX This project was supported by subcontract 8067-S04 from Westat, Inc., under Retrovirus Epidemiology Donor Study II, which was supported by National Heart, Lung, and Blood Institute contract HHSN268200417175C. NR 34 TC 3 Z9 3 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAR PY 2014 VL 21 IS 3 BP 391 EP 398 DI 10.1128/CVI.00748-13 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AB8JT UT WOS:000332036900016 PM 24403525 ER PT J AU Wang, B Chang, L Kreitman, RJ Ibrahim, R Goswami, T Pastan, I Liang, M Roskos, L AF Wang, B. Chang, L. Kreitman, R. J. Ibrahim, R. Goswami, T. Pastan, I. Liang, M. Roskos, L. TI PHARMACOKINETICS OF MOXETUMOMAB PASUDOTOX, AN INVESTIGATIONAL IMMUNOTOXIN TARGETING CD22, IN PATIENTS WITH RELAPSED OR REFRACTORY HAIRY CELL LEUKEMIA. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 18-22, 2014 CL Atlanta, GA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wang, B.; Chang, L.; Liang, M.; Roskos, L.] MedImmune, Hayward, CA USA. [Kreitman, R. J.; Pastan, I.] NCI, NIH, Bethesda, MD 20892 USA. [Ibrahim, R.; Goswami, T.] MedImmune, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2014 VL 95 SU 1 BP S36 EP S37 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AB7ZL UT WOS:000332009800106 ER PT J AU Wang, B Chang, L Kreitman, RJ Ibrahim, R Goswami, T Pastan, I Liang, M Roskos, L AF Wang, B. Chang, L. Kreitman, R. J. Ibrahim, R. Goswami, T. Pastan, I. Liang, M. Roskos, L. TI PHARMACOKINETICS OF MOXETUMOMAB PASUDOTOX, AN INVESTIGATIONAL IMMUNOTOXIN TARGETING CD22, IN PATIENTS WITH RELAPSED OR REFRACTORY HAIRY CELL LEUKEMIA SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 18-22, 2014 CL Atlanta, GA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wang, B.; Chang, L.; Liang, M.; Roskos, L.] MedImmune, Hayward, CA USA. [Kreitman, R. J.; Pastan, I.] NCI, NIH, Bethesda, MD 20892 USA. [Ibrahim, R.; Goswami, T.] MedImmune, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2014 VL 95 SU 1 BP S6 EP S6 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AB7ZL UT WOS:000332009800015 ER PT J AU Franks, PW Christophi, CA Jablonski, KA Billings, LK Delahanty, LM Horton, ES Knowler, WC Florez, JC AF Franks, Paul W. Christophi, Costas A. Jablonski, Kathleen A. Billings, Liana K. Delahanty, Linda M. Horton, Edward S. Knowler, William C. Florez, Jose C. CA Diabet Prevention Program Res Grp TI Common variation at PPARGC1A/B and change in body composition and metabolic traits following preventive interventions: the Diabetes Prevention Program SO DIABETOLOGIA LA English DT Article DE Cholesterol; Dyslipidaemia; Gene x environment interaction; Gene x lifestyle interaction; Genetics; Lifestyle intervention; Metformin; Pharmacogenetics; PPARGC1A; PPARGC1B; Randomised controlled trial; Triacylglycerol ID LIFE-STYLE INTERVENTION; GAMMA COACTIVATOR-1-ALPHA PGC-1-ALPHA; ENVIRONMENT INTERACTIONS; INSULIN SENSITIVITY; CANDIDATE GENES; GLY482SER; ASSOCIATION; VARIANTS; RISK; POLYMORPHISMS AB PPARGC1A and PPARGCB encode transcriptional coactivators that regulate numerous metabolic processes. We tested associations and treatment (i.e. metformin or lifestyle modification) interactions with metabolic traits in the Diabetes Prevention Program, a randomised controlled trial in persons at high risk of type 2 diabetes. We used Tagger software to select 75 PPARGCA1 and 94 PPARGC1B tag single-nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for associations with relevant cardiometabolic quantitative traits using generalised linear models. Aggregate genetic effects were tested using the sequence kernel association test. In aggregate, PPARGC1A variation was strongly associated with baseline triacylglycerol concentrations (p = 2.9 x 10(-30)), BMI (p = 2.0 x 10(-5)) and visceral adiposity (p = 1.9 x 10(-4)), as well as with changes in triacylglycerol concentrations (p = 1.7 x 10(-5)) and BMI (p = 9.9 x 10(-5)) from baseline to 1 year. PPARGC1B variation was only associated with baseline subcutaneous adiposity (p = 0.01). In individual SNP analyses, Gly482Ser (rs8192678, PPARGC1A) was associated with accumulation of subcutaneous adiposity and worsening insulin resistance at 1 year (both p < 0.05), while rs2970852 (PPARGC1A) modified the effects of metformin on triacylglycerol levels (p (interaction) = 0.04). These findings provide several novel and other confirmatory insights into the role of PPARGC1A variation with respect to diabetes-related metabolic traits. Trial registration ClinicalTrials.gov NCT00004992. C1 [Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, Paul W.; Christophi, Costas A.; Jablonski, Kathleen A.] George Washington Univ, Diabet Prevent Program, Ctr Biostat, Coordinating Ctr, Rockville, MD 20852 USA. [Billings, Liana K.; Delahanty, Linda M.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Billings, Liana K.; Delahanty, Linda M.; Horton, Edward S.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Horton, Edward S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ USA. [Florez, Jose C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP Franks, PW (reprint author), George Washington Univ, Diabet Prevent Program, Ctr Biostat, Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM paul.franks@med.lu.se RI Uwaifo, Gabriel/M-2361-2016; OI Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 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; Swedish Research Council; Swedish Diabetes Association; Swedish Heart-Lung Foundation; Pahlssons Foundation; Novo Nordisk Foundation; [R01 DK072041] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centres and the coordinating centre for the design and conduct of the study, and for 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 centres. 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. The DPP was also supported, in part, by the intramural research programme 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 centre. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. The work described in this paper was supported in part by R01 DK072041 to D. Altshuler (Broad Institute of Harvard and MIT, Cambridge, MA, USA), JCF and KAJ (WCK and PWF were unpaid co-investigators). PWF was supported by the Swedish Research Council, Swedish Diabetes Association, Swedish Heart-Lung Foundation, Pahlssons Foundation and Novo Nordisk Foundation. NR 30 TC 8 Z9 8 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2014 VL 57 IS 3 BP 485 EP 490 DI 10.1007/s00125-013-3133-4 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB1NG UT WOS:000331558400008 PM 24317794 ER PT J AU Kang, L Mayes, WH James, FD Bracy, DP Wasserman, DH AF Kang, Li Mayes, Wesley H. James, Freyja D. Bracy, Deanna P. Wasserman, David H. TI Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice SO DIABETOLOGIA LA English DT Article DE Capillary density; Collagen IV; Extracellular matrix; High-fat diet ID MATRIX-METALLOPROTEINASE INHIBITORS; SKELETAL-MUSCLE; INDIVIDUAL TISSUES; ENDOTHELIAL-CELLS; GROWTH-FACTORS; OBESITY; MOUSE; PATHOGENESIS; CONTRIBUTES; DYSFUNCTION AB Increased extracellular matrix (ECM) collagen is a characteristic of muscle insulin resistance. Matrix metalloproteinase (MMP) 9 is a primary enzyme that degrades collagen IV (ColIV). As a component of the basement membrane, ColIV plays a key role in ECM remodelling. We tested the hypotheses that genetic deletion of MMP9 in mice increases muscle ColIV, induces insulin resistance in lean mice and worsens diet-induced muscle insulin resistance. Wild-type (Mmp9 (+/+)) and Mmp9-null (Mmp9 (-/-)) mice were chow or high-fat (HF) fed for 16 weeks. Insulin action was measured by the hyperinsulinaemic-euglycaemic clamp in conscious weight-matched surgically catheterised mice. Mmp9 (-/-) and HF feeding independently increased muscle ColIV. ColIV in HF-fed Mmp9 (-/-) mice was further increased. Mmp9 (-/-) did not affect fasting insulin or glucose in chow- or HF-fed mice. The glucose infusion rate (GIR), endogenous glucose appearance (EndoRa) and glucose disappearance (Rd) rates, and a muscle glucose metabolic index (Rg), were the same in chow-fed Mmp9 (+/+) and Mmp9 (-/-) mice. In contrast, HF-fed Mmp9 (-/-) mice had decreased GIR, insulin-stimulated increase in Rd and muscle Rg. Insulin-stimulated suppression of EndoRa, however, remained the same in HF-fed Mmp9 (-/-) and Mmp9 (+/+) mice. Decreased muscle Rg in HF-fed Mmp9 (-/-) was associated with decreased muscle capillaries. Despite increased muscle ColIV, genetic deletion of MMP9 does not induce insulin resistance in lean mice. In contrast, this deletion results in a more profound state of insulin resistance, specifically in the skeletal muscle of HF-fed mice. These results highlight the importance of ECM remodelling in determining muscle insulin resistance in the presence of HF diet. C1 [Kang, Li; Mayes, Wesley H.; James, Freyja D.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Kang, Li; Wasserman, David H.] Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37235 USA. RP Kang, L (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 2215 Garland Ave, Nashville, TN 37232 USA. EM li.kang@vanderbilt.edu FU National Institutes of Health [DK054902, DK059637]; Vanderbilt Diabetes Research and Training Center [DK020593] FX This work was supported by National Institutes of Health Grants DK054902 (DHW) and DK059637 (Mouse Metabolic Phenotyping Center; DHW). We would also like to thank the Vanderbilt Diabetes Research and Training Center (DK020593). NR 45 TC 7 Z9 7 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2014 VL 57 IS 3 BP 603 EP 613 DI 10.1007/s00125-013-3128-1 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB1NG UT WOS:000331558400020 PM 24305966 ER PT J AU Gardner, M Bann, D Wiley, L Cooper, R Hardy, R Nitsch, D Martin-Ruiz, C Shiels, P Sayer, AA Barbieri, M Bekaert, S Bischoff, C Brooks-Wilson, A Chen, W Cooper, C Christensen, K De Meyer, T Deary, I Der, G Roux, AD Fitzpatrick, A Hajat, A Halaschek-Wiener, J Harris, S Hunt, SC Jagger, C Jeon, HS Kaplan, R Kimura, M Lansdorp, P Li, CY Maeda, T Mangino, M Nawrot, TS Nilsson, P Nordfjall, K Paolisso, G Ren, F Riabowol, K Robertson, T Roos, G Staessen, JA Spector, T Tang, N Unryn, B van der Harst, P Woo, J Xing, C Yadegarfar, ME Park, JY Young, N Kuh, D von Zglinicki, T Ben-Shlomo, Y AF Gardner, Michael Bann, David Wiley, Laura Cooper, Rachel Hardy, Rebecca Nitsch, Dorothea Martin-Ruiz, Carmen Shiels, Paul Sayer, Avan Aihie Barbieri, Michelangela Bekaert, Sofie Bischoff, Claus Brooks-Wilson, Angela Chen, Wei Cooper, Cyrus Christensen, Kaare De Meyer, Tim Deary, Ian Der, Geoff Roux, Ana Diez Fitzpatrick, Annette Hajat, Anjum Halaschek-Wiener, Julius Harris, Sarah Hunt, Steven C. Jagger, Carol Jeon, Hyo-Sung Kaplan, Robert Kimura, Masayuki Lansdorp, Peter Li, Changyong Maeda, Toyoki Mangino, Massimo Nawrot, Tim S. Nilsson, Peter Nordfjall, Katarina Paolisso, Giuseppe Ren, Fu Riabowol, Karl Robertson, Tony Roos, Goran Staessen, Jan A. Spector, Tim Tang, Nelson Unryn, Brad van der Harst, Pim Woo, Jean Xing, Chao Yadegarfar, Mohammad E. Park, Jae Yong Young, Neal Kuh, Diana von Zglinicki, Thomas Ben-Shlomo, Yoav CA Halcyon Study Team TI Gender and telomere length: Systematic review and meta-analysis SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE Gender; Telomere length; Systematic review and meta-analysis; Measurement methods; Epidemiology ID CARDIOVASCULAR HEALTH; OLDEST-OLD; SUBTELOMERIC METHYLATION; NO ASSOCIATION; HEART-DISEASE; CANCER-RISK; MORTALITY; AGE; BLOOD; CHROMOSOME AB Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females thanmales, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. (C) 2013 Published by Elsevier Inc. C1 [Gardner, Michael; Ben-Shlomo, Yoav] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PS, Avon, England. [Bann, David; Cooper, Rachel; Hardy, Rebecca; Kuh, Diana] UCL, MRC Univ Unit Lifelong Hlth & Ageing, London WC1E 6BT, England. [Wiley, Laura; Martin-Ruiz, Carmen; Jagger, Carol; Yadegarfar, Mohammad E.; von Zglinicki, Thomas] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Nitsch, Dorothea] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London, England. [Shiels, Paul] Univ Glasgow, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland. [Sayer, Avan Aihie; Cooper, Cyrus] Univ Southampton, Med Res Council Lifecourse Epidemiol Unit, Southampton SO9 5NH, Hants, England. [Barbieri, Michelangela; Paolisso, Giuseppe] Univ Naples 2, Dept Geriatr & Metab Dis, Naples, Italy. [Bekaert, Sofie; De Meyer, Tim] Univ Ghent, Clin Res Ctr, B-9000 Ghent, Belgium. [Bischoff, Claus; Christensen, Kaare] Univ Southern Denmark, Danish Aging Res Ctr, Odense, Denmark. [Brooks-Wilson, Angela; Halaschek-Wiener, Julius] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada. [Chen, Wei] Tulane Univ Hlth Sci, Tulane Ctr Cardiovasc Hlth, New Orleans, LA USA. [Deary, Ian; Harris, Sarah] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland. [Der, Geoff; Robertson, Tony] MRC, Chief Scientist Off Social & Publ Hlth Sci Unit, Glasgow, Lanark, Scotland. [Roux, Ana Diez; Hajat, Anjum] Univ Michigan, Dept Epidemiol, Ctr Integrat Approaches Hlth Dispar, Ann Arbor, MI 48109 USA. [Fitzpatrick, Annette] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Hunt, Steven C.] Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT USA. [Jeon, Hyo-Sung; Park, Jae Yong] Kyungpook Natl Univ Daegu, Sch Med, Dept Biochem & Cell Biol, Taegu, South Korea. [Kaplan, Robert] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Kimura, Masayuki] Univ Med & Dent New Jersey, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Lansdorp, Peter] Univ British Columbia, Dept Med, Div Hematol, Vancouver, BC, Canada. [Li, Changyong; Ren, Fu] Liaoning Med Univ, Dept Anat, Jinzhou, Liaoning Provin, Peoples R China. [Maeda, Toyoki] Kyushu Univ, Dept Mol & Cellular Biol, Oita, Japan. [Mangino, Massimo; Spector, Tim] Kings Coll London, Twin Res & Genet Epidemiol Unit, London WC2R 2LS, England. [Nawrot, Tim S.; Staessen, Jan A.] Univ Louvain, Dept Cardiovasc Sci, Div Hypertens & Cardiovasc Rehabil, Louvain, Belgium. [Nilsson, Peter] Malmo Univ Hosp, Dept Clin Sci Med, Malmo, Sweden. [Nordfjall, Katarina; Roos, Goran] Umea Univ, Dept Med Biosci, S-90187 Umea, Sweden. [Riabowol, Karl; Unryn, Brad] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. [Tang, Nelson] Chinese Univ Hong Kong, Fac Med, Dept Chem Pathol, Hong Kong, Hong Kong, Peoples R China. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Woo, Jean] Chinese Univ Hong Kong, Fac Med, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Xing, Chao] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX USA. [Young, Neal] NHLBI, Bethesda, MD 20892 USA. RP Ben-Shlomo, Y (reprint author), Univ Bristol, Sch Social & Community Med, 39 Whatley Rd,Canynge Hall, Bristol BS8 2PS, Avon, England. EM Y.Ben-Shlomo@bristol.ac.uk RI Christensen, Kaare/C-2360-2009; Brooks-Wilson, Angela/E-9399-2012; Staessen, Jan/A-1065-2011; Barbieri, Michelangela/K-2192-2016; Woo, Jean/K-2625-2014; mangino, massimo/F-5134-2011; Robertson, Tony/L-5062-2015; OI Bann, David/0000-0002-6454-626X; Cooper, Rachel/0000-0003-3370-5720; Christensen, Kaare/0000-0002-5429-5292; Aihie Sayer, Avan/0000-0003-1283-6457; Brooks-Wilson, Angela/0000-0003-1009-6408; Staessen, Jan/0000-0002-3026-1637; Barbieri, Michelangela/0000-0002-9223-5792; Woo, Jean/0000-0001-7593-3081; mangino, massimo/0000-0002-2167-7470; Yadegarfar, Mohammad Esmaeil/0000-0002-7200-9763; Robertson, Tony/0000-0002-1962-5874; Paolisso, Giuseppe/0000-0002-2137-455X; Tang, Nelson/0000-0002-3607-5819 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-RR-024156, UL1-RR-025005]; National Heart, Lung and Blood Institute (NHLBI) [HL80698, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG023629]; National R & D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [0720550-2] FX We are very grateful to all cohort members who participated in the studies. Regarding the MESA study: This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-RR-024156 and UL1-RR-025005 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. Regarding the Cardiovascular Health Study: This research was supported by grant HL80698 and contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and grant HL080295 from the National Heart, Lung and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support from provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. Jang et al.'s (2008) study was supported by a grant from the National R & D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720550-2). We acknowledge the help of Christine Garcia, the corresponding author of the Cronkhite et al. (2008) study. NR 79 TC 76 Z9 76 U1 8 U2 62 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD MAR PY 2014 VL 51 BP 15 EP 27 DI 10.1016/j.exger.2013.12.004 PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AB2FE UT WOS:000331607800003 PM 24365661 ER PT J AU Yin, HQ Hu, M Liang, XM Ajmo, JM Li, XL Bataller, R Odena, G Stevens, SM You, M AF Yin, Huquan Hu, Ming Liang, Xiaomei Ajmo, Joanne M. Li, Xiaoling Bataller, Ramon Odena, Gemma Stevens, Stanley M., Jr. You, Min TI Deletion of SIRT1 From Hepatocytes in Mice Disrupts Lipin-1 Signaling and Aggravates Alcoholic Fatty Liver SO GASTROENTEROLOGY LA English DT Article DE Alcoholic Fatty Liver; Lipid Metabolism; Inflammation; Signal Transduction ID PHOSPHATIDATE PHOSPHOHYDROLASE; SUBCELLULAR-LOCALIZATION; THERAPEUTIC TARGETS; DISEASE; ETHANOL; METABOLISM; EXPRESSION; HEPATITIS; STRESS; INFLAMMATION AB BACKGROUND & AIMS: Sirtuin (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls). METHODS: We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1 beta and lipin-1a in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls). RESULTS: On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1 beta/alpha messenger RNAs than controls. CONCLUSIONS: In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease. C1 [Yin, Huquan; Hu, Ming; Liang, Xiaomei; Ajmo, Joanne M.; You, Min] Univ S Florida, Hlth Sci Ctr, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA. [Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Bataller, Ramon; Odena, Gemma] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Bataller, Ramon; Odena, Gemma] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Bataller, Ramon] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain. [Stevens, Stanley M., Jr.] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33612 USA. RP You, M (reprint author), Univ S Florida, Coll Med, Sch Basic Biomed Sci, Dept Mol Pharmacol & Physiol, 12901 Bruce B Downs Blvd, Tampa, FL 33612 USA. EM myou@health.usf.edu OI Odena, Gemma/0000-0002-9317-4725 FU National Institute on Alcoholism and Alcohol Abuse [AA013623, AA015951, R21AA021247]; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill; Fundacion Espanola para el Estudio del Higado FX This study was supported by grants from National Institute on Alcoholism and Alcohol Abuse (AA013623 and AA015951 to M You and R21AA021247 to SM Stevens Jr), Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill and Fundacion Espanola para el Estudio del Higado (to G Odena). NR 34 TC 37 Z9 42 U1 0 U2 13 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 MAR PY 2014 VL 146 IS 3 BP 801 EP 811 DI 10.1053/j.gastro.2013.11.008 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AB3ZY UT WOS:000331729900038 PM 24262277 ER PT J AU Gheorghiade, M Vaduganathan, M Greene, SJ Mentz, RJ Adams, KF Anker, SD Arnold, M Baschiera, F Cleland, JGF Cotter, G Fonarow, GC Giordano, C Metra, M Misselwitz, F Muhlhofer, E Nodari, S Peacock, WF Pieske, BM Sabbah, HN Sato, N Shah, MR Stockbridge, NL Teerlink, JR van Veldhuisen, DJ Zalewski, A Zannad, F Butler, J AF Gheorghiade, Mihai Vaduganathan, Muthiah Greene, Stephen J. Mentz, Robert J. Adams, Kirkwood F., Jr. Anker, Stefan D. Arnold, Malcolm Baschiera, Fabio Cleland, John G. F. Cotter, Gadi Fonarow, Gregg C. Giordano, Christopher Metra, Marco Misselwitz, Frank Muehlhofer, Eva Nodari, Savina Peacock, W. Frank Pieske, Burkert M. Sabbah, Hani N. Sato, Naoki Shah, Monica R. Stockbridge, Norman L. Teerlink, John R. van Veldhuisen, Dirk J. Zalewski, Andrew Zannad, Faiez Butler, Javed TI Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions SO HEART FAILURE REVIEWS LA English DT Article DE Heart failure; Site selection; Clinical trials; FDA ID QUALITY-OF-CARE; UNITED-STATES; OPTIMIZE-HF; END-POINTS; OUTCOMES; ASSOCIATION; RATIONALE; REGISTRY; PROGRAM; DESIGN AB There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF. C1 [Gheorghiade, Mihai; Greene, Stephen J.] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Vaduganathan, Muthiah] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Mentz, Robert J.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC USA. [Adams, Kirkwood F., Jr.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Anker, Stefan D.] Ctr Clin & Basic Res, IRCCS San Raffaele, Rome, Italy. [Arnold, Malcolm] Univ Western Ontario, Div Cardiol, London, ON, Canada. [Baschiera, Fabio] Novartis Pharma AG, Basel, Switzerland. [Cleland, John G. F.] Castle Hill Hosp, Kingston Upon Hull, Yorks, England. [Cotter, Gadi] Momentum Res Inc, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Giordano, Christopher] Quintiles, Cardiovasc & Metab Therapeut Delivery Unit, Durham, NC USA. [Metra, Marco; Nodari, Savina] Univ Brescia, Div Cardiol, Brescia, Italy. [Misselwitz, Frank] Bayer Healthcare Pharmaceut, Berlin, Germany. [Muehlhofer, Eva] Bayer Vital GmbH, Leverkusen, Germany. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Houston, TX 77030 USA. [Pieske, Burkert M.] Med Univ Graz, Div Cardiol, Graz, Austria. [Sabbah, Hani N.] Henry Ford Hosp, Dept Med, Detroit, MI 48202 USA. [Sato, Naoki] Musahi Kosugi Hosp, Nippon Med Sch, Dept Internal Med & Cardiol, Kanagawa, Japan. [Shah, Monica R.] NHLBI, Bethesda, MD 20892 USA. [Stockbridge, Norman L.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Teerlink, John R.] Univ Calif San Francisco, Cardiol Sect, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Zalewski, Andrew] Novartis Pharmaceut, E Hanover, NJ USA. [Zannad, Faiez] Univ Lorraine, CHU Cardiol, INSERM, CIC 9501, Nancy, France. [Zannad, Faiez] Univ Lorraine, CHU Cardiol, U961, Nancy, France. [Butler, Javed] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 645 N Michigan Ave,Suite 1006, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu RI van Veldhuisen, Dirk Jan/E-8967-2014; OI Metra, Marco/0000-0001-6691-8568; Cleland, John/0000-0002-1471-7016 FU Vifor International; PsiOxus Therapeutics; Bayer Healthcare; Corthera; Novartis; Cytokinetics; Amgen; NIH; Roche Diagnostics; BG Medicine; Pfizer; Sorbent; Vifor; GE Healthcare; Medtronic FX Mihai Gheorghiade: Consultant for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokinetics, DebioPharm S. A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical and Trevena Therapeutics. Stefan D Anker: Consultant for Vifor International, Amgen, Bayer, Bosch GmbH, PsiOxus Therapeutics, Professional Dietetics, Novartis. Research support from Vifor International, PsiOxus Therapeutics. John G F Cleland: Received an honorarium from Bayer for an advisory board. Gregg C Fonarow: Consultant to Medtronic, Novartis, Gambro and Ortho-McNeill. Marco Metra: Received honoraria from Bayer, Corthera, Novartis, and Servier for speeches or participation in advisory boards/steering committees. Frank Misselwitz and Eva Muhlhofer: Employed by Bayer Healthcare. Hani N Sabbah: Research Grants and Consultant to Bayer Healthcare. Naoki Sato: Consultant to Chugai Pharmaceutical Company and honoraria from Daiichi-Sankyo, Otsuka, Philips Respironics, Astellas, Ono, Eisai, Chugai, Mitsubishi-Tanabe, Sanofi-Aventis, and Novartis pharmaceuticals. John R Teerlink: Research Grants from Corthera, Novartis, Cytokinetics, Amgen, NIH. Consultant to Amgen, Anexon, Cardio3 Bioscience, CardioMEMS, Cytokinetics, Gambro, Johnson and Johnson, Merck, NovaCardia, Novartis, Scios, Sorbent Therapeutics, St. Jude Medical, Teva, Theravance, Trevena. Faiez Zannad: Reports receiving consultant honoraria from Servier, Pfizer, Novartis, ResMed, Takeda, and Boston Scientific, and that his institution receives research grants from Roche Diagnostics and BG Medicine. Dirk J van Veldhuisen: Board Membership fees from Amgen, BG Medicine, Pfizer, Sorbent and Vifor. Javed Butler: Consultant to Cardiomems, Trevena, Bayer Healthcare, Takeda, Gambro, Ono Pharma, and Amgen; Events Committee for WorldHeart, Corthera, Abbott Vascular, Celladon, Research Support, NIH, GE Healthcare and Medtronic. All other authors have no conflicts of interest to declare. NR 30 TC 24 Z9 24 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 EI 1573-7322 J9 HEART FAIL REV JI Heart Fail. Rev. PD MAR PY 2014 VL 19 IS 2 BP 135 EP 152 DI 10.1007/s10741-012-9361-8 PG 18 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB5JY UT WOS:000331825900001 PM 23099992 ER PT J AU Lin, HH Sinner, MF Brody, JA Arking, DE Lunetta, KL Rienstra, M Lubitz, SA Magnani, JW Sotoodehnia, N McKnight, B McManus, DD Boerwinkle, E Psaty, BM Rotter, JI Bis, JC Gibbs, RA Muzny, D Kovar, CL Morrison, AC Gupta, M Folsom, AR Kaab, S Heckbert, SR Alonso, A Ellinor, PT Benjamin, EJ AF Lin, Honghuang Sinner, Moritz F. Brody, Jennifer A. Arking, Dan E. Lunetta, Kathryn L. Rienstra, Michiel Lubitz, Steven A. Magnani, Jared W. Sotoodehnia, Nona McKnight, Barbara McManus, David D. Boerwinkle, Eric Psaty, Bruce M. Rotter, Jerome I. Bis, Joshua C. Gibbs, Richard A. Muzny, Donna Kovar, Christie L. Morrison, Alanna C. Gupta, Mayetri Folsom, Aaron R. Kaeaeb, Stefan Heckbert, Susan R. Alonso, Alvaro Ellinor, Patrick T. Benjamin, Emelia J. CA CHARGE Atrial Fibrillation Working TI Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study SO HEART RHYTHM LA English DT Article DE Arrhythmia; Genetics; Atrial fibrillation; Epidemiology ID WIDE ASSOCIATION; RARE VARIANTS; RISK-FACTOR; INFLAMMATION; COMMON; SUSCEPTIBILITY; RECEPTOR; MARKERS; DESIGN; LOCI AB BACKGROUND Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. OBJECTIVE To study the association of genetic variants with AF at GWAS top loci. METHODS In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. RESULTS One common variant (rs11265611; P = 1.70 x 10-6) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r2 =.69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P =.01). CONCLUSIONS We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants. (C) 2014 Heart Rhythm Society. All rights reserved. C1 [Lin, Honghuang; Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Lin, Honghuang; Sinner, Moritz F.; Lunetta, Kathryn L.; Magnani, Jared W.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Sinner, Moritz F.; Rienstra, Michiel; Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Sinner, Moritz F.; Kaeaeb, Stefan] Univ Munich, Univ Hosp Munich, Dept Med 1, Munich, Germany. [Brody, Jennifer A.; Sotoodehnia, Nona; Psaty, Bruce M.; Bis, Joshua C.; Heckbert, Susan R.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Lunetta, Kathryn L.; Gupta, Mayetri] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Folsom, Aaron R.; Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Boerwinkle, Eric; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Gibbs, Richard A.; Muzny, Donna; Kovar, Christie L.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Kaeaeb, Stefan] Munich Heart Alliance, Munich, Germany. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ellinor, Patrick T.] Harvard Univ, Sch Med, Boston, MA USA. RP Lin, HH (reprint author), Boston Univ, Sch Med, Dept Med, 72 E Concord St,B-616, Boston, MA 02118 USA. EM hhlin@bu.edu RI Alonso, Alvaro/A-4917-2010; OI Alonso, Alvaro/0000-0002-2225-8323; Lin, Honghuang/0000-0003-3043-3942; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Institutes of Health (NIB) through the American Recovery and Reinvestment Act [5RC211L102419]; National Heart, Lung, and Blood Institute (NHLBI) [HH5N268201100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26820110000.E0C, HHSN2682011000011 C, HH5N2682011000012C]; NHLBI in collaboration with the Boston University [N0I-HC-25195]; Linux Cluster for Genetic Analysis; NIILBI [N01-11C-85239, N01-11C-85079, NO 1-HC-85080, N01-HC-85081, NO1-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, NOI-HC-75150, NO1-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756]; National Institute on Aging of the Nzitional Institutes of Public Health [AC 021629 AG-15928, AG-20098, AG-027058]; NIH [NOI-HC 25195, 6R01-NS 17950, 1ROHIL092577, 5R21DA027021, 1R0111L104156, 1K24111-105780, IRO1 HL102214, 1RC1111-101056]; American Heart Association [09SDG2280087, 016.136.055]; Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University FX Dr Lin, Dr Sinner, Dr Ellinor, and Dr Benjamin contributed equally to this work. Funding support for "Building on GWAS for NHLB1-diseases: the U.S. CHARGE Consortium" was provided by the National Institutes of Health (NIB) through the American Recovery and Reinvestment Act of 2009 (5RC211L102419). Data for "Building on GWAS for MILBI-diseases: the U.S. CHARGE Consortium" were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities Study; L Adrienne Cupples, principal investigator for the Framingham Heart Study; and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HH5N268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26820110000.E0C, HHSN2682011000011 C, and HH5N2682011000012C). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with the Boston University (contract no. N0I-HC-25195) and its contract with Affymetrix, Inc, for genome-wide genotyping services (contract no. NO2-11L-6-4278) and for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis computing resources at Boston University Medical Campus. This CHS research was supported by NIILBI contracts N01-11C-85239, N01-11C-85079, NO 1-HC-85080, N01-HC-85081, NO1-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, NOI-HC-75150, NO1-HC-45133, and HHSN268201200036C as well as by NHLBI grants HL080295, HL087652, HL105756, with additional contribution from NINT)S. Additionzil support was provided through National Institute on Aging of the Nzitional Institutes of Public Health giants AC 021629 AG-15928. AG-20098, and AG-027058. See also h This project was also supported by NIH grants NOI-HC 25195 and 6R01-NS 17950 (to Dr Beamin); 1ROHIL092577, 5R21DA027021, 1R0111L104156, 1K24111-105780, IRO1 HL102214, and 1RC1111-101056 (to Dr Ellinory 1RC111L099452 and American Heart Association grant 09SDG2280087 (to Dr Mons), and the Netherlands Organisation for Scientific Research grant (Veni grant 016.136.055; to Dr Rienstral. This work was partially supported by thc Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University ainp://www.bitmc.1%.ediiievanseenteribrO. Dr Psaty serves on the Data and Safety Monitoring Board of a clinical trial of a device funded by Zoll LifeCor and on the Steering Committee of die Yale Open Data Access Project funded by Medtronic. NR 34 TC 9 Z9 11 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2014 VL 11 IS 3 BP 452 EP 457 DI 10.1016/j.hrthm.2014.11.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB4AJ UT WOS:000331731000022 PM 24239840 ER PT J AU Lemaitre, RN Johnson, CO Hesselson, S Sotoodhenia, N McKnight, B Sitlani, CM Rea, TD King, IB Kwok, PY Mak, A Li, G Brody, J Larson, E Mozaffarian, D Psaty, BM Huertas-Vazquez, A Tardif, JC Albert, CM Lyytikainen, LP Arking, DE Kaab, S Huikuri, HV Krijthe, BP Eijgelsheim, M Wang, YA Reinier, K Lehtimaki, T Pulit, SL Brugada, R Muller-Nurasyid, M Newton-Cheh, CH Karhunen, PJ Stricker, BH Goyette, P Rotter, JI Chugh, SS Chakravarti, A Jouven, X Siscovick, DS AF Lemaitre, Rozenn N. Johnson, Catherine O. Hesselson, Stephanie Sotoodhenia, Nona McKnight, Barbara Sitlani, Colleen M. Rea, Thomas D. King, Irena B. Kwok, Pui-Yan Mak, Angel Li, Guo Brody, Jennifer Larson, Eric Mozaffarian, Dariush Psaty, Bruce M. Huertas-Vazquez, Adriana Tardif, Jean-Claude Albert, Christine M. Lyytikaeinen, Leo-Pekka Arking, Dan E. Kaeaeb, Stefan Huikuri, Heikki V. Krijthe, Bouwe P. Eijgelsheim, Mark Wang, Ying A. Reinier, Kyndaron Lehtimaeki, Terho Pulit, Sara L. Brugada, Ramon Mueller-Nurasyid, Martina Newton-Cheh, Chris H. Karhunen, Pekka J. Stricker, Bruno H. Goyette, Philippe Rotter, Jerome I. Chugh, Sumeet S. Chakravarti, Aravinda Jouven, Xavier Siscovick, David S. TI Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest SO HEART RHYTHM LA English DT Article DE Death; Sudden; Genetic epidemiology ID LIPID DROPLETS; MYOCARDIAL-INFARCTION; DEATH; HEART; ATHEROSCLEROSIS; ASSOCIATION; ARRHYTHMIAS; ISCHEMIA; PHOSPHATIDYLCHOLINE; EPIDEMIOLOGY AB BACKGROUND There is limited information on genetic factors OBJECTIVE To assess the association of common variation in associated with sudden cardiac arrest (SCA). genes in fatty acid pathways with SCA risk. METHODS We selected 85 candidate genes and 1155 single nucleotide poLymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used Linear Logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases. RESULTS Eight SN Ps in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the CPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% Lower SCA risk (95% confidence interval 21% to 5%) in the discovery phase and 9 /a lower SCA risk ( 9 5 % confidence interval 16% to 1%) in the replication phase. CONCLUSIONS While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation. (C) 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. C1 [Lemaitre, Rozenn N.; Johnson, Catherine O.; Sotoodhenia, Nona; Sitlani, Colleen M.; Rea, Thomas D.; Li, Guo; Brody, Jennifer; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98101 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Hesselson, Stephanie; Kwok, Pui-Yan; Mak, Angel] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Hesselson, Stephanie; Kwok, Pui-Yan; Mak, Angel] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [King, Irena B.] Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA. [Larson, Eric; Psaty, Bruce M.] Grp Hlth Res Inst, Seattle, WA USA. [Mozaffarian, Dariush] Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. [Mozaffarian, Dariush; Albert, Christine M.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Albert, Christine M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Pulit, Sara L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Huertas-Vazquez, Adriana; Reinier, Kyndaron; Chugh, Sumeet S.] Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA. [Tardif, Jean-Claude; Goyette, Philippe] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Tardif, Jean-Claude; Goyette, Philippe] Univ Montreal, Montreal, PQ, Canada. [Lyytikaeinen, Leo-Pekka; Lehtimaeki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Karhunen, Pekka J.] Fimlab Labs, Dept Forens Med, Tampere, Finland. [Karhunen, Pekka J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Kaeaeb, Stefan; Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Kaeaeb, Stefan] Munich Heart Alliance, Munich, Germany. [Huikuri, Heikki V.] Univ Oulu, Med Res Ctr Oulu, Inst Clin Med, Oulu, Finland. [Krijthe, Bouwe P.; Eijgelsheim, Mark; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Wang, Ying A.] Novartis Inst BioMed Res, Cambridge, MA USA. [Pulit, Sara L.] Broad Inst Massachusetts Inst Technol & Harvard U, Program Med & Populat Genet, Cambridge, MA USA. [Brugada, Ramon] IDIBGI Univ Girona, Inst Invest Biomed Girona, Cardiovasc Genet Ctr, Girona, Spain. [Mueller-Nurasyid, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Newton-Cheh, Chris H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Chris H.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Chris H.] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [Stricker, Bruno H.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. [Rotter, Jerome I.] Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Jouven, Xavier] Univ Paris 05, Dept Cardiol, Paris, France. [Jouven, Xavier] Univ Paris 05, Dept Epidemiol, Paris, France. RP Lemaitre, RN (reprint author), Univ Washington, Cardiovasc Hlth Res Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101 USA. EM rozenl@uw.edu RI Kwok, Pui-Yan/F-7725-2014; Lyytikainen, Leo-Pekka/C-8544-2016 OI Kwok, Pui-Yan/0000-0002-5087-3059; Lyytikainen, Leo-Pekka/0000-0002-7200-5455 FU National Lune; Heart, and Blood Institute [R0111E092144, R01-11L092111, R01-11L088456] FX Dr Mozaffarian has received research grants from (3laxoSmithKlinc, Sigma Tau; Pronova; and the National Institutes of Health for an investigatorinitiated, not-for-protit clinical trial of fish oil and postsurgical complications as well as small annual royalties from UpToDate for an online scientific chapter on fish oil. The Sudden Cardiac Blood Repository Study was financed by the National Lune; Heart, and Blood Institute (grants R0111E092144, R01-11L092111, and R01-11L088456). Funding sources for the other contributing studies are listed in the Online Supplement. NR 35 TC 5 Z9 5 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2014 VL 11 IS 3 BP 471 EP 477 DI 10.1016/j.hrthm.2014.01.008 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB4AJ UT WOS:000331731000026 PM 24418166 ER PT J AU Teerlink, CC Thibodeau, SN McDonnell, SK Schaid, DJ Rinckleb, A Maier, C Vogel, W Cancel-Tassin, G Egrot, C Cussenot, O Foulkes, WD Giles, GG Hopper, JL Severi, G Eeles, R Easton, D Kote-Jarai, Z Guy, M Cooney, KA Ray, AM Zuhlke, KA Lange, EM FitzGerald, LM Stanford, JL Ostrander, EA Wiley, KE Isaacs, SD Walsh, PC Isaacs, WB Wahlfors, T Tammela, T Schleutker, J Wiklund, F Gronberg, H Emanuelsson, M Carpten, J Bailey-Wilson, J Whittemore, AS Oakley-Girvan, I Hsieh, CL Catalona, WJ Zheng, SL Jin, GF Lu, LY Xu, JF Camp, NJ Cannon-Albright, LA AF Teerlink, Craig C. Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Rinckleb, Antje Maier, Christiane Vogel, Walther Cancel-Tassin, Geraldine Egrot, Christophe Cussenot, Olivier Foulkes, William D. Giles, Graham G. Hopper, John L. Severi, Gianluca Eeles, Ros Easton, Douglas Kote-Jarai, Zsofia Guy, Michelle Cooney, Kathleen A. Ray, Anna M. Zuhlke, Kimberly A. Lange, Ethan M. FitzGerald, Liesel M. Stanford, Janet L. Ostrander, Elaine A. Wiley, Kathleen E. Isaacs, Sarah D. Walsh, Patrick C. Isaacs, William B. Wahlfors, Tiina Tammela, Teuvo Schleutker, Johanna Wiklund, Fredrik Gronberg, Henrik Emanuelsson, Monica Carpten, John Bailey-Wilson, Joan Whittemore, Alice S. Oakley-Girvan, Ingrid Hsieh, Chih-Lin Catalona, William J. Zheng, S. Lilly Jin, Guangfu Lu, Lingyi Xu, Jianfeng Camp, Nicola J. Cannon-Albright, Lisa A. CA Int Consortium Prostate Canc Genet TI Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RISK; VARIANTS; LOCI; SUSCEPTIBILITY AB Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p a parts per thousand currency sign 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease. C1 [Teerlink, Craig C.; Camp, Nicola J.; Cannon-Albright, Lisa A.] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT 84112 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, ICPCG Grp, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [McDonnell, Shannon K.; Schaid, Daniel J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Rinckleb, Antje; Maier, Christiane; Vogel, Walther] Univ Ulm, ICPCG Grp, D-89069 Ulm, Germany. [Rinckleb, Antje; Maier, Christiane; Vogel, Walther] Univ Ulm, Dept Urol, D-89069 Ulm, Germany. [Rinckleb, Antje; Maier, Christiane] Univ Ulm, Inst Human Genet, D-89069 Ulm, Germany. [Cancel-Tassin, Geraldine; Egrot, Christophe; Cussenot, Olivier] Hop Tenon, AP HP, CeRePP ICPCG Grp, F-75020 Paris, France. [Foulkes, William D.; Giles, Graham G.; Hopper, John L.; Severi, Gianluca; Eeles, Ros; Easton, Douglas; Kote-Jarai, Zsofia; Guy, Michelle] ICPCG Grp, ACTANE Consortium, Surrey, England. [Foulkes, William D.] McGill Univ, Program Canc Genet, Montreal, PQ H3T 1E2, Canada. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic 3053, Australia. [Giles, Graham G.; Hopper, John L.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Eeles, Ros; Kote-Jarai, Zsofia; Guy, Michelle] Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Easton, Douglas] Strangeways Lab, Cambridge CB1 8RN, England. [Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.; Lange, Ethan M.] Univ Michigan, ICPCG Grp, Ann Arbor, MI 48109 USA. [Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.] Univ Michigan, Dept Urol, Sch Med, Ann Arbor, MI 48109 USA. [Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.] Univ Michigan, Dept Internal Med, Sch Med, Ann Arbor, MI 48109 USA. [Lange, Ethan M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [FitzGerald, Liesel M.; Stanford, Janet L.; Ostrander, Elaine A.] NHGRI, FHCRC, ICPCG Grp, Seattle, WA USA. [FitzGerald, Liesel M.; Stanford, Janet L.] FHCRC, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Isaacs, William B.] Johns Hopkins Univ, Dept Urol, ICPCG Grp, Johns Hopkins Med Inst, Baltimore, MD 21287 USA. [Wahlfors, Tiina; Tammela, Teuvo; Schleutker, Johanna] Univ Tampere, ICPCG Grp, FIN-33101 Tampere, Finland. [Wahlfors, Tiina] Univ Tampere, Inst Biomed Technol, BioMediTech, Tampere 33520, Finland. [Wahlfors, Tiina] Tampere Univ Hosp, Ctr Lab Med, Tampere 33520, Finland. [Tammela, Teuvo] Univ Tampere, Dept Urol, Tampere 33520, Finland. [Tammela, Teuvo] Tampere Univ Hosp, Tampere 33520, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, FIN-20520 Turku, Finland. [Wiklund, Fredrik; Gronberg, Henrik; Emanuelsson, Monica] Umea Univ, ICPCG Grp, Umea, Sweden. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Emanuelsson, Monica] Umea Univ, Ctr Oncol, S-90187 Umea, Sweden. [Carpten, John] TGen, Integrated Canc Genom Div, Phoenix, AZ 85004 USA. [Bailey-Wilson, Joan] NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Whittemore, Alice S.; Oakley-Girvan, Ingrid; Hsieh, Chih-Lin] Stanford Univ, ICPCG Grp, Palo Alto, CA 94304 USA. [Whittemore, Alice S.] Stanford Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Oakley-Girvan, Ingrid] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Oakley-Girvan, Ingrid] Stanford Sch Med, Stanford Canc Inst, Palo Alto, CA USA. [Oakley-Girvan, Ingrid] Stanford Sch Med, Dept Hlth Res & Policy, Palo Alto, CA USA. [Hsieh, Chih-Lin] Univ So Calif, Dept Urol, Los Angeles, CA 90089 USA. [Hsieh, Chih-Lin] Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. [Catalona, William J.; Zheng, S. Lilly] Northwestern Univ, ICPCG Grp, Feinberg Sch Med, Chicago, IL 60611 USA. [Jin, Guangfu; Lu, Lingyi; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Data Coordinating Ctr ICPCG, Winston Salem, NC 27157 USA. [Jin, Guangfu; Lu, Lingyi; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. [Cannon-Albright, Lisa A.] Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA. RP Teerlink, CC (reprint author), Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT 84112 USA. EM craig.teerlink@utah.edu RI Whittemore, Alice/F-9925-2014; OI foulkes, william/0000-0001-7427-4651; Bailey-Wilson, Joan/0000-0002-9153-2920; Eeles, Rosalind/0000-0002-3698-6241; Teerlink, Craig/0000-0002-1992-2326; albright, lisa/0000-0003-2602-3668; Giles, Graham/0000-0003-4946-9099; Ostrander, Elaine/0000-0001-6075-9738; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU Huntsman Cancer Institute, University of Utah; Huntsman Cancer Institute's Cancer Center Support grant, National Cancer Institute [P30 CA42014]; Utah Cancer Registry; National Cancer Institute's SEER Program [HHSN261201000026C]; Utah State Department of Health; University of Utah; Johns Hopkins University; NIH National Cancer Institute [R01 CA89600]; Cancer Research UK; Prostate Cancer UK; National Institute of Health Research FX Partial support for L. A. C. A. and for all data sets with in the Utah Population Database (UPDB) was provided by Huntsman Cancer Institute, University of Utah and the Huntsman Cancer Institute's Cancer Center Support grant, P30 CA42014 from National Cancer Institute. Research was supported by the Utah Cancer Registry, which is funded by Contract No. HHSN261201000026C from the National Cancer Institute's SEER Program with additional support from the Utah State Department of Health and the University of Utah. A subcontract from Johns Hopkins University with funds provided by grant R01 CA89600 from the NIH National Cancer Institute (to L. A. Cannon Albright). The International Consortium for Prostate Cancer Genetics has provided access to genotyping for this study (U01CA089600). RE is supported by Cancer Research UK and Prostate Action (now Prostate Cancer UK) and National Institute of Health Research support to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. Robert Stephenson generously donated funds for the data analysis aspects of this project. NR 22 TC 8 Z9 8 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD MAR PY 2014 VL 133 IS 3 BP 347 EP 356 DI 10.1007/s00439-013-1384-2 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AB2KX UT WOS:000331622700009 PM 24162621 ER PT J AU Figueroa, JD Ye, Y Siddiq, A Garcia-Closas, M Chatterjee, N Prokunina-Olsson, L Cortessis, VK Kooperberg, C Cussenot, O Benhamou, S Prescott, J Porru, S Dinney, CP Malats, N Baris, D Purdue, M Jacobs, EJ Albanes, D Wang, Z Deng, X Chung, CC Tang, W Bueno-De-Mesquita, HB Trichopoulos, D Ljungberg, B Clavel-Chapelon, F Weiderpass, E Krogh, V Dorronsoro, M Travis, R Tjonneland, A Brenan, P Chang-Claude, J Riboli, E Conti, D Gago-Dominguez, M Stern, MC Pike, MC Van den Berg, D Yuan, JM Hohensee, C Rodabough, R Cancel-Tassin, G Roupret, M Comperat, E Chen, C De Vivo, I Giovannucci, E Hunter, DJ Kraft, P Lindstrom, S Carta, A Pavanello, S Arici, C Mastrangelo, G Kamat, AM Lerner, SP Grossman, HB Lin, J Gu, J Pu, X Hutchinson, A Burdette, L Wheeler, W Kogevinas, M Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Schwenn, M Karagas, MR Johnson, A Schned, A Armenti, KR Hosain, GM Andriole, G Grubb, R Black, A Diver, WR Gapstur, SM Weinstein, SJ Virtamo, J Haiman, CA Landi, MT Caporaso, N Fraumeni, JF Vineis, P Wu, X Silverman, DT Chanock, S Rothman, N AF Figueroa, Jonine D. Ye, Yuanqing Siddiq, Afshan Garcia-Closas, Montserrat Chatterjee, Nilanjan Prokunina-Olsson, Ludmila Cortessis, Victoria K. Kooperberg, Charles Cussenot, Olivier Benhamou, Simone Prescott, Jennifer Porru, Stefano Dinney, Colin P. Malats, Nuria Baris, Dalsu Purdue, Mark Jacobs, Eric J. Albanes, Demetrius Wang, Zhaoming Deng, Xiang Chung, Charles C. Tang, Wei Bueno-De-Mesquita, H. Bas Trichopoulos, Dimitrios Ljungberg, Borje Clavel-Chapelon, Frangoise Weiderpass, Elisabete Krogh, Vittorio Dorronsoro, Miren Travis, Ruth Tjonneland, Anne Brenan, Paul Chang-Claude, Jenny Riboli, Elio Conti, David Gago-Dominguez, Manuela Stern, Mariana C. Pike, Malcolm C. Van den Berg, David Yuan, Jian-Min Hohensee, Chancellor Rodabough, Rebecca Cancel-Tassin, Geraldine Roupret, Morgan Comperat, Eva Chen, Constance De Vivo, Immaculata Giovannucci, Edward Hunter, David J. Kraft, Peter Lindstrom, Sara Carta, Angela Pavanello, Sofia Arici, Cecilia Mastrangelo, Giuseppe Kamat, Ashish M. Lerner, Seth P. Grossman, H. Barton Lin, Jie Gu, Jian Pu, Xia Hutchinson, Amy Burdette, Laurie Wheeler, William Kogevinas, Manolis Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Schwenn, Molly Karagas, Margaret R. Johnson, Alison Schned, Alan Armenti, Karla R. Hosain, G. M. Andriole, Gerald, Jr. Grubb, Robert, III Black, Amanda Diver, W. Ryan Gapstur, Susan M. Weinstein, Stephanie J. Virtamo, Jarmo Haiman, Chris A. Landi, Maria T. Caporaso, Neil Fraumeni, Joseph F., Jr. Vineis, Paolo Wu, Xifeng Silverman, Debra T. Chanock, Stephen Rothman, Nathaniel TI Genome-wide association study identifies multiple loci associated with bladder cancer risk SO HUMAN MOLECULAR GENETICS LA English DT Article ID NAT2 SLOW ACETYLATION; SUSCEPTIBILITY LOCI; CONFERS SUSCEPTIBILITY; BREAST-CANCER; RECOMBINATION HOTSPOTS; GENETIC POLYMORPHISMS; COLORECTAL-CANCER; SEQUENCE VARIANT; TELOMERE LENGTH; CROHNS-DISEASE AB Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 x 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 x 10(-9)) and rs907611 on 11p15.5 (P = 4.11 x 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 x 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 x 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. C1 [Figueroa, Jonine D.; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Baris, Dalsu; Purdue, Mark; Albanes, Demetrius; Tang, Wei; Black, Amanda; Weinstein, Stephanie J.; Landi, Maria T.; Caporaso, Neil; Fraumeni, Joseph F., Jr.; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ye, Yuanqing; Lin, Jie; Gu, Jian; Pu, Xia; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Ye, Yuanqing; Dinney, Colin P.; Kamat, Ashish M.; Lin, Jie; Gu, Jian; Pu, Xia; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Siddiq, Afshan; Riboli, Elio; Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, London, England. [Siddiq, Afshan; Riboli, Elio; Vineis, Paolo] Human Genet Fdn HuGeF, London, England. [Siddiq, Afshan; Riboli, Elio; Vineis, Paolo] Inst Canc Res, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Cortessis, Victoria K.; Conti, David; Stern, Mariana C.; Van den Berg, David] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Cortessis, Victoria K.; Hohensee, Chancellor; Rodabough, Rebecca] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Kooperberg, Charles; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Tenon Hosp, AP HP, Dept Urol, Paris, France. [Cussenot, Olivier] Ctr Rech Pathol Prostat, Paris, France. [Benhamou, Simone] Fdn Jean Dausset, CEPH, INSERM, U946, Paris, France. [Benhamou, Simone; De Vivo, Immaculata; Hunter, David J.] Inst Gustave Roussy, CNRS, UMR8200, Villejuif, France. [Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Med, Boston, MA USA. [Prescott, Jennifer; Trichopoulos, Dimitrios; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Prescott, Jennifer; Carta, Angela; Arici, Cecilia; Grossman, H. Barton] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Porru, Stefano] Univ Brescia, Dept Med & Surg Specialties, I-25121 Brescia, Italy. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Jacobs, Eric J.; Hutchinson, Amy; Burdette, Laurie; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Wang, Zhaoming; Deng, Xiang; Chung, Charles C.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Bueno-De-Mesquita, H. Bas] NatL Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-De-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Kaisareias, Hellen Hlth Fdn, Athens, Greece. [Ljungberg, Borje] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Clavel-Chapelon, Frangoise] Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Villejuif, France. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Dorronsoro, Miren; Kogevinas, Manolis] Hlth Dept Basque Reg, BioDonostia Res Inst, Pubilc Hlth Div Gipuzkoa, San Sebastian, Spain. [Dorronsoro, Miren; Lloreta, Josep] CIBERESP, Madrid, Spain. [Travis, Ruth] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Tjonneland, Anne] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Brenan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Chang-Claude, Jenny] DKFZ, Heidelberg, Germany. [Gago-Dominguez, Manuela] Complejo Hospitalario Univ Santiago, Galician Fdn Genom Med, Genom Med Grp, Serv Galego Saude SERGAS,Inst Invest Sanitaria Sa, Santiago De Compostela, Spain. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Yuan, Jian-Min] Univ Pittsburgh Canc Inst, Pittsburgh, PA USA. [Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva] Univ Paris 06, ONCOTYPE URO, GRC 5, Paris, France. [Hunter, David J.] Broad Inst Harvard & MIT, Embridge, MA USA. [Pavanello, Sofia; Mastrangelo, Giuseppe] Univ Padua, Dept Cardiac Thorac & Vasc Sci, Padua, Italy. [Lerner, Seth P.] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [Wheeler, William] Informat Management Syst, Silver Spring, MD USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] IMIM Hosp del Mar, Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Tardon, Adonina] Univ Oviedo, Inst Univ Oncol, Oviedo, Spain. [Serra, Consol] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Karagas, Margaret R.; Schned, Alan] Geisel Sch Med Dartmouth, Hanover, NH USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Armenti, Karla R.; Hosain, G. M.] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Andriole, Gerald, Jr.; Grubb, Robert, III] Washington Univ Sch Med, Dept Urol, St Louis, MO USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. [Haiman, Chris A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. RP Figueroa, JD (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 9609 Med Ctr Dr,Rm 7-E122,MSC 9774, Bethesda, MD 20892 USA. EM figueroaj@mail.nih.gov RI Serra, C/E-6879-2014; Clavel-Chapelon, Francoise/G-6733-2014; Lloreta, J/I-2112-2014; Albanes, Demetrius/B-9749-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Benhamou, Simone/K-6554-2015; Krogh, Vittorio/K-2628-2016; Weiderpass, Elisabete/M-4029-2016; Kogevinas, Manolis/C-3918-2017; OI Serra, C/0000-0001-8337-8356; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Yuan, Jian-Min/0000-0002-4620-3108; Lloreta, J/0000-0003-1644-9470; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Krogh, Vittorio/0000-0003-0122-8624; Weiderpass, Elisabete/0000-0003-2237-0128; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU ATBC; Intramural Research Program of the NIH; National Cancer Institute; US Public Health Service contracts from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; EPIC-ICL-Europe Against Cancer Program of the European Commission (SANCO); IARC-International Agency for Research on Cancer; France-Ligue contre le Cancer Societe 3M; Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM); Italy-Italian Association for Research on Cancer National Research Council; Spain-Health Research Fund (FIS) of the Spanish Ministry of Health; CIBER en Epidemiologia y Salud Publica (CIBERESP), Spain; ISCIII RETIC [RD06/0020]; Spanish Regional Government of Andalusia [N 6236]; Spanish Regional Government of Asturias [N 6236]; Spanish Regional Government of Basque Country [N 6236]; Spanish Regional Government of Murcia [N 6236]; Navarra; Catalan Institute of Oncology; UK-Cancer Research UK Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; Wellcome Trust; Netherlands-Dutch Ministry of Public Health Dutch Prevention Funds LK Research Funds Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Greece-Hellenic Ministry of Health; Stavros Niarchos Foundation; Hellenic Health Foundation; Germany-German Cancer Aid; German Cancer Research Center Federal Ministry of Education and Research [01-EA-9401]; Sweden-Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane; Sweden and Denmark-Danish Cancer Society; FBCS-Ligue Contre le Cancer du Val-de-Marne; Fondation de France; Groupement d'Entreprises Francaises dans la Lutte contre le Cancer; Association pour la Recherche sur le Cancer, France [TXBCS-U01 CA 127615, R01 CA 74880, P50 CA 91846]; UT MD Anderson Cancer Centre Research Trust; Centre for Translational and Public Health Genomics at MD Anderson Cancer Centre; LABCS-NIH [R01CA65726, R01CA114665, 1R01CA114665, 1P01CA86871]; NEBCS-Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural [NCI N02-CP-01037]; NHS; HPFS [CA055075, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262, UM1 CA167552]; PLCO-The NIH Genes, Environment and Health Initiative (GEI); DNA extraction and statistical analyses [HG-06-033-NCI-01, RO1HL091172-01]; Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health; SBCS-Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural [NCI N02-CP-11015, FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, G03/174]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN26820 1100001C, HHSN268201100002C, HHSN268201100003C, HH SN268201100004C, HHSN271201100004C] FX Funding support for individual studies that participated in the effort is as follows: ATBC (D.A.)-This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services. EPIC (P.V.)-ICL-Europe Against Cancer Program of the European Commission (SANCO); IARC-International Agency for Research on Cancer; France-Ligue contre le Cancer Societe 3M, Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM); Italy-Italian Association for Research on Cancer National Research Council; Spain-Health Research Fund (FIS) of the Spanish Ministry of Health; the CIBER en Epidemiologia y Salud Publica (CIBERESP), Spain; ISCIII RETIC (RD06/0020); Spanish Regional Governments of Andalusia, Asturias, Basque Country, Murcia (N 6236) and Navarra and the Catalan Institute of Oncology; UK-Cancer Research UK Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust; The Netherlands-Dutch Ministry of Public Health Dutch Prevention Funds LK Research Funds Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); Greece-Hellenic Ministry of Health, the Stavros Niarchos Foundation and the Hellenic Health Foundation; Germany-German Cancer Aid, German Cancer Research Center Federal Ministry of Education and Research (Grant 01-EA-9401); Sweden-Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane, Sweden and Denmark-Danish Cancer Society. FBCS (S.B.)-Ligue Contre le Cancer du Val-de-Marne; Fondation de France; Groupement d'Entreprises Francaises dans la Lutte contre le Cancer; Association pour la Recherche sur le Cancer, France (TXBCS-U01 CA 127615 (X. W.), R01 CA 74880 (X. W.) and P50 CA 91846 (X. W. and C. P. D.), UT MD Anderson Cancer Centre Research Trust (X. W.), Centre for Translational and Public Health Genomics at MD Anderson Cancer Centre. LABCS (M.P.)-NIH (grants R01CA65726, R01CA114665, 1R01CA114665 and 1P01CA86871). NEBCS (D.T.S.)-Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-01037. NHS and HPFS (I.D.V.)-CA055075, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262 and UM1 CA167552. PLCO (M.P.P.)-The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA (N. C.) Coordination Center (U01HG004446) for the genotyping of the lung studies with controls from EAGLE study and part of the PLCO. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. SBCS (D. T. S.; )-Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614 and G03/174, Fundacio Marato TV3, Red Tematica Investigacion Cooperativa en Cancer (RTICC), Consolider ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. WHI (C. K.)-The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN26820 1100001C, HHSN268201100002C, HHSN268201100003C, HH SN268201100004C and HHSN271201100004C. NR 58 TC 46 Z9 47 U1 3 U2 34 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2014 VL 23 IS 5 BP 1387 EP 1398 DI 10.1093/hmg/ddt519 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AB5FT UT WOS:000331815000022 PM 24163127 ER PT J AU Tal, R Segars, JH AF Tal, Reshef Segars, James H. TI The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy SO HUMAN REPRODUCTION UPDATE LA English DT Review DE uterine leiomyoma; angiogenesis; hypoxia; vasculature; anti-angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; HUMAN UTERINE LEIOMYOMA; MESSENGER-RIBONUCLEIC-ACID; PROGESTERONE-RECEPTOR MODULATOR; SMOOTH-MUSCLE-CELLS; SCANNING-ELECTRON-MICROSCOPY; HYPOXIA-INDUCIBLE FACTOR-1; FUMARASE TUMOR-SUPPRESSOR; TYROSINE KINASE INHIBITOR; HORMONE AGONIST THERAPY AB It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor- and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroids abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids. C1 [Tal, Reshef] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov OI Tal, Reshef/0000-0002-2500-9904 FU intramural research Program of Reproductive and Adult Endocrinology, NICHD, National Institutes of Health, Bethesda, MD, USA FX This manuscript was supported, in part, by the intramural research Program of Reproductive and Adult Endocrinology, NICHD, National Institutes of Health, Bethesda, MD, USA. NR 303 TC 18 Z9 23 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 EI 1460-2369 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD MAR-APR PY 2014 VL 20 IS 2 BP 194 EP 216 DI 10.1093/humupd/dmt042 PG 23 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AB5IZ UT WOS:000331823400003 PM 24077979 ER PT J AU Yang, PY Yoo, PD Fernando, J Zhou, BB Zhang, ZL Zomaya, AY AF Yang, Pengyi Yoo, Paul D. Fernando, Juanita Zhou, Bing B. Zhang, Zili Zomaya, Albert Y. TI Sample Subset Optimization Techniques for Imbalanced and Ensemble Learning Problems in Bioinformatics Applications SO IEEE TRANSACTIONS ON CYBERNETICS LA English DT Article DE Bioinformatics applications; ensemble learning; imbalanced learning; sample subset optimization (SSO); undersampling ID SUPPORT VECTOR MACHINES; PROMOTER RECOGNITION; CLASS PREDICTION; GENE PREDICTION; EXPRESSION DATA; DATA SETS; CLASSIFICATION; CLASSIFIERS; ALGORITHMS; NETWORKS AB Data sampling is a widely used technique in a broad range of machine learning problems. Traditional sampling approaches generally rely on random resampling from a given dataset. However, these approaches do not take into consideration additional information, such as sample quality and usefulness. We recently proposed a data sampling technique, called sample subset optimization (SSO). The SSO technique relies on a cross-validation procedure for identifying and selecting the most useful samples as subsets. In this paper, we describe the application of SSO techniques to imbalanced and ensemble learning problems, respectively. For imbalanced learning, the SSO technique is employed as an under-sampling technique for identifying a subset of highly discriminative samples in the majority class. In ensemble learning, the SSO technique is utilized as a generic ensemble technique where multiple optimized subsets of samples from each class are selected for building an ensemble classifier. We demonstrate the utilities and advantages of the proposed techniques on a variety of bioinformatics applications where class imbalance, small sample size, and noisy data are prevalent. C1 [Yang, Pengyi] Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia. [Yoo, Paul D.] Khalifa Univ Sci, Dept Elect & Comp Engn Res & Technol, Abu Dhabi 127788, U Arab Emirates. [Fernando, Juanita] Monash Univ, Fac Med Nursing & Hlth Sci, Clayton, Vic 3800, Australia. [Zhou, Bing B.; Zomaya, Albert Y.] Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia. [Zhang, Zili] Univ Sydney, Fac Comp & Informat Sci, Chongqing, Peoples R China. [Zhang, Zili] Deakin Univ, Sch Informat Technol, Melbourne, Vic 3217, Australia. RP Yang, PY (reprint author), NIEHS, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. EM pengyi.yang@nih.gov; paul.usyd@gmail.com; juanita.fernando@med.monash.edu.au; bing.zhou@sydney.edu.au; zhangzl@swu.edu.cn; albert.zomaya@sydney.edu.au RI Yang, Pengyi/B-1002-2010 OI Yang, Pengyi/0000-0003-1098-3138 FU NICTA International Postgraduate Award; NICTA Research Project Award FX The work of P. Yang was supported in part by the NICTA International Postgraduate Award and the NICTA Research Project Award during his Ph. D. candidature. This paper was recommended by Associate Editor V. Marik. NR 40 TC 8 Z9 8 U1 0 U2 11 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2168-2267 EI 2168-2275 J9 IEEE T CYBERNETICS JI IEEE T. Cybern. PD MAR PY 2014 VL 44 IS 3 BP 445 EP 455 DI 10.1109/TCYB.2013.2257480 PG 11 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics SC Computer Science GA AB6NM UT WOS:000331906100012 PM 24108722 ER PT J AU Tereshchenk, LG Rizzi, P Mewton, N Volpe, GJ Murthy, S Strauss, DG Liu, CY Marchlinski, FE Spooner, P Berger, RD Kellman, P Lima, JAC AF Tereshchenk, Larisa G. Rizzi, Patricia Mewton, Nathan Volpe, Gustavo Jardim Murthy, Sindhoora Strauss, David G. Liu, Chia Y. Marchlinski, Francis E. Spooner, Peter Berger, Ronald D. Kellman, Peter Lima, Joao A. C. TI Infiltrated atrial fat characterizes underlying atrial fibrillation substrate in patients at risk as defined by the ARIC atrial fibrillation risk score SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Atrial fibrillation; Cardiac magnetic resonance; Intraatrial infiltrated fat; Risk score ID QRS-T ANGLE; LIPOMATOUS HYPERTROPHY; INTERATRIAL SEPTUM; ADIPOSE-TISSUE; MAGNETIC-RESONANCE; PERICARDIAL FAT; FOLLOW-UP; HEART; ABLATION; POPULATION AB Background: It is known that expanded epicardial fat is associated with atrial fibrillation (AF). However, infiltrated intraatrial fat has not been previously quantified in individuals at risk as determined by the ARIC AF risk score. Methods: Patients in sinus rhythm (N = 90, age 57 +/- 10 years; 55 men [63.2%]), in 3 groups at risk of AF as determined by the ARIC AF risk score [low (<= 11 points; n = 15), moderate (12-18 points; n = 40), high (>= 19 points; n = 23) risk of AF], and paroxysmal AF (n = 12) underwent cardiac magnetic resonance study. Intraatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. OsiriX DICOMviewer (Geneva, Switzerland) was used to quantify the intraatrial fat area. Width of the cephalad portion of the interatrial septum was measured at the level of the fossa ovalis. Results: Intraatrial fat monotonically increasedwith growing AF risk in study groups (low AF risk 16 > 4 vs. moderate AF risk 32 +/- 18 vs. high AF risk 81 +/- 83mm(2); ANOVA P= 0.012). Log-transformed intraatrial fat predicted ARIC AF risk score inmultivariate ordered probit regression after adjustment for sex, race, left and right atrial area indices, and body mass index (beta-coefficient 0.50 [95% CI 0.03-0.97]; P = 0.037), whereas epicardial fat did not. Interatrial septumwidth showed similar association (3.0 +/- 1.4 vs. 5.0 +/- 1.8 vs. 7.1 +/- 2.7mm; ANOVA P< 0.001; adjusted beta-coefficient 2.80 [95% CI 1.19-4.41]; P = 0.001). Conclusions: Infiltrated intraatrial fat characterizes evolving substrate in individuals at risk of AF. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Tereshchenk, Larisa G.; Rizzi, Patricia; Mewton, Nathan; Volpe, Gustavo Jardim; Liu, Chia Y.; Spooner, Peter; Berger, Ronald D.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Murthy, Sindhoora] Johns Hopkins Univ, Whiting Sch Engn, Baltimore, MD 21205 USA. [Strauss, David G.] US FDA, Silver Spring, MD USA. [Marchlinski, Francis E.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Kellman, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. RP Tereshchenk, LG (reprint author), Carnegie 568,600 N Wolfe St, Baltimore, MD 21287 USA. EM lteresh1@jhmi.edu OI Tereshchenko, Larisa/0000-0002-6976-1313 FU NHLBI NIH HHS [R01 HL118277, P20HL101397, P20 HL101397] NR 31 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 1 PY 2014 VL 172 IS 1 BP 196 EP 201 DI 10.1016/j.ijcard.2014.01.012 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WT UT WOS:000331721600134 PM 24485635 ER PT J AU Ibrayeva, A Kozhamkulov, U Raiymbek, D Alenova, A Igilikova, S Zholdybayeva, E Abildaev, T Momynaliev, K AF Ibrayeva, A. Kozhamkulov, U. Raiymbek, D. Alenova, A. Igilikova, S. Zholdybayeva, E. Abildaev, T. Momynaliev, K. TI Molecular epidemiology of Mycobacterium tuberculosis strains circulating in the penitentiary system of Kazakhstan SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE Mycobacterium tuberculosis; penitentiary system; MIRU-VNTR genotyping; DNA sequencing ID TRANSMISSION AB A total of 60 Mycobacterium tuberculosis isolates collected from patients in prisons in Kazakhstan and 125 from the civilian sector were examined using mycobacterial interspersed repetitive units-variable number of tandem repeat analysis in 2012. The proportion of tuberculosis strains with unique genotypes isolated from the civilian patients was 50.4%, while that in the prison patients was 31.7%. This difference was statistically significant (chi(2) 4.42, P = 0.035), and may reflect a low genetic diversity of M. tuberculosis strains isolated from prison patients. The frequencies of mutations in the rpoB531 and katG315 genes of the M. tuberculosis strains isolated from the civilians and in the penitentiary system were not significantly different (rpoB531: 82.4% vs. 88.3%, and katG315: 98.4% vs. 100%, respectively). C1 [Ibrayeva, A.; Kozhamkulov, U.; Raiymbek, D.; Zholdybayeva, E.; Momynaliev, K.] Natl Biotechnol Ctr, Astana 010000, Kazakhstan. [Alenova, A.; Igilikova, S.; Abildaev, T.] Natl TB Ctr, Alma Ata, Kazakhstan. RP Ibrayeva, A (reprint author), Natl Biotechnol Ctr, 13-1 Valikhanov St, Astana 010000, Kazakhstan. EM albina.ibrayeva@gmail.com RI Kozhamkulov, Ulan/H-6805-2016 NR 12 TC 4 Z9 4 U1 0 U2 5 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD MAR PY 2014 VL 18 IS 3 BP 298 EP 301 DI 10.5588/ijtld.13.0558 PG 4 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA AB6TF UT WOS:000331921700010 PM 24670565 ER PT J AU Nguyen, TT Jayadeva, V Cizza, G Brown, RJ Nandagopal, R Rodriguez, LM Rother, KI AF Nguyen, Tammy T. Jayadeva, Vikas Cizza, Giovanni Brown, Rebecca J. Nandagopal, Radha Rodriguez, Luisa M. Rother, Kristina I. TI Challenging Recruitment of Youth With Type 2 Diabetes Into Clinical Trials SO JOURNAL OF ADOLESCENT HEALTH LA English DT Review DE Type 2 diabetes; Pediatric; Adolescents; Youth; Young adults; Recruitment; Retention; Clinical trials ID SMOKING-CESSATION; GLYCEMIC CONTROL; RETENTION; ADOLESCENTS; SEARCH; INTERVENTION; PREVALENCE; PROGRAM; COHORT; PARTICIPATION AB Purpose: To better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes. Methods: We compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions. Results: The number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors. Conclusions: Adolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e. g., weight loss, body image, and stress management) combined with less tangible outcomes (e. g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities. Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine. C1 [Nguyen, Tammy T.; Jayadeva, Vikas; Brown, Rebecca J.; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20852 USA. [Cizza, Giovanni] NIDDK, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20852 USA. [Nandagopal, Radha] Childrens Natl Med Ctr, Div Endocrinol, Washington, DC 20010 USA. [Rodriguez, Luisa M.] Baylor Coll Med, Sect Endocrinol & Metab, Houston, TX 77030 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab, DEOB, NIH, 9000 Rockville Pike,Bldg 10,Room 8C-432A, Bethesda, MD 20852 USA. EM kristina.rother@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 46 TC 8 Z9 8 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAR PY 2014 VL 54 IS 3 BP 247 EP 254 DI 10.1016/j.jadohealth.2013.08.017 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AB3XF UT WOS:000331722800003 PM 24161585 ER PT J AU Ke, RA Loverdo, C Qi, HF Olson, CA Wu, NC Sun, R Lloyd-Smith, JO AF Ke, Ruian Loverdo, Claude Qi, Hangfei Olson, C. Anders Wu, Nicholas C. Sun, Ren Lloyd-Smith, James O. TI Modelling clinical data shows active tissue concentration of daclatasvir is 10-fold lower than its plasma concentration SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE hepatitis C virus; resistance; pharmacokinetics/pharmacodynamics; mathematical modeling ID REPLICATION COMPLEX INHIBITOR; NS5A INHIBITOR; GENOTYPE 1; IN-VIVO; BMS-790052; RESISTANT; VARIANTS; THERAPY; AGENTS AB Objectives: Daclatasvir is a highly potent inhibitor of hepatitis C virus. We estimated the active tissue concentration of daclatasvir in vivo. Methods: We developed a mathematical model incorporating pharmacokinetic/pharmacodynamic and viral dynamics. By fitting the model to clinical data reported previously, we estimated the ratio between plasma drug concentration and active tissue concentration in vivo. Results: The modelling results show that the active tissue concentration of daclatasvir is similar to 9% of the concentration measured in plasma (95% CI 1%-29%). Conclusions: Using plasma concentrations as surrogates for clinical recommendations may lead to substantial underestimation of the risk of resistance. C1 [Ke, Ruian; Loverdo, Claude; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Qi, Hangfei; Olson, C. Anders; Sun, Ren] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Wu, Nicholas C.; Sun, Ren] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Sun, Ren] Novartis Inst BioMed Res, Dept Infect Dis, Emeryville, CA 94608 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ke, RA (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM rke.work@gmail.com RI Lloyd-Smith, James/K-4080-2012; Wu, Nicholas/H-3822-2015; OI Lloyd-Smith, James/0000-0001-7941-502X; Wu, Nicholas/0000-0002-9078-6697; Loverdo, Claude/0000-0002-0888-1717 FU National Science Foundation [EF-0928690]; National Institutes of Health [AI078133]; Margaret E. Early Medical Research Trust [P30CA016042]; UCLA AIDS Institute/CFAR [P30AI028697]; De Logi Chair in Biological Sciences; RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the National Science Foundation (grant number EF-0928690), National Institutes of Health (grant number AI078133), Margaret E. Early Medical Research Trust (grant number P30CA016042) and UCLA AIDS Institute/CFAR (grant number P30AI028697). J. O. L.-S. is grateful for support from the De Logi Chair in Biological Sciences, and from the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 15 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD MAR PY 2014 VL 69 IS 3 BP 724 EP 727 DI 10.1093/jac/dkt423 PG 4 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA AB5KL UT WOS:000331827200021 PM 24169581 ER PT J AU Boltz, VF Bao, YJ Lockman, S Halvas, EK Kearney, MF McIntyre, JA Schooley, RT Hughes, MD Coffin, JM Mellors, JW AF Boltz, Valerie F. Bao, Yajing Lockman, Shahin Halvas, Elias K. Kearney, Mary F. McIntyre, James A. Schooley, Robert T. Hughes, Michael D. Coffin, John M. Mellors, John W. CA OCTANE A5208 Team TI Low-Frequency Nevirapine (NVP)-Resistant HIV-1 Variants Are Not Associated With Failure of Antiretroviral Therapy in Women Without Prior Exposure to Single-Dose NVP SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE minor drug-resistant variants; single-dose nevirapine; antiretroviral therapy failure ID IMMUNODEFICIENCY-VIRUS TYPE-1; DRUG-RESISTANCE MUTATIONS; REVERSE-TRANSCRIPTASE; VIROLOGICAL FAILURE; POPULATIONS; TRANSMISSION; SUPPRESSION; PERSISTENCE; INFECTION; PROTEASE AB Background. Low-frequency nevirapine (NVP)-resistant variants have been associated with virologic failure (VF) of initial NVP-based combination antiretroviral therapy (cART) in women with prior exposure to single-dose NVP (sdNVP). We investigated whether a similar association exists in women without prior sdNVP exposure. Methods. Pre-cART plasma was analyzed by allele-specific polymerase chain reaction to quantify NVP-resistant mutants in human immunodeficiency virus-infected African women without prior sdNVP who were starting first-line NVP-based cART in the OCTANE/A5208 trial 2. Associations between NVP-resistant mutants and VF or death were determined and compared with published results from women participating in the OCTANE/A5208 trial 1 who had taken sdNVP and initiated NVP-based cART. Results. Pre-cART NVP-resistant variants were detected in 18% (39/219) of women without prior sdNVP exposure, compared to 45% (51/114) with prior sdNVP exposure (P < .001). Among women without prior sdNVP exposure, 8 of 39 (21%) with NVP-resistant variants experienced VF or death vs 31 of 180 (17%) without such variants (P = .65); this compares with 21 of 51 (41%) vs 9 of 63 (14%) among women with prior exposure (P = .001). Conclusions. The risk of VF on NVP-based cART from NVP-resistant variants differs between sdNVP-exposed and -unexposed women. This difference may be driven by drug-resistance mutations emerging after sdNVP exposure that are linked on the same viral genome. Clinical Trials Registration NCT00089505. C1 [Boltz, Valerie F.; Kearney, Mary F.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Bao, Yajing; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lockman, Shahin] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Halvas, Elias K.; Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA 15261 USA. [McIntyre, James A.] Anova Hlth Inst, Johannesburg, South Africa. [McIntyre, James A.] Univ Cape Town, Sch Publ Hlth & Family Med, ZA-7700 Rondebosch, South Africa. [Schooley, Robert T.] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Mellors, JW (reprint author), Univ Pittsburgh, Div Infect Dis, 81-8 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM jwm1@pitt.edu FU National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (University of Pittsburgh CTU Grant) [1U01 AI069494-01]; Virology Support Laboratory subcontract of the ACTG Central Group [204VC009, 1 U01AI068636-01]; ACTG Statistical and Data Management Center [1 U01-AI068634]; National Cancer Institute (SAIC contract) [25XS119]; FM Kirby Foundation FX This work was supported by intramural funding from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (University of Pittsburgh CTU Grant 1U01 AI069494-01), a Virology Support Laboratory subcontract (204VC009) of the ACTG Central Group (grant 1 U01AI068636-01) and ACTG Statistical and Data Management Center (1 U01-AI068634), and the National Cancer Institute (SAIC contract 25XS119). J. M. C was the recipient of a research professorship from the American Cancer Society, with support from the FM Kirby Foundation. NR 35 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2014 VL 209 IS 5 BP 703 EP + DI 10.1093/infdis/jit635 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AB6BY UT WOS:000331873700001 PM 24443547 ER PT J AU Tran, TM Ongoiba, A Coursen, J Crosnier, C Diouf, A Huang, CY Li, SP Doumbo, S Doumtabe, D Kone, Y Bathily, A Dia, S Niangaly, M Dara, C Sangala, J Miller, LH Doumbo, OK Kayentao, K Long, CA Miura, K Wright, GJ Traore, B Crompton, PD AF Tran, Tuan M. Ongoiba, Aissata Coursen, Jill Crosnier, Cecile Diouf, Ababacar Huang, Chiung-Yu Li, Shanping Doumbo, Safiatou Doumtabe, Didier Kone, Younoussou Bathily, Aboudramane Dia, Seydou Niangaly, Moussa Dara, Charles Sangala, Jules Miller, Louis H. Doumbo, Ogobara K. Kayentao, Kassoum Long, Carole A. Miura, Kazutoyo Wright, Gavin J. Traore, Boubacar Crompton, Peter D. TI Naturally Acquired Antibodies Specific for Plasmodium falciparum Reticulocyte-Binding Protein Homologue 5 Inhibit Parasite Growth and Predict Protection From Malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE RH5; blood-stage immunity; endemic population; Plasmodium falciparum; prospective cohort study; malaria ID APICAL MEMBRANE ANTIGEN-1; MEROZOITE ANTIGENS; ERYTHROCYTE INVASION; SEQUENCE DIVERSITY; VACCINE DESIGN; PFRH5; INFECTION; CHILDREN; IMMUNITY; TRIAL AB Background. Plasmodium falciparum reticulocyte-binding protein homologue 5 (PfRH5) is a blood-stage parasite protein essential for host erythrocyte invasion. PfRH5-specific antibodies raised in animals inhibit parasite growth in vitro, but the relevance of naturally acquired PfRH5-specific antibodies in humans is unclear. Methods. We assessed pre-malaria season PfRH5-specific immunoglobulin G (IgG) levels in 357 Malian children and adults who were uninfected with Plasmodium. Subsequent P. falciparum infections were detected by polymerase chain reaction every 2 weeks and malaria episodes by weekly physical examination and self-referral for 7 months. The primary outcome was time between the first P. falciparum infection and the first febrile malaria episode. PfRH5-specific IgG was assayed for parasite growth-inhibitory activity. Results. The presence of PfRH5-specific IgG at enrollment was associated with a longer time between the first blood-stage infection and the first malaria episode (PfRH5-seropositive median: 71 days, PfRH5-seronegative median: 18 days; P = .001). This association remained significant after adjustment for age and other factors associated with malaria risk/exposure (hazard ratio, .62; P = .02). Concentrated PfRH5-specific IgG purified from Malians inhibited P. falciparum growth in vitro. Conclusions. Naturally acquired PfRH5-specific IgG inhibits parasite growth in vitro and predicts protection from malaria. These findings strongly support efforts to develop PfRH5 as an urgently needed blood-stage malaria vaccine. Clinical Trials Registration NCT01322581. C1 [Tran, Tuan M.; Coursen, Jill; Li, Shanping; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Ongoiba, Aissata; Doumbo, Safiatou; Doumtabe, Didier; Kone, Younoussou; Bathily, Aboudramane; Dia, Seydou; Niangaly, Moussa; Dara, Charles; Sangala, Jules; Doumbo, Ogobara K.; Kayentao, Kassoum; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Mali Int Ctr Excellence Res, Bamako, Mali. [Crosnier, Cecile; Wright, Gavin J.] Wellcome Trust Sanger Inst, Cell Surface Signalling Lab, Cambridge, England. [Diouf, Ababacar; Miller, Louis H.; Long, Carole A.; Miura, Kazutoyo] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Huang, Chiung-Yu] Johns Hopkins Univ, Res Program Quantitat Sci, Div Oncol Biostat Bioinformat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Tran, TM (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr,Twinbrook 2,Rm 125, Rockville, MD 20852 USA. EM tuan.tran@nih.gov RI Crompton, Peter/N-1130-2016 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Wellcome Trust [098051]; PATH Malaria Vaccine Initiative FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the Wellcome Trust (grant number 098051 to G. J. W.). The PATH Malaria Vaccine Initiative provided support for the GIA Reference Center. NR 48 TC 37 Z9 37 U1 0 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 MAR 1 PY 2014 VL 209 IS 5 BP 789 EP 798 DI 10.1093/infdis/jit553 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AB6BY UT WOS:000331873700021 PM 24133188 ER PT J AU Solomon, BD Baker, LA Bear, KA Cunningham, BK Giampietro, PF Hadigan, C Hadley, DW Harrison, S Levitt, MA Niforatos, N Paul, SM Raggio, C Reutter, H Warren-Mora, N AF Solomon, Benjamin D. Baker, Linda A. Bear, Kelly A. Cunningham, Bridget K. Giampietro, Philip F. Hadigan, Colleen Hadley, Donald W. Harrison, Steven Levitt, Marc A. Niforatos, Nickie Paul, Scott M. Raggio, Cathleen Reutter, Heiko Warren-Mora, Nicole TI An Approach to the Identification of Anomalies and Etiologies in Neonates with Identified or Suspected VACTERL (Vertebral Defects, Anal Atresia, Tracheo-Esophageal Fistula with Esophageal Atresia, Cardiac Anomalies, Renal Anomalies, and Limb Anomalies) Association SO JOURNAL OF PEDIATRICS LA English DT Article ID TETHERED SPINAL-CORD; SIDED AORTIC-ARCH; ANORECTAL-MALFORMATIONS; VATER ASSOCIATION; HYDROCEPHALUS; CHILDREN; DELINEATION; EXPERIENCE; INFANTS; ULTRASONOGRAPHY C1 [Solomon, Benjamin D.] Inova Translat Med Inst, Div Med Genom, Falls Church, VA 22042 USA. [Solomon, Benjamin D.] Inova Translat Med Inst, Dept Pediat, Falls Church, VA 22042 USA. [Solomon, Benjamin D.; Bear, Kelly A.; Cunningham, Bridget K.; Hadley, Donald W.; Warren-Mora, Nicole] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Baker, Linda A.; Harrison, Steven] Univ Texas Southwestern, Eugene McDermott Ctr Human Growth & Dev, Dept Urol, Dallas, TX USA. [Bear, Kelly A.; Cunningham, Bridget K.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD USA. [Giampietro, Philip F.] Univ Wisconsin, Dept Pediat, Madison, WI USA. [Hadigan, Colleen] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Levitt, Marc A.] Cincinnati Childrens Hosp, Med Ctr, Colorectal Ctr Children, Dept Pediat Surg, Cincinnati, OH USA. [Niforatos, Nickie] Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. [Paul, Scott M.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Raggio, Cathleen] Hosp Special Surg, Dept Pediat Orthoped, New York, NY 10021 USA. [Reutter, Heiko] Univ Bonn, Childrens Hosp, Inst Human Genet, Bonn, Germany. [Reutter, Heiko] Univ Bonn, Childrens Hosp, Dept Neonatol, Bonn, Germany. RP Solomon, BD (reprint author), Inova Translat Med Inst, Div Med Genom, 3300 Gallows Rd, Falls Church, VA 22042 USA. EM benjamin.solomon@inova.org FU National Human Genome Research Institute, National Institutes of Health FX We thank Dr Max Muenke (Editor of Molecular Genetics and Genomic Medicine) for support and mentorship and Julia Fekecs for help with illustrations (both funded by National Human Genome Research Institute, National Institutes of Health). All authors express their deepest gratitude to the patients and families who participate in their research on VACTERL association and related disorders. NR 64 TC 13 Z9 13 U1 3 U2 12 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 MAR PY 2014 VL 164 IS 3 BP 451 EP + DI 10.1016/j.jpeds.2013.10.086 PG 8 WC Pediatrics SC Pediatrics GA AB1GI UT WOS:000331539100007 PM 24332453 ER PT J AU Dagalakis, U Lodish, M Dombi, E Sinaii, N Sabo, J Baldwin, A Steinberg, SM Stratakis, CA Widemann, BC AF Dagalakis, Urania Lodish, Maya Dombi, Eva Sinaii, Ninet Sabo, Jessica Baldwin, Andrea Steinberg, Seth M. Stratakis, Constantine A. Widemann, Brigitte C. TI Puberty and Plexiform Neurofibroma Tumor Growth in Patients with Neurofibromatosis Type I SO JOURNAL OF PEDIATRICS LA English DT Article ID SCHWANN-CELLS; STEROID-HORMONES; PROGESTERONE; AGE; PREGNANCY AB Objective To assess the relationship between pubertal progression and change in plexiform neurofibroma (PN) burden over time in pediatric and young adult patients with neurofibromatosis type 1 and PNs. Study design Analyses accounted for sex, age, race, and chemotherapy. Forty-one patients with neurofibromatosis type 1 (15 female and 26 male patients) were studied at the National Institutes of Health. Tanner stage, testosterone, progesterone, estradiol, insulin-like growth factor -1, luteinizing hormone, and follicle-stimulating hormone were assessed. Tumor volume was measured using magnetic resonance imaging and lesion detection software developed locally. Patients were divided into 2 groups based on whether they were actively progressing through puberty (n = 16) or were peripubertal (n = 25) and were followed for an average of 20 months. Tumor growth rates in the puberty and peripubertal group were analyzed for a subset of patients. Results There was no statistically significant difference in tumor burden change over time (cm(2)/kg per month) between the pubertal and peripubertal groups (-0.16 +/- 0.34 vs 0.03 +/- 1.8, P = .31) and in the PN growth rates before and during puberty (P = .90). Change in tumor volume/patient weight/time did not correlate with testosterone change/time in males or estradiol change/time in females. Conclusion These findings support that hormonal changes of puberty do not accelerate PN growth. Additional long-term follow-up of patients is necessary to further characterize the interaction between puberty and tumor growth. C1 [Dagalakis, Urania; Lodish, Maya; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Dombi, Eva; Sabo, Jessica; Baldwin, Andrea; Widemann, Brigitte C.] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Clin Res Ctr, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Clin Res Ctr, Bethesda, MD 20892 USA. RP Lodish, M (reprint author), NICHD, NIH, Bldg 10-CRC,Room 9D42,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the intramural programs of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors declare no conflicts of interest. NR 16 TC 6 Z9 6 U1 0 U2 5 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 MAR PY 2014 VL 164 IS 3 BP 620 EP 624 DI 10.1016/j.jpeds.2013.10.081 PG 5 WC Pediatrics SC Pediatrics GA AB1GI UT WOS:000331539100037 PM 24321536 ER PT J AU Hingson, R White, A AF Hingson, Ralph White, Aaron TI One-fifth of high-school seniors participate in binge drinking SO JOURNAL OF PEDIATRICS LA English DT Editorial Material C1 [Hingson, Ralph; White, Aaron] NIAAA, Bethesda, MD 20892 USA. RP Hingson, R (reprint author), NIAAA, Bethesda, MD 20892 USA. NR 3 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 MAR PY 2014 VL 164 IS 3 BP 675 EP 676 PG 2 WC Pediatrics SC Pediatrics GA AB1GI UT WOS:000331539100058 PM 24560320 ER PT J AU Turegano, MM Lee, CCR Malech, HL De Ravin, SS Cowen, EW Brownell, I AF Turegano, Mamina M. Lee, Chyi-Chia R. Malech, Harry L. De Ravin, Suk S. Cowen, Edward W. Brownell, Isaac TI Recurrent erythematous plaques on sun-exposed sites in an African American boy with chronic granulomatous disease SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE chronic granulomatous disease; discoid lupus erythematosus; drug reaction; lupuslike eruption; photoeruption; phototoxicity; voriconazole ID LUPUS-LIKE LESIONS; VORICONAZOLE THERAPY; ANTIFUNGAL AGENT; PHOTOSENSITIVITY; CHILDREN; CARRIERS; PHOTOTOXICITY C1 [Turegano, Mamina M.] Medstar Washington Hosp Ctr, Dept Dermatol, Washington, DC USA. [Turegano, Mamina M.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Lee, Chyi-Chia R.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Cowen, Edward W.; Brownell, Isaac] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Malech, Harry L.; De Ravin, Suk S.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Brownell, I (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10 Room 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov OI Malech, Harry/0000-0001-5874-5775 FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 1 Z9 1 U1 0 U2 2 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 MAR PY 2014 VL 70 IS 3 BP 576 EP 580 DI 10.1016/j.jaad.2013.09.051 PG 5 WC Dermatology SC Dermatology GA AB2FA UT WOS:000331607400033 PM 24528905 ER PT J AU Morton, LM Kim, CJ Weiss, LM Bhatia, K Cockburn, M Hawes, D Wang, SS Chang, C Altekruse, SF Engels, EA Cozen, W AF Morton, Lindsay M. Kim, Clara J. Weiss, Lawrence M. Bhatia, Kishor Cockburn, Myles Hawes, Debra Wang, Sophia S. Chang, Cindy Altekruse, Sean F. Engels, Eric A. Cozen, Wendy TI Molecular characteristics of diffuse large B-cell lymphoma in human immunodeficiency virus-infected and -uninfected patients in the pre-highly active antiretroviral therapy and pre-rituximab era SO LEUKEMIA & LYMPHOMA LA English DT Article DE Diffuse large B-cell lymphoma; Epstein-Barr virus; activated B-cell; germinal center B-cell ID NON-HODGKINS-LYMPHOMA; GENE-EXPRESSION; AIDS; PROFILE; PATHOGENESIS; PROGNOSIS; CANCER; BCL-6; HISTOGENESIS; INDUCTION AB Human immunodeficiency virus (HIV) infection substantially elevates diffuse large B-cell lymphoma (DLBCL) risk, but its impact on the distinct DLBCL subtypes defined by cell of origin is unclear. We compared DLBCL molecular characteristics and prognosis in 51 HIV-infected and 116 HIV-uninfected cases diagnosed during 1977-2003. Using immunohistochemistry to classify cell of origin based on the Tally algorithm, activated B-cell (ABC)-DLBCL was substantially more common in HIV-infected (83%) than in HIV-uninfected (54%) cases (p < 0.001). Epstein-Barr virus (EBV) was detected in 63% of DLBCLs in HIV-infected cases, occurring almost exclusively in ABC-DLBCL (74% vs. 13% of germinal center B-cell [GCB]-DLBCL, p = 0.002), but was rarely detected in DLBCLs among HIV-uninfected cases (3%). Among HIV-uninfected cases, MYC/IgH [t(8; 14)(q24; q32)] and IgH/BCL2 [t(14; 18)(q32; q21)] translocations were significantly more common and BCL6/IgH [t(3; 14)(q27; q32)] significantly less common in GCB-DLBCL than in ABC-DLBCL (p = 0.010, < 0.001 and = 0.039, respectively). Among HIV-infected cases, translocations other than MYC/IgH [t(8; 14)(q24; q32)] (21%) were rare (<= 6%) and unrelated to cell of origin. ABC-DLBCL was associated with adverse overall survival compared with GCB-DLBCL regardless of HIV status (p(HIV-infected) = 0.066; p(HIV-uninfected) = 0.038). Our data demonstrate key differences in the molecular characteristics, cell of origin and prognosis of DLBCL by HIV status in the pre-highly active antiretroviral therapy (HAART) and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV. C1 [Morton, Lindsay M.; Kim, Clara J.; Bhatia, Kishor; Chang, Cindy; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [Weiss, Lawrence M.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Cockburn, Myles; Hawes, Debra; Cozen, Wendy] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cockburn, Myles; Hawes, Debra; Cozen, Wendy] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Altekruse, Sean F.] NCI, Div Canc Control & Populat Sci, NIH, DHHS, Rockville, MD 20852 USA. RP Morton, LM (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7040,MSC 7238, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural Program of the National Cancer Institute (National Institutes of Health); NCI [NO1-PC-35139]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services [N01-PC-2010-00035]; Centers for Disease Control and Prevention [1U58DP000807-3] FX This study was supported by the Intramural Program of the National Cancer Institute (National Institutes of Health). The NCI contract for the Los Angeles Residual Tissue Repository support was NO1-PC-35139 (Los Angeles). The collection of data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services under Contract No. N01-PC-2010-00035; and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. NR 36 TC 9 Z9 9 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR PY 2014 VL 55 IS 3 BP 551 EP 557 DI 10.3109/10428194.2013.813499 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA AB5ZB UT WOS:000331866100016 PM 23772639 ER PT J AU Tembhare, PR Yuan, CM Venzon, D Braylan, R Korde, N Manasanch, E Zuchlinsky, D Calvo, K Kurlander, R Bhutani, M Tageja, N Maric, I Mulquin, M Roschewski, M Kwok, M Liewehr, D Landgren, O Stetler-Stevenson, M AF Tembhare, Prashant R. Yuan, Constance M. Venzon, David Braylan, Raul Korde, Neha Manasanch, Elisabet Zuchlinsky, Diamond Calvo, Katherine Kurlander, Roger Bhutani, Manisha Tageja, Nishant Maric, Irina Mulquin, Marcia Roschewski, Mark Kwok, Mary Liewehr, David Landgren, Ola Stetler-Stevenson, Maryalice TI Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases SO LEUKEMIA RESEARCH LA English DT Article DE Monoclonal gammopathy of uncertain; significance; Smoldering multiple myeloma; Multiple myeloma; Normal plasma cell immunophenotype; CD81 ID MINIMAL RESIDUAL DISEASE; MONOCLONAL GAMMOPATHY; PERIPHERAL-BLOOD; B-CELLS; RISK; EXPRESSION; TRANSPLANTATION; PROGRESSION; DISORDERS; SURVIVAL AB Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(-), CD20(+), CD45(-) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002). Published by Elsevier Ltd. C1 [Tembhare, Prashant R.; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Lab, Pathol Lab, CCR,NIH, Bethesda, MD 20892 USA. [Venzon, David; Liewehr, David] NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. [Braylan, Raul; Calvo, Katherine; Kurlander, Roger; Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Korde, Neha; Manasanch, Elisabet; Kwok, Mary] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Zuchlinsky, Diamond; Bhutani, Manisha; Tageja, Nishant; Mulquin, Marcia; Roschewski, Mark; Landgren, Ola] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov OI Calvo, Katherine/0000-0002-0771-4191 FU intramural program of the National Cancer Institute, National Institutes of Health FX This research was funded by the intramural program of the National Cancer Institute, National Institutes of Health. The authors wish to acknowledge the technical assistance of Catharine McCoy, Gregory Jasper and Linda Weaver. NR 28 TC 20 Z9 22 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD MAR PY 2014 VL 38 IS 3 BP 371 EP 376 DI 10.1016/j.leukres.2013.12.007 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AB3WV UT WOS:000331721800021 PM 24462038 ER PT J AU Kaczmarek, MZ Holland, RJ Lavanier, SA Troxler, JA Fesenkova, VI Hanson, CA Cmarik, JL Saavedra, JE Keefer, LK Ruscetti, SK AF Kaczmarek, Monika Z. Holland, Ryan J. Lavanier, Stephen A. Troxler, Jami A. Fesenkova, Valentyna I. Hanson, Charlotte A. Cmarik, Joan L. Saavedra, Joseph E. Keefer, Larry K. Ruscetti, Sandra K. TI Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells SO LEUKEMIA RESEARCH LA English DT Article DE JS-K; Murine erythroleukemia cells; FoxO3a; Apoptosis ID FOXO TRANSCRIPTION FACTORS; ANTICANCER DRUG-RESISTANCE; S-TRANSFERASE; OXIDATIVE STRESS; IN-VITRO; ACTIVATION; APOPTOSIS; CANCER; PATHWAYS; GROWTH AB The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor. Published by Elsevier Ltd. C1 [Kaczmarek, Monika Z.; Lavanier, Stephen A.; Troxler, Jami A.; Fesenkova, Valentyna I.; Hanson, Charlotte A.; Cmarik, Joan L.; Ruscetti, Sandra K.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Saavedra, Joseph E.] NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. [Holland, Ryan J.; Keefer, Larry K.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Ruscetti, SK (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, PO Box B, Frederick, MD 21702 USA. EM ruscetts@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 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 30 TC 6 Z9 9 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD MAR PY 2014 VL 38 IS 3 BP 377 EP 382 DI 10.1016/j.leukres.2013.12.002 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AB3WV UT WOS:000331721800022 PM 24461365 ER PT J AU Jaffe, AE Eaton, WW Straub, RE Marenco, S Weinberger, DR AF Jaffe, A. E. Eaton, W. W. Straub, R. E. Marenco, S. Weinberger, D. R. TI Paternal age, de novo mutations and schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Letter ID PARENTAL AGE; BIRTH-ORDER; RISK C1 [Jaffe, A. E.; Straub, R. E.; Weinberger, D. R.] Johns Hopkins Med Campus, Lieber Inst Brain Dev, Baltimore, MD 21287 USA. [Eaton, W. W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Marenco, S.] NIMH, IRP, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Weinberger, D. R.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Dept Psychiat, Dept Neurol,Dept Neurosci, Baltimore, MD USA. RP Weinberger, DR (reprint author), Johns Hopkins Med Campus, Lieber Inst Brain Dev, Baltimore, MD 21287 USA. EM drweinberger@libd.org RI Marenco, Stefano/A-2409-2008; Jaffe, Andrew/L-3089-2016 OI Marenco, Stefano/0000-0002-2488-2365; Jaffe, Andrew/0000-0001-6886-1454 FU Intramural NIH HHS [Z01 MH002904-02, Z99 MH999999, ZIA MH002734-16, ZIA MH002942-01] NR 13 TC 12 Z9 13 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2014 VL 19 IS 3 BP 274 EP 275 DI 10.1038/mp.2013.76 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AB7EH UT WOS:000331951600001 PM 23752248 ER PT J AU Papaleo, F Burdick, MC Callicott, JH Weinberger, DR AF Papaleo, F. Burdick, M. C. Callicott, J. H. Weinberger, D. R. TI Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans SO MOLECULAR PSYCHIATRY LA English DT Article DE cognition; fMRI; genes; translational research; working memory ID CATECHOL-O-METHYLTRANSFERASE; WORKING-MEMORY; GENETIC-VARIATION; RECEPTOR MECHANISMS; HUMAN BRAIN; DOPAMINE; SCHIZOPHRENIA; DYSBINDIN; COGNITION; CORTEX AB Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes-catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))-implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits. C1 [Papaleo, F.] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Burdick, M. C.] Univ Padua, Dept Sci Farmaco, Padua, Italy. [Papaleo, F.; Burdick, M. C.; Callicott, J. H.; Weinberger, D. R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Weinberger, D. R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, D. R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, D. R.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, D. R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, D. R.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Technol, Baltimore, MD USA. RP Papaleo, F (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. EM francesco.papaleo@iit.it; drweinberger@libd.org OI Papaleo, Francesco/0000-0002-6326-0657 FU Intramural Program of the NIMH; Lieber Institute for Brain Development; Istituto Italiano di Tecnologia; Marie Curie FP7-Reintegration [268247] FX We thank L Erickson, S. Garcia and T. Qingjun for technical assistance. We thank Dr M. Karayiorgou and Dr J A Gogos (Columbia University, New York, NY, USA) and Dr B. Lu (NIMH, Bethesda, MD, USA) for generously donating the COMT-/- and dys-/- mouse breeders, respectively. We thank Dr JN Crawley (NIMH, Bethesda, MD, USA) for important support in the mouse phenotyping and Dr J Chen for help with many aspects of mouse husbandry. This research was supported by the Intramural Program of the NIMH, the Lieber Institute for Brain Development, the Istituto Italiano di Tecnologia and the Marie Curie FP7-Reintegration-Grant No. 268247. NR 46 TC 13 Z9 14 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2014 VL 19 IS 3 BP 311 EP 316 DI 10.1038/mp.2013.133 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AB7EH UT WOS:000331951600009 PM 24145376 ER PT J AU Pecina, M Martinez-Jauand, M Hodgkinson, C Stohler, CS Goldman, D Zubieta, JK AF Pecina, M. Martinez-Jauand, M. Hodgkinson, C. Stohler, C. S. Goldman, D. Zubieta, J. K. TI FAAH selectively influences placebo effects SO MOLECULAR PSYCHIATRY LA English DT Article DE cannabinoids; PET; placebo effect; opioids ID ACID AMIDE HYDROLASE; RECEPTOR KNOCKOUT MICE; ENDOCANNABINOID SYSTEM; CANNABINOID RECEPTORS; AFFECTIVE DIMENSIONS; OPIOID ADDICTION; COCAINE; PAIN; SENSITIZATION; TRANSMISSION AB Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms. To further understand the human implications of the interaction between these two systems, we investigated the role of the common, functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, on psychophysical and neurotransmitter (dopaminergic, opioid) responses to pain and placebo-induced analgesia in humans. FAAH Pro129/Pro129 homozygotes, who constitute nearly half of the population, reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration; no effects on pain report in the absence of placebo were observed. Pro129/Pro129 homozygotes also showed greater placebo-induced mu-opioid, but not D-2/3 dopaminergic, enhancements in neurotransmission in regions known involved in placebo effects. These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects. C1 [Pecina, M.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Martinez-Jauand, M.] IUNICS, Res Inst Hlth Sci, Palma de Mallorca, Spain. [Hodgkinson, C.; Goldman, D.] NIAAA, Lab Neurogenet, Rockville, MD 20852 USA. [Stohler, C. S.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. [Zubieta, J. K.] Univ Michigan, Psychiat Radiol Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Zubieta, J. K.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Zubieta, JK (reprint author), Univ Michigan, Psychiat Radiol Mol & Behav Neurosci Inst, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM Zubieta@umich.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Phil F Jenkins Foundation; Spanish Ministry of Education [AP2008-03742]; [R01 DA 022520]; [R01 DA027494] FX We wish to acknowledge the nuclear medicine technologists of the PET Center at the University of Michigan for the assistance in PET data acquisition and reconstruction. Funding: work was supported by R01 DA 022520, R01 DA027494 and the Phil F Jenkins Foundation (JKZ). MMJ was supported by the Spanish Ministry of Education (MMJ: AP2008-03742). NR 38 TC 25 Z9 25 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2014 VL 19 IS 3 BP 385 EP 391 DI 10.1038/mp.2013.124 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AB7EH UT WOS:000331951600018 PM 24042479 ER PT J AU Blois, SM Sulkowski, G Tirado-Gonzalez, I Warren, J Freitag, N Klapp, BF Rifkin, D Fuss, I Strober, W Dveksler, GS AF Blois, S. M. Sulkowski, G. Tirado-Gonzalez, I. Warren, J. Freitag, N. Klapp, B. F. Rifkin, D. Fuss, I. Strober, W. Dveksler, G. S. TI Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-beta and prevents dextran sodium sulfate (DSS)-induced colitis in mice SO MUCOSAL IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; DENDRITIC CELLS; EXPRESSION; TGF-BETA-1; ISOFORM; BETA-1-GLYCOPROTEIN; IDENTIFICATION; INFLAMMATION; INDUCTION AB Transforming growth factor-beta s (TGF-beta s) are secreted from cells as latent complexes and the activity of TGF-beta s is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-beta 1 and TGF-beta 2 play important roles in regulating these processes. Pregnancy-specific beta-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-beta 1 and TGF-beta 2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS)-induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the numberof Tregulatory cells. The PSG1-mediated protectionwasgreatly inhibited by the coadministration of neutralizing anti-TGF-beta antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-beta and identify PSG1 as one of the few known biological activators of TGF-beta 2. C1 [Blois, S. M.; Tirado-Gonzalez, I.; Freitag, N.; Klapp, B. F.] Med Univ Berlin, Reprod Med Res Grp, Charite Ctr Internal Med & Dermatol 12, Berlin, Germany. [Sulkowski, G.; Warren, J.; Dveksler, G. S.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. [Rifkin, D.] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Fuss, I.; Strober, W.] NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Dveksler, GS (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM gabriela.dveksler@usuhs.edu OI Blois, Sandra/0000-0002-0434-2660; Freitag, Nancy/0000-0001-5972-1863 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R21AI101979]; National Institutes of Child Health and Human Development of the NIH [R01HD035832]; Deutsche Forschungsgemeinschaft (DFG) [BL1115/1-1] FX Research reported in this publication was supported by National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award number R21AI101979 and by the National Institutes of Child Health and Human Development of the NIH under award number R01HD035832 to G.S.D.; and S.M.B. was supported by a Deutsche Forschungsgemeinschaft (DFG) grant BL1115/1-1. We thank Dr Wyss-Coray (Stanford University) for the MFB-F11 reporter cells and MEF derived from TGF-beta 1-null mice, Dr L. Wakefield (NIH) and Dr C. Stuelten (NIH) for their invaluable advice, Dr W. Zimmermann (University of Munich) for providing us with the HeLa-PSG1 cells and the plasmid encoding CEACAM9-Fc, Dr F. Lisboa for helpful discussions, and Dr S. Jonjic for the anti-PSG1 #4 Ab (University of Rijeka). NR 45 TC 12 Z9 13 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAR PY 2014 VL 7 IS 2 BP 348 EP 358 DI 10.1038/mi.2013.53 PG 11 WC Immunology SC Immunology GA AB7DA UT WOS:000331948300015 PM 23945545 ER PT J AU Amendola, A Butera, A Sanchez, M Strober, W Boirivant, M AF Amendola, A. Butera, A. Sanchez, M. Strober, W. Boirivant, M. TI Nod2 deficiency is associated with an increased mucosal immunoregulatory response to commensal microorganisms SO MUCOSAL IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; INCREASED INTESTINAL PERMEABILITY; CROHNS-DISEASE; INDUCED COLITIS; PEYERS-PATCHES; MICE; MUTATION; BETA; SUSCEPTIBILITY; MICROBIOTA AB On the basis of previous studies demonstrating that a breach of the colonic epithelial barrier is associated with a microbiota-dependent increase in lamina propria (LP) regulatory cells, we investigated if the lack of spontaneous intestinal inflammation observed in nucleotide-binding oligomerization domain 2 (Nod2)-/- mice was due to enhanced intestinal regulatory function. We found that the LP CD4+ T-cell population of Nod2-/- mice contains an increased percentage of CD4+ regulatory T cells bearing transforming growth factor -beta/latency peptide (LP CD4+ LAP (latency-associated peptide) + T cells) both under baseline conditions and following an intentional breach of the colonic barrier induced by ethanol administration. In addition, we found that Nod2-/- mice manifest decreased severity of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis and that TNBS-colitis in Nod2-/- or Nod2-/- mice is ameliorated by adoptive transfer of LP cells from ethanol-treated mice before, but not after, depletion of LAP+ T cells. This increased regulatory T-cell response in Nod2-/- mice could explain why NOD2 polymorphisms in humans are not in themselves sufficient to establish inflammatory lesions. C1 [Amendola, A.; Butera, A.; Boirivant, M.] Dept Infect Parasit & Immune Mediated Dis, Immune Mediated Dis Sect, Rome, Italy. [Sanchez, M.] Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. [Strober, W.] NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. RP Boirivant, M (reprint author), Dept Infect Parasit & Immune Mediated Dis, Immune Mediated Dis Sect, Rome, Italy. EM monica.boirivant@iss.it RI BOIRIVANT, MONICA/B-9977-2016; AMENDOLA, ANTONELLO/B-9979-2016; Butera, Alessia /I-3399-2014 OI Butera, Alessia /0000-0002-7659-4066 FU Italian Ministry of Health [ISS/NIH: FASC. 11US/27] FX We thank Nazzareno Di Carlo (Immune-Mediated Diseases Section, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita, Rome, Italy) for animal care and technical assistance. This work was supported in part by Grant ISS/NIH: FASC. 11US/27 "Regulation of cell responses of components of the commensal microflora in Nod2-deficient mice'' from the Italian Ministry of Health. NR 36 TC 11 Z9 11 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAR PY 2014 VL 7 IS 2 BP 391 EP 404 DI 10.1038/mi.2013.58 PG 14 WC Immunology SC Immunology GA AB7DA UT WOS:000331948300019 PM 23962873 ER PT J AU Ricketts, CJ Linehan, WM AF Ricketts, Christopher J. Linehan, W. Marston TI Intratumoral heterogeneity in kidney cancer SO NATURE GENETICS LA English DT Editorial Material ID RENAL-CELL CARCINOMA; GENETIC-BASIS; DISEASE AB Clear cell renal cell carcinoma (CCRCC) is characterized by mutation of the VHL gene and loss of a segment of chromosome 3. A new study using multi-region exome sequencing has identified substantial intratumoral heterogeneity within large primary CCRCCs, which has profound implications for understanding tumor evolution and for developing effective therapies. C1 [Ricketts, Christopher J.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Ricketts, CJ (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM wml@nih.gov FU Intramural NIH HHS [ZIA BC011038-06, ZIA BC011028-06] NR 15 TC 15 Z9 16 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2014 VL 46 IS 3 BP 214 EP 215 DI 10.1038/ng.2904 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA AB8JR UT WOS:000332036700002 PM 24569233 ER PT J AU Mahajan, A Go, MJ Zhang, WH Below, JE Gaulton, KJ Ferreira, T Horikoshi, M Johnson, AD Ng, MCY Prokopenko, I Saleheen, D Wang, X Zeggini, E Abecasis, GR Adair, LS Almgren, P Atalay, M Aung, T Baldassarre, D Balkau, B Bao, YQ Barnett, AH Barroso, I Basit, A Been, LF Beilby, J Bell, GI Benediktsson, R Bergman, RN Boehm, BO Boerwinkle, E Bonnycastle, LL Burtt, N Cai, QY Campbell, H Carey, J Cauchi, S Caulfield, M Chan, JCN Chang, LC Chang, TJ Chang, YC Charpentier, G Chen, CH Chen, H Chen, YT Chia, KS Chidambaram, M Chines, PS Cho, NH Cho, YM Chuang, LM Collins, FS Cornelis, MC Couper, DJ Crenshaw, AT van Dam, RM Danesh, J Das, D de Faire, U Dedoussis, G Deloukas, P Dimas, AS Dina, C Doney, ASF Donnelly, PJ Dorkhan, M van Duijn, C Dupuis, J Edkins, S Elliott, P Emilsson, V Erbel, R Eriksson, JG Escobedo, J Esko, T Eury, E Florez, JC Fontanillas, P Forouhi, NG Forsen, T Fox, C Fraser, RM Frayling, TM Froguel, P Frossard, P Gao, YT Gertow, K Gieger, C Gigante, B Grallert, H Grant, GB Groop, LC Groves, CJ Grundberg, E Guiducci, C Hamsten, A Han, BG Hara, K Hassanali, N Hattersley, AT Hayward, C Hedman, AK Herder, C Hofman, A Holmen, OL Hovingh, K Hreidarsson, AB Hu, C Hu, FB Hui, J Humphries, SE Hunt, SE Hunter, DJ Hveem, K Hydrie, ZI Ikegami, H Illig, T Ingelsson, E Islam, M Isomaa, B Jackson, AU Jafar, T James, A Jia, WP Jockel, KH Jonsson, A Jowett, JBM Kadowaki, T Kang, HM Kanoni, S Kao, WHL Kathiresan, S Kato, N Katulanda, P Keinanen-Kiukaanniemi, SM Kelly, AM Khan, H Khaw, KT Khor, CC Kim, HL Kim, S Kim, YJ Kinnunen, L Klopp, N Kong, A Korpi-Hyovalti, E Kowlessur, S Kraft, P Kravic, J Kristensen, MM Krithika, S Kumar, A Kumate, J Kuusisto, J Kwak, SH Laakso, M Lagou, V Lakka, TA Langenberg, C Langford, C Lawrence, R Leander, K Lee, JM Lee, NR Li, M Li, XZ Li, Y Liang, JB Liju, S Lim, WY Lind, L Lindgren, CM Lindholm, E Liu, CT Liu, JJ Lobbens, S Long, JR Loos, RJF Lu, W Luan, JA Lyssenko, V Ma, RCW Maeda, S Magi, R Mannisto, S Matthews, DR Meigs, JB Melander, O Metspalu, A Meyer, J Mirza, G Mihailov, E Moebus, S Mohan, V Mohlke, KL Morris, AD Muhleisen, TW Muller-Nurasyid, M Musk, B Nakamura, J Nakashima, E Navarro, P Ng, PK Nica, AC Nilsson, PM Njolstad, I Nothen, MM Ohnaka, K Ong, TH Owen, KR Palmer, CNA Pankow, JS Park, KS Parkin, M Pechlivanis, S Pedersen, NL Peltonen, L Perry, JRB Peters, A Pinidiyapathirage, JM Platou, CGP Potter, S Price, JF Qi, L Radha, V Rallidis, L Rasheed, A Rathmann, W Rauramaa, R Raychaudhuri, S Rayner, NW Rees, SD Rehnberg, E Ripatti, S Robertson, N Roden, M Rossin, EJ Rudan, I Rybin, D Saaristo, TE Salomaa, V Saltevo, J Samuel, M Sanghera, DK Saramies, J Scott, J Scott, LJ Scott, RA Segre, AV Sehmi, J Sennblad, B Shah, N Shah, S Shera, AS Shu, XO Shuldiner, AR Sigurdsson, G Sijbrands, E Silveira, A Sim, X Sivapalaratnam, S Small, KS So, WY Stancakova, A Stefansson, K Steinbach, G Steinthorsdottir, V Stirrups, K Strawbridge, RJ Stringham, HM Sun, Q Suo, C Syvanen, AC Takayanagi, R Takeuchi, F Tay, WT Teslovich, TM Thorand, B Thorleifsson, G Thorsteinsdottir, U Tikkanen, E Trakalo, J Tremoli, E Trip, MD Tsai, FJ Tuomi, T Tuomilehto, J Uitterlinden, AG Valladares-Salgado, A Vedantam, S Veglia, F Voight, BF Wang, CR Wareham, NJ Wennauer, R Wickremasinghe, AR Wilsgaard, T Wilson, JF Wiltshire, S Winckler, W Wong, TY Wood, AR Wu, JY Wu, Y Yamamoto, K Yamauchi, T Yang, MY Yengo, L Yokota, M Young, R Zabaneh, D Zhang, F Zhang, R Zheng, W Zimmet, PZ Altshuler, D Bowden, DW Cho, YS Cox, NJ Cruz, M Hanis, CL Kooner, J Lee, JY Seielstad, M Teo, YY Boehnke, M Parra, EJ Chambers, JC Tai, ES McCarthy, MI Morris, AP AF Mahajan, Anubha Go, Min Jin Zhang, Weihua Below, Jennifer E. Gaulton, Kyle J. Ferreira, Teresa Horikoshi, Momoko Johnson, Andrew D. Ng, Maggie C. Y. Prokopenko, Inga Saleheen, Danish Wang, Xu Zeggini, Eleftheria Abecasis, Goncalo R. Adair, Linda S. Almgren, Peter Atalay, Mustafa Aung, Tin Baldassarre, Damiano Balkau, Beverley Bao, Yuqian Barnett, Anthony H. Barroso, Ines Basit, Abdul Been, Latonya F. Beilby, John Bell, Graeme I. Benediktsson, Rafn Bergman, Richard N. Boehm, Bernhard O. Boerwinkle, Eric Bonnycastle, Lori L. Burtt, Noel Cai, Qiuyin Campbell, Harry Carey, Jason Cauchi, Stephane Caulfield, Mark Chan, Juliana C. N. Chang, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Charpentier, Guillaume Chen, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chia, Kee-Seng Chidambaram, Manickam Chines, Peter S. Cho, Nam H. Cho, Young Min Chuang, Lee-Ming Collins, Francis S. Cornelis, Marilyn C. Couper, David J. Crenshaw, Andrew T. van Dam, Rob M. Danesh, John Das, Debashish de Faire, Ulf Dedoussis, George Deloukas, Panos Dimas, Antigone S. Dina, Christian Doney, Alex S. F. Donnelly, Peter J. Dorkhan, Mozhgan van Duijn, Cornelia Dupuis, Josee Edkins, Sarah Elliott, Paul Emilsson, Valur Erbel, Raimund Eriksson, Johan G. Escobedo, Jorge Esko, Tonu Eury, Elodie Florez, Jose C. Fontanillas, Pierre Forouhi, Nita G. Forsen, Tom Fox, Caroline Fraser, Ross M. Frayling, Timothy M. Froguel, Philippe Frossard, Philippe Gao, Yutang Gertow, Karl Gieger, Christian Gigante, Bruna Grallert, Harald Grant, George B. Groop, Leif C. Groves, Christopher J. Grundberg, Elin Guiducci, Candace Hamsten, Anders Han, Bok-Ghee Hara, Kazuo Hassanali, Neelam Hattersley, Andrew T. Hayward, Caroline Hedman, Asa K. Herder, Christian Hofman, Albert Holmen, Oddgeir L. Hovingh, Kees Hreidarsson, Astradur B. Hu, Cheng Hu, Frank B. Hui, Jennie Humphries, Steve E. Hunt, Sarah E. Hunter, David J. Hveem, Kristian Hydrie, Zafar I. Ikegami, Hiroshi Illig, Thomas Ingelsson, Erik Islam, Muhammed Isomaa, Bo Jackson, Anne U. Jafar, Tazeen James, Alan Jia, Weiping Joeckel, Karl-Heinz Jonsson, Anna Jowett, Jeremy B. M. Kadowaki, Takashi Kang, Hyun Min Kanoni, Stavroula Kao, Wen Hong L. Kathiresan, Sekar Kato, Norihiro Katulanda, Prasad Keinanen-Kiukaanniemi, Sirkka M. Kelly, Ann M. Khan, Hassan Khaw, Kay-Tee Khor, Chiea-Chuen Kim, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kinnunen, Leena Klopp, Norman Kong, Augustine Korpi-Hyovalti, Eeva Kowlessur, Sudhir Kraft, Peter Kravic, Jasmina Kristensen, Malene M. Krithika, S. Kumar, Ashish Kumate, Jesus Kuusisto, Johanna Kwak, Soo Heon Laakso, Markku Lagou, Vasiliki Lakka, Timo A. Langenberg, Claudia Langford, Cordelia Lawrence, Robert Leander, Karin Lee, Jen-Mai Lee, Nanette R. Li, Man Li, Xinzhong Li, Yun Liang, Junbin Liju, Samuel Lim, Wei-Yen Lind, Lars Lindgren, Cecilia M. Lindholm, Eero Liu, Ching-Ti Liu, Jian Jun Lobbens, Stephane Long, Jirong Loos, Ruth J. F. Lu, Wei Luan, Jian'an Lyssenko, Valeriya Ma, Ronald C. W. Maeda, Shiro Maegi, Reedik Mannisto, Satu Matthews, David R. Meigs, James B. Melander, Olle Metspalu, Andres Meyer, Julia Mirza, Ghazala Mihailov, Evelin Moebus, Susanne Mohan, Viswanathan Mohlke, Karen L. Morris, Andrew D. Muehleisen, Thomas W. Mueller-Nurasyid, Martina Musk, Bill Nakamura, Jiro Nakashima, Eitaro Navarro, Pau Peng-Keat Ng Nica, Alexandra C. Nilsson, Peter M. Njolstad, Inger Noethen, Markus M. Ohnaka, Keizo Ong, Twee Hee Owen, Katharine R. Palmer, Colin N. A. Pankow, James S. Park, Kyong Soo Parkin, Melissa Pechlivanis, Sonali Pedersen, Nancy L. Peltonen, Leena Perry, John R. B. Peters, Annette Pinidiyapathirage, Janani M. Platou, Carl G. P. Potter, Simon Price, Jackie F. Qi, Lu Radha, Venkatesan Rallidis, Loukianos Rasheed, Asif Rathmann, Wolfgang Rauramaa, Rainer Raychaudhuri, Soumya Rayner, N. William Rees, Simon D. Rehnberg, Emil Ripatti, Samuli Robertson, Neil Roden, Michael Rossin, Elizabeth J. Rudan, Igor Rybin, Denis Saaristo, Timo E. Salomaa, Veikko Saltevo, Juha Samuel, Maria Sanghera, Dharambir K. Saramies, Jouko Scott, James Scott, Laura J. Scott, Robert A. Segre, Ayellet V. Sehmi, Joban Sennblad, Bengt Shah, Nabi Shah, Sonia Shera, A. Samad Shu, Xiao Ou Shuldiner, Alan R. Sigurdsson, Gunnar Sijbrands, Eric Silveira, Angela Sim, Xueling Sivapalaratnam, Suthesh Small, Kerrin S. So, Wing Yee Stancakova, Alena Stefansson, Kari Steinbach, Gerald Steinthorsdottir, Valgerdur Stirrups, Kathleen Strawbridge, Rona J. Stringham, Heather M. Sun, Qi Suo, Chen Syvanen, Ann-Christine Takayanagi, Ryoichi Takeuchi, Fumihiko Tay, Wan Ting Teslovich, Tanya M. Thorand, Barbara Thorleifsson, Gudmar Thorsteinsdottir, Unnur Tikkanen, Emmi Trakalo, Joseph Tremoli, Elena Trip, Mieke D. Tsai, Fuu Jen Tuomi, Tiinamaija Tuomilehto, Jaakko Uitterlinden, Andre G. Valladares-Salgado, Adan Vedantam, Sailaja Veglia, Fabrizio Voight, Benjamin F. Wang, Congrong Wareham, Nicholas J. Wennauer, Roman Wickremasinghe, Ananda R. Wilsgaard, Tom Wilson, James F. Wiltshire, Steven Winckler, Wendy Wong, Tien Yin Wood, Andrew R. Wu, Jer-Yuarn Wu, Ying Yamamoto, Ken Yamauchi, Toshimasa Yang, Mingyu Yengo, Loic Yokota, Mitsuhiro Young, Robin Zabaneh, Delilah Zhang, Fan Zhang, Rong Zheng, Wei Zimmet, Paul Z. Altshuler, David Bowden, Donald W. Cho, Yoon Shin Cox, Nancy J. Cruz, Miguel Hanis, Craig L. Kooner, Jaspal Lee, Jong-Young Seielstad, Mark Teo, Yik Ying Boehnke, Michael Parra, Esteban J. Chambers, John C. Tai, E. Shyong McCarthy, Mark I. Morris, Andrew P. CA DIAbet Genetics Replication & Meta Asian Genetic Epidemiology Network South Asian Type Diabet SAT2D Cons Mexican Amer Type 2 Diabet MAT2D C Type 2 Diabet Genetic Exploration TI Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility SO NATURE GENETICS LA English DT Article ID SCALE ASSOCIATION ANALYSIS; TRANSETHNIC METAANALYSIS; GLUCOSE-HOMEOSTASIS; LOCI; VARIANTS; POPULATIONS; MAP; INDIVIDUALS; IMPUTATION; CHROMATIN AB To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. C1 [Mahajan, Anubha; Gaulton, Kyle J.; Ferreira, Teresa; Horikoshi, Momoko; Prokopenko, Inga; Dimas, Antigone S.; Donnelly, Peter J.; Hedman, Asa K.; Ingelsson, Erik; Kumar, Ashish; Lagou, Vasiliki; Lindgren, Cecilia M.; Mirza, Ghazala; Perry, John R. B.; Rayner, N. William; Robertson, Neil; Trakalo, Joseph; Wiltshire, Steven; McCarthy, Mark I.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Go, Min Jin; Han, Bok-Ghee; Kim, Young Jin; Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Gangoe Myeon, Yeonje Ri, South Korea. [Zhang, Weihua; Boehm, Bernhard O.; Elliott, Paul; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Below, Jennifer E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Horikoshi, Momoko; Prokopenko, Inga; Groves, Christopher J.; Hassanali, Neelam; Katulanda, Prasad; Matthews, David R.; Owen, Katharine R.; Rayner, N. William; Robertson, Neil; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Johnson, Andrew D.; Dupuis, Josee; Fox, Caroline] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ng, Maggie C. Y.; Bowden, Donald W.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Ng, Maggie C. Y.; Bowden, Donald W.] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA. [Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Saleheen, Danish; Danesh, John; Khan, Hassan; Khaw, Kay-Tee; Young, Robin] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Saleheen, Danish; Frossard, Philippe; Rasheed, Asif; Samuel, Maria; Shah, Nabi] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan. [Wang, Xu; Chia, Kee-Seng; Lee, Jen-Mai; Peng-Keat Ng; Ong, Twee Hee; Teo, Yik Ying; Tai, E. Shyong] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore. [Zeggini, Eleftheria; Barroso, Ines; Deloukas, Panos; Edkins, Sarah; Hunt, Sarah E.; Kanoni, Stavroula; Langford, Cordelia; Peltonen, Leena; Potter, Simon; Ripatti, Samuli; Small, Kerrin S.; Stirrups, Kathleen] Wellcome Trust Sanger Inst, Cambridge, England. [Abecasis, Goncalo R.; Jackson, Anne U.; Kang, Hyun Min; Scott, Laura J.; Sim, Xueling; Stringham, Heather M.; Teslovich, Tanya M.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Almgren, Peter; Dorkhan, Mozhgan; Groop, Leif C.; Jonsson, Anna; Kravic, Jasmina; Lindholm, Eero; Lyssenko, Valeriya; Melander, Olle; Nilsson, Peter M.] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden. [Atalay, Mustafa; Lakka, Timo A.] Univ Eastern Finland, Inst Biomed, Kuopio, Finland. [Aung, Tin; Khor, Chiea-Chuen; Tay, Wan Ting; Wong, Tien Yin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Aung, Tin; Wong, Tien Yin] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Baldassarre, Damiano; Tremoli, Elena; Veglia, Fabrizio] IRCCS, Ctr Cardiol Monzino, Milan, Italy. [Baldassarre, Damiano; Tremoli, Elena] Univ Milan, Dept Pharmacol Sci, Milan, Italy. [Balkau, Beverley] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France. [Balkau, Beverley] Univ Paris 11, UMRS 1018, Villejuif, France. [Bao, Yuqian; Hu, Cheng; Jia, Weiping; Wang, Congrong; Zhang, Rong] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Shanghai 200030, Peoples R China. [Barnett, Anthony H.; Kelly, Ann M.; Rees, Simon D.] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England. [Barnett, Anthony H.; Kelly, Ann M.; Rees, Simon D.] Heart England Natl Hlth Serv NHS Fdn Trust, Ctr Biomed Res, Birmingham, W Midlands, England. [Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England. [Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England. [Basit, Abdul; Hydrie, Zafar I.] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan. [Been, Latonya F.; Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA. [Beilby, John; Hui, Jennie; James, Alan; Musk, Bill] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia. [Beilby, John] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia. [Beilby, John] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia. [Bell, Graeme I.; Cox, Nancy J.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Bell, Graeme I.; Cox, Nancy J.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Benediktsson, Rafn; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Benediktsson, Rafn; Hreidarsson, Astradur B.; Sigurdsson, Gunnar] Landspitali Univ Hosp, Reykjavik, Iceland. [Bergman, Richard N.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA. [Boehm, Bernhard O.] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany. [Boehm, Bernhard O.] Nanyang Technol Univ, Lee Kong Chian LKC Sch Med, Singapore 639798, Singapore. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Bonnycastle, Lori L.; Chines, Peter S.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Burtt, Noel; Carey, Jason; Crenshaw, Andrew T.; Fontanillas, Pierre; Grant, George B.; Guiducci, Candace; Kathiresan, Sekar; Lindgren, Cecilia M.; Parkin, Melissa; Peltonen, Leena; Raychaudhuri, Soumya; Rossin, Elizabeth J.; Segre, Ayellet V.; Voight, Benjamin F.; Winckler, Wendy; Altshuler, David] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA. [Cai, Qiuyin; Long, Jirong; Shu, Xiao Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37212 USA. [Campbell, Harry; Fraser, Ross M.; Price, Jackie F.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Campbell, Harry; Hayward, Caroline; Navarro, Pau; Wilson, James F.] Univ Edinburgh, Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Cauchi, Stephane; Eury, Elodie; Froguel, Philippe; Lobbens, Stephane; Yengo, Loic] CNRS, Unite Mixte Rech UMR 8199, Inst Biol, Lille, France. [Cauchi, Stephane; Eury, Elodie; Froguel, Philippe; Lobbens, Stephane; Yengo, Loic] Univ Lille 2, Inst Pasteur, Lille, France. [Caulfield, Mark] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England. [Caulfield, Mark] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England. [Chan, Juliana C. N.; Ma, Ronald C. W.; So, Wing Yee] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Chang, Li-Ching; Chen, Chien-Hsiun; Chen, Yuan-Tsong; Wu, Jer-Yuarn] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Chang, Tien-Jyun; Chang, Yi-Cheng; Chuang, Lee-Ming] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Charpentier, Guillaume] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France. [Chen, Chien-Hsiun; Tsai, Fuu Jen; Wu, Jer-Yuarn] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Chen, Han; Dupuis, Josee; Liu, Ching-Ti] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chia, Kee-Seng; Khor, Chiea-Chuen; Lim, Wei-Yen; Sim, Xueling; Suo, Chen; Teo, Yik Ying] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Chidambaram, Manickam; Liju, Samuel; Mohan, Viswanathan; Radha, Venkatesan] Indian Council Med Res, Adv Ctr Genom Diabet, Madras Diabet Res Fdn, Dept Mol Genet, Madras, Tamil Nadu, India. [Cho, Nam H.] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 441749, South Korea. [Cho, Young Min; Kwak, Soo Heon; Park, Kyong Soo] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. [Chuang, Lee-Ming; Maeda, Shiro] Natl Taiwan Univ, Sch Med, Grad Inst Clin Med, Taipei 10764, Taiwan. [Cornelis, Marilyn C.; van Dam, Rob M.; Hu, Frank B.; Hunter, David J.; Kraft, Peter; Qi, Lu; Sun, Qi] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Das, Debashish; Sehmi, Joban; Kooner, Jaspal; Chambers, John C.] Ealing Hosp NHS Trust, Southall, Middx, England. [de Faire, Ulf; Gigante, Bruna; Leander, Karin] Karolinska Inst, Inst Environm Med, Divis Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Dimas, Antigone S.; Nica, Alexandra C.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Dimas, Antigone S.] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece. [Dina, Christian] INSERM, UMR 1087, Nantes, France. [Dina, Christian] CNRS, UMR 6291, Nantes, France. [Dina, Christian] Univ Nantes, Nantes, France. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland. [Donnelly, Peter J.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [van Duijn, Cornelia; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [van Duijn, Cornelia; Uitterlinden, Andre G.] Netherlands Consortium Healthy Ageing, Netherland Genom Initiat, Rotterdam, Netherlands. [van Duijn, Cornelia; Uitterlinden, Andre G.] Ctr Med Syst Biol, Rotterdam, Netherlands. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England. [Emilsson, Valur; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Erbel, Raimund] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany. [Eriksson, Johan G.; Mannisto, Satu; Peltonen, Leena; Ripatti, Samuli; Salomaa, Veikko; Tikkanen, Emmi] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Eriksson, Johan G.; Forsen, Tom] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.; Isomaa, Bo; Tuomi, Tiinamaija] Folkhalsan Res Ctr, Helsinki, Finland. [Escobedo, Jorge] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico. [Esko, Tonu; Maegi, Reedik; Metspalu, Andres; Mihailov, Evelin] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Esko, Tonu; Florez, Jose C.; Rossin, Elizabeth J.; Vedantam, Sailaja] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Esko, Tonu; Florez, Jose C.; Vedantam, Sailaja] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Florez, Jose C.; Meigs, James B.; Segre, Ayellet V.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.; Kathiresan, Sekar; Segre, Ayellet V.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Forouhi, Nita G.; Langenberg, Claudia; Loos, Ruth J. F.; Luan, Jian'an; Scott, Robert A.; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Forsen, Tom] Vaasa Hlth Care Ctr, Vaasa, Finland. [Fox, Caroline] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline; Hu, Frank B.; Hunter, David J.; Qi, Lu; Sun, Qi] Harvard Univ, Sch Med, Boston, MA USA. [Frayling, Timothy M.; Perry, John R. B.; Wood, Andrew R.] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Gao, Yutang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Gertow, Karl; Hamsten, Anders; Sennblad, Bengt; Silveira, Angela; Strawbridge, Rona J.] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden. [Gertow, Karl; Hamsten, Anders; Sennblad, Bengt; Silveira, Angela; Strawbridge, Rona J.] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden. [Gieger, Christian; Meyer, Julia; Mueller-Nurasyid, Martina] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany. [Grallert, Harald; Illig, Thomas; Klopp, Norman] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Grallert, Harald] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany. [Grallert, Harald] Helmholtz Zentrum Muenchen, Munich, Germany. [Grallert, Harald] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany. [Grallert, Harald] German Ctr Diabet Res DZD, Neuherberg, Germany. [Grundberg, Elin; Small, Kerrin S.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Hara, Kazuo; Kadowaki, Takashi; Yamauchi, Toshimasa] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan. [Hattersley, Andrew T.] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. [Herder, Christian; Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Holmen, Oddgeir L.; Hveem, Kristian; Platou, Carl G. P.] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway. [Hovingh, Kees; Sivapalaratnam, Suthesh; Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Hu, Frank B.; Hunter, David J.; Qi, Lu; Sun, Qi] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hui, Jennie; Musk, Bill] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia. [Humphries, Steve E.] UCL, Inst Cardiovasc Sci, London, England. [Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Ikegami, Hiroshi] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan. [Illig, Thomas; Klopp, Norman] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Ingelsson, Erik] Univ Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Islam, Muhammed; Jafar, Tazeen] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari, Finland. [Jafar, Tazeen] Aga Khan Univ, Dept Med, Karachi, Pakistan. [James, Alan] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia. [James, Alan; Musk, Bill] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia. [Joeckel, Karl-Heinz; Moebus, Susanne; Pechlivanis, Sonali] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Jowett, Jeremy B. M.; Kristensen, Malene M.; Zimmet, Paul Z.] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia. [Kao, Wen Hong L.; Li, Man] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kato, Norihiro; Takeuchi, Fumihiko] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan. [Katulanda, Prasad] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka. [Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland. [Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland. [Khor, Chiea-Chuen; Liu, Jian Jun; Seielstad, Mark; Teo, Yik Ying] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore. [Kim, Hyung-Lae] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea. [Kim, Sangsoo] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea. [Kinnunen, Leena; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Kong, Augustine; Stefansson, Kari; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Korpi-Hyovalti, Eeva] South Ostrobothnia Cent Hosp, Seinajoki, Finland. [Kowlessur, Sudhir] Minist Hlth, Port Louis, Mauritius. [Krithika, S.; Parra, Esteban J.] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada. [Kumate, Jesus] Fdn IMSS, Mexico City, DF, Mexico. [Kuusisto, Johanna; Laakso, Markku; Stancakova, Alena] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku; Stancakova, Alena] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Lakka, Timo A.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Kuopio, Finland. [Lawrence, Robert] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia. [Lee, Nanette R.] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines. [Li, Xinzhong; Scott, James; Sehmi, Joban; Kooner, Jaspal] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Li, Yun; Mohlke, Karen L.; Wu, Ying] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Liang, Junbin; Yang, Mingyu; Zhang, Fan] Beijing Genom Inst, Shenzhen, Peoples R China. [Lind, Lars] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden. [Loos, Ruth J. F.] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA. [Loos, Ruth J. F.] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA. [Loos, Ruth J. F.] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA. [Lu, Wei] Shanghai Inst Prevent Med, Shanghai, Peoples R China. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Mohan, Viswanathan] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Musk, Bill] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Nakamura, Jiro; Nakashima, Eitaro] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan. [Nakashima, Eitaro] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan. [Njolstad, Inger; Wilsgaard, Tom] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Ohnaka, Keizo] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan. [Owen, Katharine R.; McCarthy, Mark I.] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Park, Kyong Soo] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea. [Park, Kyong Soo] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Pedersen, Nancy L.; Rehnberg, Emil] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Peltonen, Leena; Ripatti, Samuli; Tikkanen, Emmi] Inst Mol Med Finland FIMM, Helsinki, Finland. [Peters, Annette; Thorand, Barbara] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany. [Pinidiyapathirage, Janani M.; Wickremasinghe, Ananda R.] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka. [Platou, Carl G. P.] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway. [Rallidis, Loukianos] Univ Gen Hosp Attikon, Athens, Greece. [Rathmann, Wolfgang] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany. [Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland. [Raychaudhuri, Soumya] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Partners Ctr Personalized Genom Med, Boston, MA USA. [Roden, Michael] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany. [Roden, Michael] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany. [Rossin, Elizabeth J.] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA. [Rossin, Elizabeth J.] MIT, Boston, MA USA. [Rossin, Elizabeth J.] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA. [Rybin, Denis] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Saaristo, Timo E.] Finnish Diabet Assoc, Tampere, Finland. [Saaristo, Timo E.] Pirkanmaa Hosp Dist, Tampere, Finland. [Saltevo, Juha] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland. [Saramies, Jouko] South Karelia Cent Hosp, Lappeenranta, Finland. [Shah, Sonia; Zabaneh, Delilah] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England. [Shera, A. Samad] Diabet Assoc Pakistan, Karachi, Pakistan. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA. [Sijbrands, Eric; Uitterlinden, Andre G.; Wennauer, Roman] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Steinbach, Gerald] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany. [Steinbach, Gerald] Univ Ulm, Cent Lab, D-89069 Ulm, Germany. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan. [Tuomi, Tiinamaija] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland. [Tuomilehto, Jaakko] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia. [Valladares-Salgado, Adan; Cruz, Miguel] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico. [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Wong, Tien Yin] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Yamamoto, Ken] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan. [Yengo, Loic] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France. [Yokota, Mitsuhiro] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Bowden, Donald W.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA. [Bowden, Donald W.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Cho, Yoon Shin] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea. [Hanis, Craig L.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Kooner, Jaspal; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London, England. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Seielstad, Mark] Blood Syst Res Inst, San Francisco, CA USA. [Teo, Yik Ying] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. RP Boehnke, M (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. EM boehnke@umich.edu; esteban.parra@utoronto.ca; john.chambers@imperial.ac.uk; e_shyong_tai@nuhs.edu.sg; mark.mccarthy@drl.ox.ac.uk; a.p.morris@liverpool.ac.uk RI Kinnunen, Leena/B-7059-2012; Prokopenko, Inga/H-3241-2014; Thorand, Barbara/B-5349-2014; Chan, Juliana /B-7918-2016; Peters, Annette/A-6117-2011; Rudan, Igor/I-1467-2012; Veglia, Fabrizio/K-1958-2016; Study, GoDARTS/K-9448-2016; Hayward, Caroline/M-8818-2016; Johnson, Andrew/G-6520-2013; Leander, Karin/C-7261-2017; Ma, Ronald/C-2788-2009; Yengo, Loic/D-2692-2017; Baldassarre, Damiano/J-3295-2016; Shah, Sonia/N-7547-2013; Palmer, Colin/C-7053-2008; Deloukas, Panos/B-2922-2013; Strawbridge, Rona/H-5422-2012; Jia, Weiping/B-7483-2012; Dina, Christian/D-3535-2015; Hu, Cheng/C-3346-2008; Boehm, Bernhard/F-8750-2015; Kwak, Soo Heon/H-1463-2011; Grallert, Harald/B-3424-2013; Tsai, Fuu-Jen/J-4140-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; OI Kumar, Ashish/0000-0002-7075-5930; Fraser, Ross/0000-0003-0488-2592; Kinnunen, Leena/0000-0001-8739-4812; van Dam, Rob/0000-0002-7354-8734; Gigante, Bruna/0000-0003-4508-7990; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Zeggini, Eleftheria/0000-0003-4238-659X; Manickam, Chidambaram/0000-0001-8750-8576; Prokopenko, Inga/0000-0003-1624-7457; Thorand, Barbara/0000-0002-8416-6440; Chan, Juliana /0000-0003-1325-1194; Rudan, Igor/0000-0001-6993-6884; Veglia, Fabrizio/0000-0002-9378-8874; Hayward, Caroline/0000-0002-9405-9550; Leander, Karin/0000-0002-1404-9222; Ma, Ronald/0000-0002-1227-803X; Yengo, Loic/0000-0002-4272-9305; Baldassarre, Damiano/0000-0002-2766-8882; Shah, Sonia/0000-0001-5860-4526; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Strawbridge, Rona/0000-0001-8506-3585; Dina, Christian/0000-0002-7722-7348; Kwak, Soo Heon/0000-0003-1230-0919; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Hydrie, Muhammad/0000-0002-1317-6975; Magi, Reedik/0000-0002-2964-6011; Sijbrands, Eric/0000-0001-8857-7389; Rybin, Denis/0000-0002-3657-4829; Chang, Yi-Cheng/0000-0002-8077-5011; Pinidiyapathirage, Mohitha/0000-0003-2947-3015; Seielstad, Mark/0000-0001-5783-1401; CHANG, TIEN-JYUN/0000-0001-9437-5847; TREMOLI, ELENA/0000-0002-0929-6106; Hedman, Asa/0000-0001-5413-204X; Nothen, Markus/0000-0002-8770-2464; Chen, Han/0000-0002-9510-4923; Tuomi, Tiinamaija/0000-0002-8306-6202; Navarro, Pau/0000-0001-5576-8584; Khor, Chiea Chuen/0000-0002-1128-4729; Eriksson, Johan/0000-0002-2516-2060; Pankow, James/0000-0001-7076-483X; Hattersley, Andrew/0000-0001-5620-473X; Tai, E Shyong/0000-0003-2929-8966; Lakka, Timo/0000-0002-9199-2871; CHUANG, LEE-MING/0000-0003-0978-2662; Forouhi, Nita/0000-0002-5041-248X; parra, esteban J/0000-0002-2057-8577; Small, Kerrin/0000-0003-4566-0005 FU Canadian Institutes of Health Research; European Commission (ENGAGE FP7) [HEALTH-F4-2007-201413]; Medical Research Council UK [G0601261]; Mexico Convocatoria [SSA/IMMS/ISSSTE-CONACYT 2012-2, clave 150352, IMSS R-2011-785-018, CONACYT Salud-2007-C01-71068]; US National Institutes of Health [DK062370, HG000376, DK085584, DK085545, DK073541, DK085501]; Wellcome Trust [WT098017, WT090532, WT090367, WT098381, WT081682, WT085475] FX Funding for the research undertaken in this study has been received from the following: the Canadian Institutes of Health Research; the European Commission (ENGAGE FP7 HEALTH-F4-2007-201413); the Medical Research Council UK (G0601261); the Mexico Convocatoria (SSA/IMMS/ISSSTE-CONACYT 2012-2, clave 150352, IMSS R-2011-785-018 and CONACYT Salud-2007-C01-71068); the US National Institutes of Health (DK062370, HG000376, DK085584, DK085545, DK073541 and DK085501); and the Wellcome Trust (WT098017, WT090532, WT090367, WT098381, WT081682 and WT085475). We acknowledge the many colleagues who contributed to collection and phenotypic characterization of the clinical samples and the genotyping and analysis of the GWAS data, full details of which are provided in the contributing consortia papers5,11,13,15. We also thank those individuals who agreed to participate in this study. NR 51 TC 207 Z9 208 U1 18 U2 119 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 MAR PY 2014 VL 46 IS 3 BP 234 EP + DI 10.1038/ng.2897 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AB8JR UT WOS:000332036700007 ER PT J AU Bachelerie, F Graham, GJ Locati, M Mantovani, A Murphy, PM Nibbs, R Rot, A Sozzani, S Thelen, M AF Bachelerie, Francoise Graham, Gerard J. Locati, Massimo Mantovani, Alberto Murphy, Philip M. Nibbs, Robert Rot, Antal Sozzani, Silvano Thelen, Marcus TI New nomenclature for atypical chemokine receptors SO NATURE IMMUNOLOGY LA English DT Letter ID BETA-ARRESTIN; CCX-CKR; SEQUESTRATION; INFLAMMATION; MIGRATION C1 [Bachelerie, Francoise] Univ Paris 11, INSERM, UMR S996, Lab Excellence Res Medicat & Innovat Therapeut, Clamart, France. [Graham, Gerard J.; Nibbs, Robert] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Biomed Res Ctr, Glasgow, Lanark, Scotland. [Locati, Massimo; Mantovani, Alberto] Univ Milan, Milan, Italy. [Locati, Massimo; Mantovani, Alberto; Sozzani, Silvano] Humanitas Clin & Res Inst, Rozzano, Italy. [Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Rot, Antal] Univ Birmingham, MRC, Ctr Immune Regulat, Inst Biomed Res,Sch Infect & Immun, Birmingham, W Midlands, England. [Sozzani, Silvano] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy. [Thelen, Marcus] Inst Res Biomed, Bellinzona, Switzerland. RP Bachelerie, F (reprint author), Univ Paris 11, INSERM, UMR S996, Lab Excellence Res Medicat & Innovat Therapeut, Clamart, France. EM alberto.mantovani@humanitasresearch.it RI BACHELERIE, FRANCOISE/F-8823-2013; OI Locati, Massimo/0000-0003-3077-590X; Mantovani, Alberto/0000-0001-5578-236X; Sozzani, Silvano/0000-0002-3144-8743 FU Medical Research Council [G0901113, G0802838]; Wellcome Trust [099251] NR 16 TC 36 Z9 38 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2014 VL 15 IS 3 BP 207 EP 208 PG 2 WC Immunology SC Immunology GA AB3HY UT WOS:000331683100001 PM 24549061 ER PT J AU Bell, BD Kitajima, M Larson, RP Stoklasek, TA Dang, K Sakamoto, K Wagner, KU Kaplan, DH Reizis, B Hennighausen, L Ziegler, SF AF Bell, Bryan D. Kitajima, Masayuki Larson, Ryan P. Stoklasek, Thomas A. Dang, Kristen Sakamoto, Kazuhito Wagner, Kay-Uwe Kaplan, Daniel H. Reizis, Boris Hennighausen, Lothar Ziegler, Steven F. TI The transcription factor STAT5 is critical in dendritic cells for the development of T(H)2 but not T(H)1 responses (vol 14, pg 364, 2013) SO NATURE IMMUNOLOGY LA English DT Correction C1 [Bell, Bryan D.; Kitajima, Masayuki; Larson, Ryan P.; Stoklasek, Thomas A.; Dang, Kristen; Ziegler, Steven F.] Benaroya Res Inst Virginia Mason, Program Immunol, Seattle, WA 98101 USA. [Bell, Bryan D.; Kitajima, Masayuki; Larson, Ryan P.; Stoklasek, Thomas A.; Ziegler, Steven F.] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98195 USA. [Sakamoto, Kazuhito; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. [Kaplan, Daniel H.] Univ Minnesota, Dept Dermatol, Ctr Immunol, Minneapolis, MN 55455 USA. [Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY USA. [Hennighausen, Lothar] US Natl Inst Hlth, Lab Genet & Physiol, Bethesda, MD USA. RP Ziegler, SF (reprint author), Benaroya Res Inst Virginia Mason, Program Immunol, Seattle, WA 98101 USA. EM sziegler@benaroyaresearch.org RI Kaplan, Daniel/N-2779-2013 OI Kaplan, Daniel/0000-0002-7851-7320 NR 1 TC 0 Z9 0 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2014 VL 15 IS 3 BP 305 EP 305 PG 1 WC Immunology SC Immunology GA AB3HY UT WOS:000331683100016 ER PT J AU Zou, P Stern, ST Sun, DX AF Zou, Peng Stern, Stephan T. Sun, Duxin TI PLGA/Liposome Hybrid Nanoparticles for Short-Chain Ceramide Delivery SO PHARMACEUTICAL RESEARCH LA English DT Article DE ceramide; FRET; liposome; PLGA; premature release ID BREAST-CANCER CELLS; IN-VIVO; LIPOSOMES; VITRO; APOPTOSIS; RELEASE; PHARMACOKINETICS; FORMULATION; RETENTION; MEMBRANES AB Rapid premature release of lipophilic drugs from liposomal lipid bilayer to plasma proteins and biological membranes is a challenge for targeted drug delivery. The purpose of this study is to reduce premature release of lipophilic short-chain ceramides by encapsulating ceramides into liposomal aqueous interior with the aid of poly (lactic-coglycolicacid) (PLGA). BODIPY FL labeled ceramide (FL-ceramide) and BODIPY-TR labeled ceramide (TR-ceramide) were encapsulated into carboxy-terminated PLGA nanoparticles. The negatively charged PLGA nanoparticles were then encapsulated into cationic liposomes to obtain PLGA/liposome hybrids. As a control, FL-ceramide and/or TR ceramide co-loaded liposomes without PLGA were prepared. The release of ceramides from PLGA/liposome hybrids and liposomes in rat plasma, cultured MDA-MB-231 cells, and rat blood circulation was compared using fluorescence resonance energy transfer (FRET) between FL-ceramide (donor) and TR-ceramide (acceptor). FRET analysis showed that FL-ceramide and TR-ceramide in liposomal lipid bilayer were rapidly released during incubation with rat plasma. In contrast, the FL-ceramide and TR-ceramide in PLGA/liposome hybrids showed extended release. FRET images of cells revealed that ceramides in liposomal bilayer were rapidly transferred to cell membranes. In contrast, ceramides in PLGA/liposome hybrids were internalized into cells with nanoparticles simultaneously. Upon intravenous administration to rats, ceramides encapsulated in liposomal bilayer were completely released in 2 min. In contrast, ceramides encapsulated in the PLGA core were retained in PLGA/liposome hybrids for 4 h. The PLGA/liposome hybrid nanoparticles reduced in vitro and in vivo premature release of ceramides and offer a viable platform for targeted delivery of lipophilic drugs. C1 [Zou, Peng; Sun, Duxin] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48108 USA. [Stern, Stephan T.] NCI, Nanotechnol Characterizat Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Sun, Duxin] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA. RP Sun, DX (reprint author), Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Room 2020,428 Church St, Ann Arbor, MI 48109 USA. EM duxins@umich.edu RI Nanotechnology Characterization Lab, NCL/K-8454-2012; Zou, Peng/J-9300-2015 FU National Institutes of Health [RO1 CA120023, R21 CA143474]; University of Michigan Cancer Center Research Grant; University of Michigan Cancer Center Core Grant FX This work was partially supported by the National Institutes of Health (RO1 CA120023 and R21 CA143474); University of Michigan Cancer Center Research Grant (Munn); and University of Michigan Cancer Center Core Grant to DS. NR 33 TC 6 Z9 6 U1 1 U2 31 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD MAR PY 2014 VL 31 IS 3 BP 684 EP 693 DI 10.1007/s11095-013-1190-5 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AB7ZB UT WOS:000332008800012 PM 24065591 ER PT J AU Keller, KL Vollrath-Smith, FR Jafari, M Ikemoto, S AF Keller, Kristine L. Vollrath-Smith, Fiori R. Jafari, Mehrnoosh Ikemoto, Satoshi TI Synergistic interaction between caloric restriction and amphetamine in food-unrelated approach behavior of rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Dietary restriction; Incentive motivation; Manic-depressive illness; Visual sensation; Drug abuse; Amphetamine; Lithium ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CHRONIC LITHIUM TREATMENT; CONDITIONED REINFORCEMENT; SELF-STIMULATION; BRAIN-STIMULATION; LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; VENTRAL STRIATUM; BIPOLAR DISORDER; REWARD-SEEKING AB Approach behavior is regulated by the brain integrating information about environment and body state. Psychoactive drugs interact with this process. We examined the extent to which caloric (i.e., food) restriction, amphetamine (AMPH) and lithium interact in potentiating locomotor activity and responding reinforced by visual stimulus (VS), a reward unrelated to energy homeostasis. Rats either had ad libitum access to food or received daily rations that maintained 85-90 % of their original body weights. Leverpressing turned on a cue light for 1 s and turned off house light for 5 s. AMPH and lithium were administered through intraperitoneal injections and diet, respectively. Food restriction or AMPH (1 mg/kg) alone had little effect on VS-reinforced responding; however, the combination of the two conditions markedly potentiated VS-reinforced responding (fourfold). Food restriction lasting 7 days or longer was needed to augment AMPH's effect on VS-reinforced responding. AMPH (0.3-3 mg/kg) potentiated locomotor activity similarly between food-restricted and ad libitum groups. Repeated injections of AMPH-sensitized locomotor activity, but not VS-reinforced responding. In addition, while chronic lithium treatments (0.2 % lithium carbonate chow) reduced VS-reinforced responding, chronic lithium further augmented AMPH-potentiated VS-reinforced responding. Food restriction interacts with psychoactive drugs to potentiate goal-directed responding unrelated to food seeking in a much more powerful manner than previously thought. The novel finding that lithium can augment a psychostimulant effect of AMPH suggests caution when combining lithium and psychostimulant drugs in clinical settings. C1 [Keller, Kristine L.; Vollrath-Smith, Fiori R.; Ikemoto, Satoshi] NIDA, Behav Neurosci Res Branch, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Jafari, Mehrnoosh] Univ Munich, Grad Sch System Neurosci, Munich, Germany. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Res Branch, NIH, US Dept Hlth & Human Serv, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM satoshi.ikemoto@nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health FX The present work was supported by the Intramural Research Program of National Institute on Drug Abuse, National Institutes of Health. The authors thank Ms. Amy N. Hamaker for conducting a pilot experiment and Dr. T. D. Gould for helping with lithium concentration analysis. NR 87 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2014 VL 231 IS 5 BP 825 EP 840 DI 10.1007/s00213-013-3300-9 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AB3VU UT WOS:000331719100003 PM 24101157 ER PT J AU Barker, DJ Simmons, SJ Servilio, LC Bercovicz, D Ma, SS Root, DH Pawlak, AP West, MO AF Barker, David J. Simmons, Steven J. Servilio, Lisa C. Bercovicz, Danielle Ma, Sisi Root, David H. Pawlak, Anthony P. West, Mark O. TI Ultrasonic vocalizations: evidence for an affective opponent process during cocaine self-administration SO PSYCHOPHARMACOLOGY LA English DT Article DE Cocaine; Addiction; Affect; Ultrasonic vocalization; Drug abuse ID INTRAVENOUS COCAINE; NUCLEUS-ACCUMBENS; APPROACH BEHAVIOR; RATS; CALLS; DRUG; WITHDRAWAL; MODEL; SENSITIZATION; AMPHETAMINE AB Preclinical models of cocaine addiction in the rodent have shown that cocaine induces both positive and negative affective states. These observations have led to the notion that the initial positive/euphoric state induced by cocaine administration may be followed by an opposing, negative process. In the rodent, one method for inferring positive and negative affective states involves measuring their ultrasonic vocalizations (USVs). Previous USV recordings from our laboratory suggested that the transition between positive and negative affect might involve decaying or sub-satiety levels of self-administered cocaine. In order to explicitly test the role of cocaine levels on these affective states, the present study examined USVs when calculated body levels of cocaine were clamped (i.e., held at a constant level via experimenter-controlled infusions) at, below, or above subjects' self-determined drug satiety thresholds. USVs indicated that (1) positive affect was predominantly observed during the drug loading period, but declined quickly to near zero during maintenance and exhibited little relation to calculated drug level, and (2) in contrast, negative affect was observed at sub-satiety cocaine levels, but was relatively absent when body levels of cocaine were clamped at or above subjects' satiety thresholds. The results reinforce the opponent-process hypothesis of addiction and suggest that an understanding of the mechanisms underlying negative affect might serve to inform behavioral and pharmacological therapies. C1 [Barker, David J.; Simmons, Steven J.; Servilio, Lisa C.; Bercovicz, Danielle; Ma, Sisi; Pawlak, Anthony P.; West, Mark O.] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08854 USA. [Root, David H.] NIDA, Neuronal Networks Sect, Integrat Neurosci Res Branch, Baltimore, MD 21224 USA. RP West, MO (reprint author), Rutgers State Univ, Dept Psychol, 152 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM markwest@rutgers.edu RI Ma, Sisi/E-6367-2015; OI Root, David/0000-0002-1927-2175; Simmons, Steven/0000-0002-6982-4740 FU National Institute on Drug Abuse Grants [DA006886, DA029873, DA032270] FX We thank Thomas Grace Sr., Jackie Thomas, and Kevin Coffey for excellent assistance. This study was supported by the National Institute on Drug Abuse Grants DA006886 (MOW), DA029873 (MOW), and DA032270 (DJB). NR 59 TC 12 Z9 12 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2014 VL 231 IS 5 BP 909 EP 918 DI 10.1007/s00213-013-3309-0 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AB3VU UT WOS:000331719100010 PM 24197178 ER PT J AU McShane, CM Murray, LJ Engels, EA Anderson, LA AF McShane, Charlene M. Murray, Liam J. Engels, Eric A. Anderson, Lesley A. TI Community-acquired infections associated with increased risk of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE lymphoplasmacytic lymphoma; Waldenstrom macroglobulinaemia; infection; respiratory tract infection; herpes zoster; community-acquired infection ID WALDENSTROMS MACROGLOBULINEMIA; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; MEDICARE DATA; POPULATION; HEPATITIS; CANCER; LYMPHOMA; LEUKEMIA; HISTORY AB Emerging evidence supports the role of immune stimulation in the development of lymphoplasmacytic lymphoma/Waldenstrom Macroglobulinaemia (LPL/WM). Using the population-based Surveillance, Epidemiology End Results-Medicare database we investigated the exposure to 14 common community-acquired infections and subsequent risk of LPL/WM in 693 LPL/WM cases and 200 000 controls. Respiratory tract infections, bronchitis [odds ratio (OR) 1.56], pharyngitis (OR 1.43), pneumonia (OR 1.42) and sinusitis (OR 1.33) and skin infection, herpes zoster (OR 1.51) were all significantly associated with subsequent increased risk of LPL/WM. For each of these infections, the findings remained significantly elevated following the exclusion of more than 6 years of Medicare claims data prior to LPL/WM diagnosis. Our findings may support a role for infections in the development of LPL/WM or could reflect an underlying immune disturbance that is present several years prior to diagnosis and thereby part of the natural history of disease progression. C1 [McShane, Charlene M.; Murray, Liam J.; Anderson, Lesley A.] Queens Univ Belfast, Canc Epidemiol & Hlth Serv Res Grp, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Anderson, LA (reprint author), Inst Clin Sci Block B, Canc Epidemiol & Hlth Serv Res Grp, Ctr Publ Hlth, Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM l.anderson@qub.ac.uk OI Anderson, Lesley/0000-0002-1000-3649 FU Department for Learning and Employment (Northern Ireland) FX This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumour registries in the creation of the SEER-Medicare database. CMcS is a PhD candidate at Queen's University Belfast and in receipt of a Department for Learning and Employment (Northern Ireland) funded scholarship. NR 23 TC 3 Z9 3 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2014 VL 164 IS 5 BP 653 EP 658 DI 10.1111/bjh.12671 PG 6 WC Hematology SC Hematology GA AA8OL UT WOS:000331354700005 PM 24528127 ER PT J AU Chang, CQ Yesupriya, A Rowell, JL Pimentel, CB Clyne, M Gwinn, M Khoury, MJ Wulf, A Schully, SD AF Chang, Christine Q. Yesupriya, Ajay Rowell, Jessica L. Pimentel, Camilla B. Clyne, Melinda Gwinn, Marta Khoury, Muin J. Wulf, Anja Schully, Sheri D. TI A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Review DE GWAS; candidate gene studies; meta-analysis; cancer ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY; POLYMORPHISMS; EPIDEMIOLOGY; DISEASE; LOCI; OPPORTUNITIES; COVERAGE; DATABASE AB Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities <= 0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era. C1 [Chang, Christine Q.; Khoury, Muin J.; Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Yesupriya, Ajay] Ctr Dis Control & Prevent, Atlanta, GA USA. [Rowell, Jessica L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Pimentel, Camilla B.; Clyne, Melinda] Univ Massachusetts, Sch Med, Grad Sch Biomed Sci, Clin & Populat Hlth Res Program, Worcester, MA USA. [Gwinn, Marta] McKing Consulting Corp, Atlanta, GA USA. [Khoury, Muin J.; Wulf, Anja] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Schully, SD (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM schullys@mail.nih.gov NR 39 TC 13 Z9 13 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAR PY 2014 VL 22 IS 3 BP 402 EP 408 DI 10.1038/ejhg.2013.161 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AA9DJ UT WOS:000331393700022 PM 23881057 ER PT J AU Sharp, D Palmore, T Grady, C AF Sharp, Daniel Palmore, Tara Grady, Christine TI COMMENTARY The Ethics of Empowering Patients as Partners in Healthcare-Associated Infection Prevention SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material ID HAND HYGIENE COMPLIANCE; PARTICIPATION; HOSPITALS C1 [Sharp, Daniel; Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Palmore, Tara] NIH, Off Director, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 19 TC 3 Z9 3 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD MAR 1 PY 2014 VL 35 IS 3 BP 307 EP 309 DI 10.1086/675288 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AA6MH UT WOS:000331211900016 PM 24521598 ER PT J AU Kuhar, DT Struble, KA Henderson, DK AF Kuhar, David T. Struble, Kimberly A. Henderson, David K. TI Selecting an Antiretroviral Regimen for Human Immunodeficiency Virus Postexposure Prophylaxis in the Occupational Setting Reply SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter ID EMTRICITABINE; TOLERABILITY; RALTEGRAVIR; ADHERENCE; TENOFOVIR; SAFETY C1 [Kuhar, David T.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Struble, Kimberly A.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Henderson, David K.] NIH, Off Deputy Director Clin Care, Ctr Clin, Bethesda, MD 20892 USA. RP Kuhar, DT (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Natl Ctr Emerging & Zoonot Infect Dis, 1600 Clifton Rd NE,MS A-31, Atlanta, GA 30333 USA. EM jto7@cdc.gov FU Intramural CDC HHS [CC999999] NR 7 TC 1 Z9 1 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD MAR 1 PY 2014 VL 35 IS 3 BP 328 EP 329 DI 10.1086/675350 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AA6MH UT WOS:000331211900023 PM 24521605 ER PT J AU Faupel-Badger, J Cameron, C Chang, S AF Faupel-Badger, Jessica Cameron, Carrie Chang, Shine TI Invigorating Cancer Prevention: Proposing Core Competencies in Cancer Prevention Research Training SO JOURNAL OF CANCER EDUCATION LA English DT Editorial Material ID FUTURE C1 [Faupel-Badger, Jessica] NCI, Bethesda, MD 20892 USA. [Cameron, Carrie; Chang, Shine] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77230 USA. RP Chang, S (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Mail Code 1340,POB 301439, Houston, TX 77230 USA. EM shinechang@mdanderson.org NR 14 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2014 VL 29 IS 1 BP 6 EP 8 DI 10.1007/s13187-013-0514-9 PG 3 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA AA3DK UT WOS:000330972900003 PM 23872950 ER PT J AU Friedman, DB Owens, OL Jackson, DD Johnson, KM Gansauer, L Dickey, J Miller, R Payne, J Bearden, JD Hebert, JR AF Friedman, Daniela B. Owens, Otis L. Jackson, Dawnyea D. Johnson, Kim M. Gansauer, Lucy Dickey, Joe miller, Ron Payne, Johnny Bearden, James D. Hebert, James R. TI An Evaluation of a Community-Academic-Clinical Partnership to Reduce Prostate Cancer Disparities in the South SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Prostate cancer; Research collaboration; Community and clinical partnerships; Assessment ID AFRICAN-AMERICAN MENS; PARTICIPATORY RESEARCH; FARMERS MARKET; HEALTH-CENTER; COMMUNICATION AB Engaging partners in the planning, implementation, and evaluation of cancer education programs is critical for improving the health of our communities. A 2-year pilot education intervention on prostate cancer decision making and participation in medical research was funded by the National Cancer Institute. The partnership involving community members and clinical staff at a cancer center was used to develop recruitment strategies and plan for the implementation of the intervention with African-American middle-age and older men and female family members. We assessed partners' perceptions of this community-academic-clinical research collaboration. In year 2, eight project advisory council members were selected among existing partners and year 1 participants to serve as a formal committee. Council members were required to participate in telephone and in person meetings and actively support recruitment/implementation efforts. At the conclusion of the project, 20 individuals (all clinical and community partners, including the eight advisory council members) were invited to complete a survey to assess their perceived impact of the collaboration on the community and provide suggestions for future collaborations. Most partners agreed that their organization benefitted from the collaboration and that various aspects of the advisory council process (e.g., both formal and informal communication) worked well. The most noted accomplishment of the partnership related to leveraging the collaboration to make men more knowledgeable about prostate cancer decision making. Suggested improvements for future collaborations included distributing more frequent updates regarding project successes. Evaluating partners' perceptions of this collaboration provided important recommendations for future planning, implementation, and evaluation of community-based cancer education programs. C1 [Friedman, Daniela B.; Owens, Otis L.; Jackson, Dawnyea D.] Univ S Carolina, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. [Friedman, Daniela B.; Hebert, James R.] Univ S Carolina, Statewide Canc Prevent & Control Program, Columbia, SC 29208 USA. [Johnson, Kim M.; Gansauer, Lucy; Bearden, James D.] NCI, Community Canc Ctr Program, Spartanburg Reg Healthcare Syst, Gibbs Canc Ctr & Res Inst, Spartanburg, SC 29303 USA. [Dickey, Joe; miller, Ron] UsTOO Int Prostate Canc Educ & Support Network, Spartanburg, SC 29303 USA. [Payne, Johnny] UsTOO Int Prostate Canc Educ & Support Network, Easley, SC 29640 USA. [Hebert, James R.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Friedman, Daniela B.] Univ S Carolina, Canc Prevent & Control Program, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Friedman, DB (reprint author), Univ S Carolina, Canc Prevent & Control Program, Arnold Sch Publ Hlth, 915 Greene St,Suite 235, Columbia, SC 29208 USA. EM dbfriedman@sc.edu FU National Cancer Institute (NCI) Community Networks Program Centers [U54 CA153461]; Cancer Training Branch of the NCI [K05 CA136975] FX Funded by the National Cancer Institute (NCI) Community Networks Program Centers U54 CA153461 (PI: Hebert; Pilot Project Leader: Friedman). Partially supported by an Established Investigator Award in Cancer Prevention and Control from the Cancer Training Branch of the NCI to J.R. Hebert (K05 CA136975). We gratefully acknowledge Dr. Dan B. Fried, MD, Dr. Drew Monitto, MD, Renee Romberger, Sharon Bartelt, Sonya Lovett, DeLisa Dawkins, Dawn Skaggs, Bruce Grant, Noel Kinnard, Tracey Thomas, Andre McCullough, Joyce Wallace, Nancy Waddell, Jacqueline Talley, the advisory council, partners, and study participants. NR 16 TC 4 Z9 4 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2014 VL 29 IS 1 BP 80 EP 85 DI 10.1007/s13187-013-0550-5 PG 6 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA AA3DK UT WOS:000330972900017 PM 24078315 ER PT J AU Allen, JD Perez, JE Tom, L Leyva, B Diaz, D Torres, MI AF Allen, Jennifer D. Perez, John E. Tom, Laura Leyva, Bryan Diaz, Daisy Torres, Maria Idali TI A Pilot Test of a Church-Based Intervention to Promote Multiple Cancer-Screening Behaviors among Latinas SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Latinas; Hispanic; Health; Disparities; Church; Cancer screening; Religion; Spirituality ID PREVENTION; BREAST; WOMEN; ADULTS; TRIAL AB We assessed the feasibility, acceptability, and initial impact of a church-based educational program to promote breast, cervical, and colorectal cancer screening among Latinas ages 18 years and over. We used a one-group pre-/post-evaluation within a low-income, Latino Baptist church in Boston, MA. Participants completed interviewer-administered assessments at baseline and at the end of the 6-month intervention. Under the guidance of a patient navigator (PN), women from the church (peer health advisors, or PHAs) were trained to deliver evidence-based screening interventions, including one-to-one outreach, small group education, client reminders, and reduction of structural barriers to screening. The PN and PHAs also implemented a health fair, and the pastor integrated health information into regular sermons. At pre-intervention, nearly half of the sample did not meet screening guidelines. The majority (97 %, n = 35) of those who completed the post-intervention assessment participated in intervention activities. Two thirds (67 %) reported talking with the PN or PHAs about health issues. Participation in small group education sessions was highest (72 %), with health fairs (61 %) and goal setting (50 %) also being popular activities. Fourteen percent also reported receiving help from the PN in finding a primary care provider. This study supports the feasibility and acceptability of churches as a setting to promote cancer screening among Latinas. C1 [Allen, Jennifer D.; Tom, Laura; Diaz, Daisy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Allen, Jennifer D.] Harvard Univ, Sch Med, Boston, MA USA. [Perez, John E.] Univ San Francisco, San Francisco, CA 94117 USA. [Leyva, Bryan] NCI, Bethesda, MD 20892 USA. [Torres, Maria Idali] Univ Massachusetts, Boston, MA 02125 USA. [Allen, Jennifer D.] Dana Farber Canc Inst, Phyllis Cantor Ctr Nursing Res & Patient Care Ser, Ctr Community Based Res, Boston, MA 02215 USA. RP Allen, JD (reprint author), Dana Farber Canc Inst, Phyllis Cantor Ctr Nursing Res & Patient Care Ser, Ctr Community Based Res, 450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_allen@dfci.harvard.edu RI Allen, Jennifer/M-2113-2015 FU National Cancer Institute [U56 CA118641, U54CA156732]; American Recovery and Reinvestment Act [3U56CA118635-05S2]; Centers for Disease Control and Prevention [U48DP001946] FX This study was supported by grants from the National Cancer Institute (U56 CA118641 and U54CA156732) with supplemental funding support from the American Recovery and Reinvestment Act of 2009 (3U56CA118635-05S2). It was also supported by Cooperative Agreement Number U48DP001946 from the Centers for Disease Control and Prevention. The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. We gratefully acknowledge the leadership and support of Drs. Karen Emmons and Adan Colon-Carmona. We also thank the following for their participation and support: Milagros Abreu, Erick Alcantata, Esteban Barreto, Lois Biener, Karen Burns White, Katia Canenguez, Magnolia Contreras, Ana Galeas, Maria De Jesus, Ericka Gonzalez, Elizabeth Gonzalez Suarez, David Hurtado, Thelma Juarez, Yolanda Martins, Yudy Muneton, Maria Nieves Sesma, Leyla Perez-Gualdron, Max Stewart, and Jamielle Walker. NR 25 TC 12 Z9 12 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2014 VL 29 IS 1 BP 136 EP 143 DI 10.1007/s13187-013-0560-3 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA AA3DK UT WOS:000330972900025 PM 24132541 ER PT J AU Tseng, MCM Gau, SSF Tseng, WL Hwu, HG Lee, MB AF Tseng, Mei-Chih Meg Gau, Susan Shur-Fen Tseng, Wan-Ling Hwu, Hai-Gwo Lee, Ming-Been TI Co-Occurring Eating and Psychiatric Symptoms in Taiwanese College Students: Effects of Gender and Parental Factors SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article ID NATIONAL-COMORBIDITY-SURVEY; OBSESSIVE-COMPULSIVE DISORDER; BULIMIA-NERVOSA; ANOREXIA-NERVOSA; RISK-FACTORS; BONDING INSTRUMENT; EARLY ADULTHOOD; UNIVERSITY-STUDENTS; SURVEY-REPLICATION; ANXIETY DISORDERS C1 [Tseng, Mei-Chih Meg; Gau, Susan Shur-Fen; Hwu, Hai-Gwo; Lee, Ming-Been] Natl Taiwan Univ Hosp, Taipei 10002, Taiwan. [Tseng, Mei-Chih Meg; Gau, Susan Shur-Fen; Hwu, Hai-Gwo; Lee, Ming-Been] Natl Taiwan Univ, Taipei, Taiwan. [Tseng, Wan-Ling] NIMH, Bethesda, MD USA. RP Gau, SSF (reprint author), Natl Taiwan Univ Hosp, Dept Psychiat, 7 Chung Shan South Rd, Taipei 10002, Taiwan. EM gaushufe@ntu.edu.tw OI Gau, Susan Shur-Fen/0000-0002-2718-8221; TSENG, MEI-CHIH MEG/0000-0002-0114-102X; LEE, MING-BEEN/0000-0002-1556-5130; HWU, HAI-GWO/0000-0002-2582-2807 NR 77 TC 1 Z9 1 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 EI 1097-4679 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD MAR PY 2014 VL 70 IS 3 BP 224 EP 237 PG 14 WC Psychology, Clinical SC Psychology GA AA5HD UT WOS:000331125800003 PM 23801021 ER PT J AU Mehta, NN Gelfand, JM AF Mehta, Nehal N. Gelfand, Joel M. TI High-Density Lipoprotein Cholesterol Function Improves after Successful Treatment of Psoriasis: A Step Forward in the Right Direction SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID POSITRON-EMISSION-TOMOGRAPHY; INTIMA-MEDIA THICKNESS; EFFLUX CAPACITY; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; HDL COMPOSITION; INCREASED RISK; IN-VIVO; INFLAMMATION; TRIAL AB There is epidemiological evidence that high-density lipoprotein (HDL) concentrations, or HDL "levels," exert protection from atherosclerosis, suggesting that HDL plays a role in vascular diseases. More accurate measures of HDL "function" are emerging, such as HDL efflux assays, which measure removal of cholesterol from peripheral tissues. Using this assay, we have demonstrated that psoriasis is associated with decreased HDL "levels" and HDL "function." The study by Holzer et al. in this issue demonstrates in an open-label, uncontrolled study that HDL function is impaired in psoriasis and improves after successful treatment of psoriasis. These findings underscore the notion that treatment of psoriasis likely extends beyond the skin and that a randomized controlled clinical trial is needed to confirm these findings. C1 [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Gelfand, Joel M.] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov FU NHLBI NIH HHS [R01 HL089744, R01 HL111293, R01-HL111293, R01HL08974]; NIAMS NIH HHS [K24-AR064310, K24 AR064310] NR 38 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2014 VL 134 IS 3 BP 592 EP 595 DI 10.1038/jid.2013.447 PG 4 WC Dermatology SC Dermatology GA AB3CV UT WOS:000331669800002 PM 24518110 ER PT J AU Li, QL Brodsky, JL Conlin, LK Pawel, B Glatz, AC Gafni, RI Schurgers, L Uitto, J Hakonarson, H Deardorff, MA Levine, MA AF Li, Qiaoli Brodsky, Jill L. Conlin, Laura K. Pawel, Bruce Glatz, Andrew C. Gafni, Rachel I. Schurgers, Leon Uitto, Jouni Hakonarson, Hakon Deardorff, Matthew A. Levine, Michael A. TI Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CONNECTIVE-TISSUE MINERALIZATION; SINGLE-NUCLEOTIDE POLYMORPHISM; PUTATIVE PATHOMECHANISMS; HYPOPHOSPHATEMIC RICKETS; MOLECULAR-GENETICS; ENPP1 GENE; OSSIFICATION; PHENOTYPE; SURVIVAL; DISEASE AB Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large- and medium-sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature death. Most cases of GACI are caused by mutations in the ENPP1 gene. We first studied two siblings with GACI from a non-consanguineous family without mutations in the ENPP1 gene. To search for disease-causing mutations, we identified genomic regions shared between the two affected siblings but not their unaffected parents or brother. The ABCC6 gene, which is mutated in pseudoxanthoma elasticum (PXE), resided within a small region of homozygosity shared by the affected siblings. Sequence analysis of ABCC6 revealed that the two affected siblings were homozygous for the missense mutation p.R1314W. Subsequently, ABCC6 mutations were identified in five additional GACI families with normal ENPP1 sequences. Genetic mutations in ABCC6 in patients with PXE are associated with ectopic tissue mineralization in the skin and arterial blood vessels. Thus, our findings provide additional evidence that the ABCC6 gene product inhibits calcification under physiologic conditions and confirm a second locus for GACI. In addition, our study emphasizes the potential utility of shared homozygosity mapping to identify genetic causes of inherited disorders. C1 [Li, Qiaoli; Uitto, Jouni] Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. [Li, Qiaoli; Uitto, Jouni] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Brodsky, Jill L.; Levine, Michael A.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Brodsky, Jill L.; Glatz, Andrew C.; Hakonarson, Hakon; Deardorff, Matthew A.; Levine, Michael A.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Conlin, Laura K.; Pawel, Bruce] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Glatz, Andrew C.] Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Gafni, Rachel I.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Schurgers, Leon] Univ Maastricht, Cardiovasc Res Inst, Dept Biochem, Maastricht, Netherlands. [Hakonarson, Hakon; Deardorff, Matthew A.] Childrens Hosp Philadelphia, Div Genet, Philadelphia, PA 19104 USA. RP Levine, MA (reprint author), Childrens Hosp Philadelphia, Suite 30 Northwest Tower 11,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM levinem@chop.edu RI Li, Qiaoli/F-8383-2013; OI Levine, Michael/0000-0003-0036-7809 FU National Institutes of Health [K08HD055488, R01AR28450]; Children's Hospital of Philadelphia; Division of Intramural Research, NIDCR, NIH, DHHS; Dermatology Foundation Research Career Development Award FX We thank Steven Mumm at Shriner's Hospital, St Louis, for sequencing the ENPP1 gene in patient 4 in Family C. Carol Kelly assisted in manuscript preparation. This work was supported by National Institutes of Health grants K08HD055488 (NICHD; MAD) and R01AR28450 (NIAMS; JU), by institutional funds from the Children's Hospital of Philadelphia, and by the Division of Intramural Research, NIDCR, NIH, DHHS. QL is recipient of a Dermatology Foundation Research Career Development Award. NR 38 TC 20 Z9 20 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2014 VL 134 IS 3 BP 658 EP 665 DI 10.1038/jid.2013.370 PG 8 WC Dermatology SC Dermatology GA AB3CV UT WOS:000331669800014 PM 24008425 ER PT J AU Colmont, CS Ketah, AB Errington, RJ Reed, SH Udey, MC Patel, GK AF Colmont, Chantal S. Ketah, Antisar B. Errington, Rachel J. Reed, Simon H. Udey, Mark C. Patel, Girish K. TI Human Basal Cell Carcinoma Tumor-Initiating Cells Are Resistant to Etoposide SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID MULTIDRUG-RESISTANCE; GENE; MICE; KERATINOCYTES; EXPRESSION; THERAPY C1 [Colmont, Chantal S.; Ketah, Antisar B.] Cardiff Univ, Sch Med, Dept Dermatol & Wound Healing, Cardiff CF10 3AX, S Glam, Wales. [Errington, Rachel J.; Reed, Simon H.] Cardiff Univ, Sch Med, Dept Med Genet Hematol & Pathol, Cardiff CF10 3AX, S Glam, Wales. [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patel, Girish K.] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. RP Colmont, CS (reprint author), Cardiff Univ, Sch Med, Dept Dermatol & Wound Healing, Cardiff CF10 3AX, S Glam, Wales. EM patelgk@cardiff.ac.uk OI Reed, Simon/0000-0002-4711-0560 FU Medical Research Council [G0400113, G0301154, MR/K000926/1] NR 10 TC 1 Z9 1 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2014 VL 134 IS 3 BP 867 EP 870 DI 10.1038/jid.2013.377 PG 4 WC Dermatology SC Dermatology GA AB3CV UT WOS:000331669800044 PM 24025552 ER PT J AU Ofek, G Zirkle, B Yang, YP Zhu, ZY McKee, K Zhang, BS Chuang, GY Georgiev, IS O'Dell, S Doria-Rose, N Mascola, JR Dimitrov, DS Kwong, PD AF Ofek, Gilad Zirkle, Brett Yang, Yongping Zhu, Zhongyu McKee, Krisha Zhang, Baoshan Chuang, Gwo-Yu Georgiev, Ivelin S. O'Dell, Sijy Doria-Rose, Nicole Mascola, John R. Dimitrov, Dimiter S. Kwong, Peter D. TI Structural Basis for HIV-1 Neutralization by 2F5-Like Antibodies m66 and m66.6 SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; 2F5 MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEIN; GP41 ECTODOMAIN; MEMBRANE; FUSION; EPITOPE; PROTEINS; HYDROPHOBICITY AB Antibodies m66.6 and 2F5 are the only effective human HIV-1-neutralizing antibodies reported thus far to recognize the N-terminal region of the membrane-proximal external region (MPER) of the gp41 subunit of the HIV-1 envelope glycoprotein. Although 2F5 has been extensively characterized, much less is known about antibody m66.6 or antibody m66, a closely related light-chain variant. Here, we report the crystal structure of m66 in complex with its gp41 epitope, along with unbound structures of m66 and m66.6. We used mutational and binding analyses to decipher antibody elements critical for their recognition of gp41 and determined the molecular basis that underlies their neutralization of HIV-1. When bound by m66, the N-terminal region of the gp41 MPER adopts a conformation comprising a helix, followed by an extended loop. Comparison of gp41-bound m66 to unbound m66.6 identified three light-chain residues of m66.6 that were confirmed through mutagenesis to underlie the greater breadth of m66.6-mediated virus neutralization. Recognition of gp41 by m66 also revealed similarities to antibody 2F5 both in the conformation of crucial epitope residues as well as in the angle of antibody approach. Aromatic residues at the tip of the m66.6 heavy-chain third complementarity-determining region, as in the case of 2F5, were determined to be critical for virus neutralization in a manner that correlated with antibody recognition of the MPER in a lipid context. Antibodies m66, m66.6, and 2F5 thus utilize similar mechanistic elements to recognize a common gp41-MPER epitope and to neutralize HIV-1. C1 [Ofek, Gilad; Zirkle, Brett; Yang, Yongping; McKee, Krisha; Zhang, Baoshan; Chuang, Gwo-Yu; Georgiev, Ivelin S.; O'Dell, Sijy; Doria-Rose, Nicole; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gofek@nih.gov; pdkwong@nih.gov FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases; Center for Cancer Research, National Cancer Institute; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-316 109-Eng-38] FX Support for this study was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the Center for Cancer Research, National Cancer Institute. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-316 109-Eng-38. NR 45 TC 16 Z9 16 U1 0 U2 9 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 MAR PY 2014 VL 88 IS 5 BP 2426 EP 2441 DI 10.1128/JVI.02837-13 PG 16 WC Virology SC Virology GA AA5JK UT WOS:000331131700007 PM 24335316 ER PT J AU deCamp, A Hraber, P Bailer, RT Seaman, MS Ochsenbauer, C Kappes, J Gottardo, R Edlefsen, P Self, S Tang, HL Greene, K Gao, HM Daniell, X Sarzotti-Kelsoe, M Gorny, MK Zolla-Pazner, S LaBranche, CC Mascola, JR Korber, BT Montefiori, DC AF deCamp, Allan Hraber, Peter Bailer, Robert T. Seaman, Michael S. Ochsenbauer, Christina Kappes, John Gottardo, Raphael Edlefsen, Paul Self, Steve Tang, Haili Greene, Kelli Gao, Hongmei Daniell, Xiaoju Sarzotti-Kelsoe, Marcella Gorny, Miroslaw K. Zolla-Pazner, Susan LaBranche, Celia C. Mascola, John R. Korber, Bette T. Montefiori, David C. TI Global Panel of HIV-1 Env Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; HIV-1-INFECTED INDIVIDUALS; POTENT NEUTRALIZATION; BROAD NEUTRALIZATION; CROSS-REACTIVITY; CD4-BINDING SITE; STRUCTURAL BASIS; RATIONAL DESIGN; V3 DOMAIN AB Standardized assessments of HIV-1 vaccine-elicited neutralizing antibody responses are complicated by the genetic and antigenic variability of the viral envelope glycoproteins (Envs). To address these issues, suitable reference strains are needed that are representative of the global epidemic. Several panels have been recommended previously, but no clear answers have been available on how many and which strains are best suited for this purpose. We used a statistical model selection method to identify a global panel of reference Env clones from among 219 Env-pseudotyped viruses assayed in TZM-bl cells with sera from 205 HIV-1-infected individuals. The Envs and sera were sampled globally from diverse geographic locations and represented all major genetic subtypes and circulating recombinant forms of the virus. Assays with a panel size of only nine viruses adequately represented the spectrum of HIV-1 serum neutralizing activity seen with the larger panel of 219 viruses. An optimal panel of nine viruses was selected and augmented with three additional viruses for greater genetic and antigenic coverage. The spectrum of HIV-1 serum neutralizing activity seen with the final 12-virus panel closely approximated the activity seen with subtype-matched viruses. Moreover, the final panel was highly sensitive for detection of many of the known broadly neutralizing antibodies. For broader assay applications, all 12 Env clones were converted to infectious molecular clones using a proviral backbone carrying a Renilla luciferase reporter gene (Env. IMC. LucR viruses). This global panel should facilitate highly standardized assessments of vaccine-elicited neutralizing antibodies across multiple HIV-1 vaccine platforms in different parts of the world. IMPORTANCE An effective HIV-1 vaccine will need to overcome the extraordinary genetic variability of the virus, where most variation occurs in the viral envelope glycoproteins that are the sole targets for neutralizing antibodies. Efforts to elicit broadly cross-reactive neutralizing antibodies that will protect against infection by most circulating strains of the virus are guided in part by in vitro assays that determine the ability of vaccine-elicited antibodies to neutralize genetically diverse HIV-1 variants. Until now, little information was available on how many and which strains of the virus are best suited for this purpose. We applied robust statistical methods to evaluate a large neutralization data set and identified a small panel of viruses that are a good representation of the global epidemic. The neutralization properties of this new panel of reference strains should facilitate the development of an effective HIV-1 vaccine. C1 [deCamp, Allan; Gottardo, Raphael; Edlefsen, Paul; Self, Steve] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hraber, Peter; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Bailer, Robert T.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Seaman, Michael S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Ochsenbauer, Christina; Kappes, John] Univ Alabama Birmingham, Birmingham, AL USA. [Kappes, John] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. [Tang, Haili; Greene, Kelli; Gao, Hongmei; Daniell, Xiaoju; Sarzotti-Kelsoe, Marcella; LaBranche, Celia C.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Sarzotti-Kelsoe, Marcella] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Gorny, Miroslaw K.; Zolla-Pazner, Susan] NYU, Dept Pathol, Langone Sch Med, New York, NY 10016 USA. [Zolla-Pazner, Susan] Vet Affairs Med Ctr, Res Ctr AIDS & HIV Infect, New York, NY USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. EM monte@duke.edu OI Gorny, Miroslaw/0000-0002-2714-8780; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Bill & Melinda Gates Foundation [38619, 1032144]; Intramural Research Program of the Vaccine Research Center, NIAID, NIH; Virology Core of the Birmingham Center for AIDS Research (CFAR) [AI27767] FX This work was funded by grants from the Bill & Melinda Gates Foundation (Collaboration for AIDS Vaccine Discovery no. 38619 and 1032144) and by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. This work was further supported by the Virology Core of the Birmingham Center for AIDS Research (CFAR, AI27767). NR 85 TC 37 Z9 37 U1 1 U2 8 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 MAR PY 2014 VL 88 IS 5 BP 2489 EP 2507 DI 10.1128/JVI.02853-13 PG 19 WC Virology SC Virology GA AA5JK UT WOS:000331131700012 PM 24352443 ER PT J AU Cairns, TM Fontana, J Huang, ZY Whitbeck, JC Atanasiu, D Rao, S Shelly, SS Lou, H de Leon, MP Steven, AC Eisenberg, RJ Cohen, GH AF Cairns, Tina M. Fontana, Juan Huang, Zhen-Yu Whitbeck, J. Charles Atanasiu, Doina Rao, Samhita Shelly, Spencer S. Lou, Huan de Leon, Manuel Ponce Steven, Alasdair C. Eisenberg, Roselyn J. Cohen, Gary H. TI Mechanism of Neutralization of Herpes Simplex Virus by Antibodies Directed at the Fusion Domain of Glycoprotein B SO JOURNAL OF VIROLOGY LA English DT Article ID 2 IMMUNODOMINANT DOMAINS; LONG TAIL-FIBER; CELL-FUSION; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; CONFORMATIONAL-CHANGE; ELECTRON-MICROSCOPY; FUNCTIONAL REGIONS; HEPARAN-SULFATE; PREFUSION FORM AB Glycoprotein B (gB), the fusogen of herpes simplex virus (HSV), is a class III fusion protein with a trimeric ectodomain of known structure for the postfusion state. Seen by negative-staining electron microscopy, it presents as a rod with three lobes (base, middle, and crown). gB has four functional regions (FR), defined by the physical location of epitopes recognized by anti-gB neutralizing monoclonal antibodies (MAbs). Located in the base, FR1 contains two internal fusion loops (FLs) and is the site of gB-lipid interaction (the fusion domain). Many of the MAbs to FR1 are neutralizing, block cell-cell fusion, and prevent the association of gB with lipid, suggesting that these MAbs affect FL function. Here we characterize FR1 epitopes by using electron microscopy to visualize purified Fab-gB ectodomain complexes, thus confirming the locations of several epitopes and localizing those of MAbs DL16 and SS63. We also generated MAb-resistant viruses in order to localize the SS55 epitope precisely. Because none of the epitopes of our anti-FR1 MAbs mapped to the FLs, we hyperimmunized rabbits with FL1 or FL2 peptides to generate polyclonal antibodies (PAbs). While the anti-FL1 PAb failed to bind gB, the anti-FL2 PAb had neutralizing activity, implying that the FLs become exposed during virus entry. Unexpectedly, the anti-FL2 PAb (and the anti-FR1 MAbs) bound to liposome-associated gB, suggesting that their epitopes are accessible even when the FLs engage lipid. These studies provide possible mechanisms of action for HSV neutralization and insight into how gB FR1 contributes to viral fusion. IMPORTANCE For herpesviruses, such as HSV, entry into a target cell involves transfer of the capsid-encased genome of the virus to the target cell after fusion of the lipid envelope of the virus with a lipid membrane of the host. Virus-encoded glycoproteins in the envelope are responsible for fusion. Antibodies to these glycoproteins are important biological tools, providing a way of examining how fusion works. Here we used electron microscopy and other techniques to study a panel of anti-gB antibodies. Some, with virus-neutralizing activity, impair gB-lipid association. We also generated a peptide antibody against one of the gB fusion loops; its properties provide insight into the way the fusion loops function as gB transits from its prefusion form to an active fusogen. C1 [Cairns, Tina M.; Huang, Zhen-Yu; Whitbeck, J. Charles; Atanasiu, Doina; Rao, Samhita; Lou, Huan; de Leon, Manuel Ponce; Cohen, Gary H.] Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Shelly, Spencer S.; Eisenberg, Roselyn J.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Fontana, Juan; Steven, Alasdair C.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Cairns, TM (reprint author), Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. EM tmcairns@biochem.dental.upenn.edu RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU NIH [AI-076231, AI-056045, AI-18289, AI-07234]; VMD/Ph.D. program of the School of Veterinary Medicine at the University of Pennsylvania; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported by the following grants from NIH: AI-076231 and AI-056045 (to R.J.E.) and AI-18289 (to G. H. C.). S. S. S. was funded in part by the VMD/Ph.D. program of the School of Veterinary Medicine at the University of Pennsylvania and by NIH training grant AI-07234. This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 61 TC 18 Z9 21 U1 0 U2 13 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 MAR PY 2014 VL 88 IS 5 BP 2677 EP 2689 DI 10.1128/JVI.03200-13 PG 13 WC Virology SC Virology GA AA5JK UT WOS:000331131700028 PM 24352457 ER PT J AU Westgeest, KB Russell, CA Lin, XD Spronken, MIJ Bestebroer, TM Bahl, J van Beek, R Skepner, E Halpin, RA de Jong, JC Rimmelzwaan, GF Osterhaus, ADME Smith, DJ Wentworth, DE Fouchier, RAM de Graaf, M AF Westgeest, Kim B. Russell, Colin A. Lin, Xudong Spronken, Monique I. J. Bestebroer, Theo M. Bahl, Justin van Beek, Ruud Skepner, Eugene Halpin, Rebecca A. de Jong, Jan C. Rimmelzwaan, Guus F. Osterhaus, Albert D. M. E. Smith, Derek J. Wentworth, David E. Fouchier, Ron A. M. de Graaf, Miranda TI Genomewide Analysis of Reassortment and Evolution of Human Influenza A(H3N2) Viruses Circulating between 1968 and 2011 SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; HONG-KONG INFLUENZA; A H3N2 VIRUSES; ANTIGENIC DRIFT; NS1 PROTEIN; ADAMANTANE RESISTANCE; PHYLOGENETIC ANALYSIS; NEURAMINIDASE GENES; MAXIMUM-LIKELIHOOD; SEQUENCE VARIATION AB Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the evolution of these viruses. IMPORTANCE Each winter, influenza virus infects approximately 5 to 15% of the world's population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and genomic evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic evolution in correlation with antigenic evolution of influenza A(H3N2) viruses. C1 [Westgeest, Kim B.; Spronken, Monique I. J.; Bestebroer, Theo M.; van Beek, Ruud; de Jong, Jan C.; Rimmelzwaan, Guus F.; Osterhaus, Albert D. M. E.; Smith, Derek J.; Fouchier, Ron A. M.; de Graaf, Miranda] Erasmus MC, Dept Virosci, Rotterdam, Netherlands. [Russell, Colin A.; Skepner, Eugene; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge, England. [Russell, Colin A.; Smith, Derek J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lin, Xudong; Wentworth, David E.] SUNY Albany, Sch Publ Hlth, Albany, NY USA. [Lin, Xudong; Halpin, Rebecca A.; Wentworth, David E.] J Craig Venter Inst, Rockville, MD USA. [Bahl, Justin] Univ Texas Houston, Sch Publ Hlth, Ctr Infect Dis, Houston, TX USA. RP de Graaf, M (reprint author), Erasmus MC, Dept Virosci, Rotterdam, Netherlands. EM m.degraaf@erasmusmc.nl RI Bahl, Justin/A-4728-2011; Fouchier, Ron/A-1911-2014; OI Bahl, Justin/0000-0001-7572-4300; Fouchier, Ron/0000-0001-8095-2869; Russell, Colin/0000-0002-2113-162X; Wentworth, David/0000-0002-5190-980X FU NWO-VICI grant; NIH [HHSN266200700010C]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C] FX This work was supported by an NWO-VICI grant and by NIH contract HHSN266200700010C. This project was also funded in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract HHSN272200900007C. NR 89 TC 32 Z9 33 U1 5 U2 29 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 MAR PY 2014 VL 88 IS 5 BP 2844 EP 2857 DI 10.1128/JVI.02163-13 PG 14 WC Virology SC Virology GA AA5JK UT WOS:000331131700042 PM 24371052 ER PT J AU Chen, GL Lamirande, EW Cheng, X Torres-Velez, F Orandle, M Jin, H Kemble, G Subbaraoa, K AF Chen, Grace L. Lamirande, Elaine W. Cheng, Xing Torres-Velez, Fernando Orandle, Marlene Jin, Hong Kemble, George Subbarao, Kanta TI Evaluation of Three Live Attenuated H2 Pandemic Influenza Vaccine Candidates in Mice and Ferrets SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-VACCINE; A VIRUSES; PROTECTION; EFFICACY; TRANSMISSION; TRIVALENT; SUBTYPES; ORIGIN; ADULTS; H3N2 AB H2 influenza viruses have not circulated in humans since 1968, and therefore a significant portion of the population would be susceptible to infection should H2 influenza viruses reemerge. H2 influenza viruses continue to circulate in avian reservoirs worldwide, and these reservoirs are a potential source from which these viruses could emerge. Three reassortant cold-adapted (ca) H2 pandemic influenza vaccine candidates with hemagglutinin (HA) and neuraminidase (NA) genes derived from the wildtype A/Japan/305/1957 (H2N2) (Jap/57), A/mallard/6750/1978 (H2N2) (mal/78), or A/swine/MO/4296424/2006 (H2N3) (sw/06) viruses and the internal protein gene segments from the A/Ann Arbor/6/60 ca virus were generated by plasmid-based reverse genetics (Jap/57 ca, mal/78 ca, and sw/06 ca, respectively). The vaccine candidates exhibited the in vitro phenotypes of temperature sensitivity and cold adaptation and were restricted in replication in the respiratory tract of ferrets. In mice and ferrets, the vaccines elicited neutralizing antibodies and conferred protection against homologous wild-type virus challenge. Of the three candidates, the sw/06 ca vaccine elicited cross-reactive antibodies and provided significant protection against the greatest number of heterologous viruses. These observations suggest that the sw/06 ca vaccine should be further evaluated in a clinical trial as an H2 pandemic influenza vaccine candidate. IMPORTANCE Influenza pandemics arise when novel influenza viruses are introduced into a population with little prior immunity to the new virus and often result in higher rates of illness and death than annual seasonal influenza epidemics. An influenza H2 subtype virus caused a pandemic in 1957, and H2 viruses circulated in humans till 1968. H2 influenza viruses continue to circulate in birds, and the development of an H2 influenza vaccine candidate is therefore considered a priority in preparing for future pandemics. However, we cannot predict whether a human H2 virus will reemerge or a novel avian H2 virus will emerge. We identified three viruses as suitable candidates for further evaluation as vaccines to protect against H2 influenza viruses and evaluated the immune responses and protection that these three vaccines provided in mice and ferrets. C1 [Chen, Grace L.; Lamirande, Elaine W.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Xing; Jin, Hong; Kemble, George] MedImmune, Mountain View, CA USA. [Torres-Velez, Fernando; Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Rockville, MD USA. RP Subbaraoa, K (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID). This research was performed as part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID, and MedImmune. X. C., H.J., and G. K. are employees of MedImmune, the manufacturer of seasonal live attenuated influenza virus vaccines. NR 25 TC 6 Z9 8 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2014 VL 88 IS 5 BP 2867 EP 2876 DI 10.1128/JVI.01829-13 PG 10 WC Virology SC Virology GA AA5JK UT WOS:000331131700044 PM 24371061 ER PT J AU Heilig, M AF Heilig, Markus TI Acamprosate: An Alcoholism Treatment That May Not Be What We Thought SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID CONSUMPTION C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20897 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr, Bethesda, MD 20897 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 NR 6 TC 4 Z9 4 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2014 VL 39 IS 4 BP 781 EP 782 DI 10.1038/npp.2013.272 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AA8KV UT WOS:000331345300001 PM 24518272 ER PT J AU Kimura, T Vukoti, K Lynch, DL Hurst, DP Grossfield, A Pitman, MC Reggio, PH Yeliseev, AA Gawrisch, K AF Kimura, Tomohiro Vukoti, Krishna Lynch, Diane L. Hurst, Dow P. Grossfield, Alan Pitman, Michael C. Reggio, Patricia H. Yeliseev, Alexei A. Gawrisch, Klaus TI Global fold of human cannabinoid type 2 receptor probed by solid-state C-13-, N-15-MAS NMR and molecular dynamics simulations SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID PROTEIN-COUPLED RECEPTOR; MUSCARINIC ACETYLCHOLINE-RECEPTOR; 2ND EXTRACELLULAR LOOP; RESOLUTION CRYSTAL-STRUCTURE; BETA(2) ADRENERGIC-RECEPTOR; BINDING-SITE CREVICE; CHEMICAL-SHIFTS; OPIOID RECEPTOR; LIGAND-BINDING; SEROTONIN RECEPTORS C1 [Kimura, Tomohiro; Vukoti, Krishna; Yeliseev, Alexei A.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Lynch, Diane L.; Hurst, Dow P.; Reggio, Patricia H.] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27402 USA. [Grossfield, Alan] Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. [Pitman, Michael C.] IBM Thomas J Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY 10598 USA. RP Yeliseev, AA (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N-17, Bethesda, MD 20892 USA. EM yeliseeva@mail.nih.gov; gawrisch@helix.nih.gov OI Grossfield, Alan/0000-0002-5877-2789 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; National Institutes of Health [RO1 DA003934, KO5 DA021358] FX Grant sponsor: T. K, K. V., A.A.Y, and K. G. were supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. This work was supported in part by National Institutes of Health Grants RO1 DA003934 and KO5 DA021358 to P.H.R. NR 66 TC 8 Z9 8 U1 2 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2014 VL 82 IS 3 BP 452 EP 465 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AA8TP UT WOS:000331368200011 PM 23999926 ER PT J AU Tobian, AAR Gaydos, C Gray, RH Kigozi, G Serwadda, D Quinn, N Grabowski, MK Musoke, R Ndyanabo, A Nalugoda, F Wawer, MJ Quinn, TC AF Tobian, Aaron A. R. Gaydos, Charlotte Gray, Ronald H. Kigozi, Godfrey Serwadda, David Quinn, Nicole Grabowski, Mary K. Musoke, Richard Ndyanabo, Anthony Nalugoda, Fred Wawer, Maria J. Quinn, Thomas C. TI Male circumcision and Mycoplasma genitalium infection in female partners: a randomised trial in Rakai, Uganda SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article DE Circumcision; Mycoplasma; Epidemiology (Clinical) ID SEX WORKERS; CHLAMYDIA-TRACHOMATIS; HUMAN-PAPILLOMAVIRUS; HIV PREVENTION; RISK-FACTORS; YOUNG MEN; WOMEN; PREVALENCE; KENYA; TRANSMISSION AB Objective Previous randomised trial data have demonstrated that male circumcision reduces Mycoplasma genitalium prevalence in men. We assessed whether male circumcision also reduces M genitalium infection in female partners of circumcised men. Methods HIV-negative men were enrolled and randomised to either male circumcision or control. Female partners of male trial participants from the intervention (n=437) and control (n=394) arms provided interview information and self-collected vaginal swabs that were tested for M genitalium by APTIMA transcription-mediated amplification-based assay. Prevalence risk ratios (PRR) and 95% CI of M genitalium prevalence in intervention versus control group were estimated using Poisson regression. Analysis was by intention-to-treat. An as-treated analysis was conducted to account for study-group crossovers. Results Male and female partner enrolment sociodemographic characteristics, sexual behaviours, and symptoms of sexually transmitted infections were similar between study arms. Female M genitalium prevalence at year 2 was 3.2% (14/437) in the intervention arm and 3.6% (14/394) in the control arm (PRR=0.90, 95% CI 0.43 to 1.89, p=0.78). In an as-treated analysis, the prevalence of M genitalium was 3.4% in female partners of circumcised men and 3.3% in female partners of uncircumcised men (PRR=1.01, 95% CI 0.48 to 2.12, p=0.97). Conclusions Contrary to findings in men, male circumcision did not affect M genitalium infection in female partners. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Tobian, Aaron A. R.; Gray, Ronald H.; Kigozi, Godfrey; Serwadda, David; Musoke, Richard; Ndyanabo, Anthony; Nalugoda, Fred; Wawer, Maria J.] Rakai Hlth Sci Program, Entebbe, Uganda. [Gaydos, Charlotte; Quinn, Thomas C.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Gray, Ronald H.; Grabowski, Mary K.; Wawer, Maria J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Bill and Melinda Gates Foundation [22006.02]; National Institutes of Health [U1AI51171]; Doris Duke Charitable Foundation [2011036]; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH; Doris Duke Charitable Foundation; NIH [1K23AI093152-01A1]; NIAID NIH [A1U0168613]; NIBIB NIH [U54EB007958] FX The trials were funded by the Bill and Melinda Gates Foundation (#22006.02) and the National Institutes of Health (#U1AI51171). The Doris Duke Charitable Foundation (grant #2011036) along with the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH provided laboratory support. The Fogarty International Center (#5D43TW001508 and #D43TW00015) contributed to training. AART was supported by the Doris Duke Charitable Foundation and NIH 1K23AI093152-01A1. CG was supported by NIAID NIH A1U0168613 and NIBIB NIH U54EB007958. NR 26 TC 3 Z9 3 U1 0 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 EI 1472-3263 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD MAR PY 2014 VL 90 IS 2 BP 150 EP 154 DI 10.1136/sextrans-2013-051293 PG 5 WC Infectious Diseases SC Infectious Diseases GA AA8IE UT WOS:000331338400018 PM 24259189 ER PT J AU Adepoju, A Micali, N Ogawa, K Hoeppner, DJ McKay, RDG AF Adepoju, Adedamola Micali, Nicola Ogawa, Kazuya Hoeppner, Daniel J. McKay, Ronald D. G. TI FGF2 and Insulin Signaling Converge to Regulate Cyclin D Expression in Multipotent Neural Stem Cells SO STEM CELLS LA English DT Article DE Cell culture; Cyclin; Fibroblast growth factor; Insulin; Neural stem cell ID FIBROBLAST-GROWTH-FACTOR; OLIGODENDROCYTE PROGENITOR CELLS; RECEPTOR TYROSINE KINASES; FACTOR-I; C-JUN; ENDOTHELIAL-CELLS; CEREBRAL-CORTEX; IGF-I; PROLIFERATION; DIFFERENTIATION AB The ex vivo expansion of stem cells is making major contribution to biomedical research. The multipotent nature of neural precursors acutely isolated from the developing central nervous system has been established in a series of studies. Understanding the mechanisms regulating cell expansion in tissue culture would support their expanded use either in cell therapies or to define disease mechanisms. Basic fibroblast growth factor (FGF2) and insulin, ligands for tyrosine kinase receptors, are sufficient to sustain neural stem cells (NSCs) in culture. Interestingly, real-time imaging shows that these cells become multipotent every time they are passaged. Here, we analyze the role of FGF2 and insulin in the brief period when multipotent cells are present. FGF2 signaling results in the phosphorylation of Erk1/2, and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels. Insulin signals through the PI3k/Akt pathway to regulate cyclins at the post-transcriptional level. This precise Boolean regulation extends our understanding of the proliferation of multipotent NSCs and provides a basis for further analysis of proliferation control in the cell states defined by real-time mapping of the cell lineages that form the central nervous system. Stem Cells 2014;32:770-778 C1 [Adepoju, Adedamola; Micali, Nicola; Ogawa, Kazuya; Hoeppner, Daniel J.; McKay, Ronald D. G.] NINDS, NIH, Bethesda, MD 20892 USA. [Adepoju, Adedamola] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. [Micali, Nicola; Ogawa, Kazuya; Hoeppner, Daniel J.; McKay, Ronald D. G.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP McKay, RDG (reprint author), Lieber Inst Brain Dev, 855 N Wolfe St, Baltimore, MD 21205 USA. EM daniel.hoeppner@libd.org; ronald.mckay@libd.org FU Intramural Research Program of the NIH, NINDS; Lieber Institute for Brain Development; Howard Hughes Medical Institute-NIH Research Scholars Program FX This research was supported in part by the Intramural Research Program of the NIH, NINDS, and the Lieber Institute for Brain Development. A.A. was supported by the Howard Hughes Medical Institute-NIH Research Scholars Program. NR 57 TC 4 Z9 4 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD MAR PY 2014 VL 32 IS 3 BP 770 EP 778 DI 10.1002/stem.1575 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA AA9BR UT WOS:000331389200015 PM 24155149 ER PT J AU Kim, S Chaudhry, A Lee, I Frank, JA AF Kim, Saejeong Chaudhry, Aneeka Lee, Inae Frank, Joseph A. TI Effects of Long-Term Hypoxia and Pro-Survival Cocktail in Bone Marrow-Derived Stromal Cell Survival SO STEM CELLS AND DEVELOPMENT LA English DT Article ID MESENCHYMAL STEM-CELLS; INFARCTED HEART; GROWTH-FACTOR; TRANSPLANTATION; EXPRESSION; THERAPY; DIFFERENTIATION; PROLIFERATION; PROSURVIVAL; ENGRAFTMENT C1 [Kim, Saejeong; Chaudhry, Aneeka; Lee, Inae; Frank, Joseph A.] NIH, Ctr Clin, Frank Lab, Bethesda, MD 20892 USA. [Frank, Joseph A.] NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. RP Kim, S (reprint author), NIH, Radiol & Imaging Sci Clin Ctr, Frank Lab, Bldg 10,Room B1N256,10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. EM kimsn@cc.nih.gov FU intramural research program of the Clinical Center; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This research was supported by the intramural research program of the Clinical Center and National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. We thank Dr. Pamela Robey for critical discussions and manuscript review. BMSCs were supplied by Dr. Pamela Robey and Dr. Marianna Sabatino at the Center for Bone Marrow Stromal Cell Transplantation at the NIH. NR 42 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD MAR 1 PY 2014 VL 23 IS 5 BP 530 EP 540 PG 11 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA AA9DX UT WOS:000331395100008 PM 24147599 ER PT J AU Longmire, MR Ogawa, M Choyke, PL Kobayashi, H AF Longmire, Michelle R. Ogawa, Mikako Choyke, Peter L. Kobayashi, Hisataka TI Dendrimers as high relaxivity MR contrast agents SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID ACUTE-RENAL-FAILURE; MAGNETIC-RESONANCE LYMPHANGIOGRAPHY; DYNAMIC MICRO-MRI; PHARMACOKINETIC PROPERTIES; NEXT-GENERATION; DRUG-DELIVERY; CANCER; CORES; ANGIOGRAPHY; SIGNALS AB Dendrimers are versatile macromolecules with tremendous potential as magnetic resonance imaging (MRI) contrast agents. Dendrimer-based agents provide distinct advantages over low-molecular-weight gadolinium chelates, including enhanced r1 relaxivity due to slow rotational dynamics, tunable pharmacokinetics that can be adapted for blood pool, liver, kidney, and lymphatic imaging, the ability to be a drug carrier, and flexibility for labeling due to their inherent multivalency. Clinical applications are increasingly being developed, particularly in lymphatic imaging. Herein we present a broad overview of dendrimer-based MRI contrast agents with attention to the unique chemistry and physical properties as well as emerging clinical applications. For further resources related to this article, please visit the . (C) 2013 Wiley Periodicals, Inc. C1 [Longmire, Michelle R.; Ogawa, Mikako; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 44 TC 15 Z9 15 U1 5 U2 52 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5116 EI 1939-0041 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD MAR PY 2014 VL 6 IS 2 BP 155 EP 162 DI 10.1002/wnan.1250 PG 8 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA AA6MD UT WOS:000331211500003 PM 24155241 ER PT J AU Burroughs, AM Ando, Y Aravind, L AF Burroughs, Alexander Maxwell Ando, Yoshinari Aravind, L. TI New perspectives on the diversification of the RNA interference system: insights from comparative genomics and small RNA sequencing SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review ID CYTOPLASMIC POLY(A) POLYMERASE; PRIMARY PIRNA BIOGENESIS; 5.8S RIBOSOMAL-RNA; PRE-MESSENGER-RNA; TRYPANOSOMA-BRUCEI MITOCHONDRIA; PIWI-INTERACTING RNAS; REGULATORY SMALL RNAS; ENDOGENOUS SMALL RNAS; EMBRYONIC STEM-CELLS; SMALL NONCODING RNAS AB Our understanding of the pervasive involvement of small RNAs in regulating diverse biological processes has been greatly augmented by recent application of deep-sequencing technologies to small RNA across diverse eukaryotes. We review the currently known small RNA classes and place them in context of the reconstructed evolutionary history of the RNA interference (RNAi) protein machinery. This synthesis indicates that the earliest versions of eukaryotic RNAi systems likely utilized small RNA processed from three types of precursors: (1) sense-antisense transcriptional products, (2) genome-encoded, imperfectly complementary hairpin sequences, and (3) larger noncoding RNA precursor sequences. Structural dissection of PIWI proteins along with recent discovery of novel families (including Med13 of the Mediator complex) suggest that emergence of a distinct architecture with the N-terminal domains (also occurring separately fused to endoDNases in prokaryotes) formed via duplication of an ancestral unit was key to their recruitment as primary RNAi effectors and use of small RNAs of certain preferred lengths. Prokaryotic PIWI proteins are typically components of several RNA-directed DNA restriction or CRISPR/Cas systems. However, eukaryotic versions appear to have emerged from a subset that evolved RNA-directed RNAi. They were recruited alongside RNaseIII domains and RNA-dependent RNA polymerase (RdRP) domains, also from prokaryotic systems, to form the core eukaryotic RNAi system. Like certain regulatory systems, RNAi diversified into two distinct but linked arms concomitant with eukaryotic nucleocytoplasmic compartmentalization. Subsequent elaboration of RNAi proceeded via diversification of the core protein machinery through lineage-specific expansions and recruitment of new components from prokaryotes (nucleases and small RNA-modifying enzymes), allowing for diversification of associating small RNAs. (C) 2013 John Wiley & Sons, Ltd. C1 Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. [Burroughs, Alexander Maxwell; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Ando, Yoshinari] Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Burroughs, AM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM burrough@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX AMB and LA's research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 314 TC 16 Z9 17 U1 4 U2 59 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD MAR PY 2014 VL 5 IS 2 BP 141 EP 181 DI 10.1002/wrna.1210 PG 41 WC Cell Biology SC Cell Biology GA AA6LV UT WOS:000331210700001 PM 24311560 ER PT J AU Casey, AH Silberberg, A Paukner, A Suomi, SJ AF Casey, Anna H. Silberberg, Alan Paukner, Annika Suomi, Stephen J. TI Defining reward value by cross-modal scaling SO ANIMAL COGNITION LA English DT Article DE Choice; Reward value; Substitutability; Cross-modal scaling; Economics; Monkey ID INEQUITY; MONKEYS; GRATIFICATION; CHIMPANZEES; RESPONSES; STRENGTH; DELAY AB Researchers in comparative psychology often use different food rewards in their studies, with food values defined by a pre-experimental preference test. While this technique rank orders food values, it provides limited information about value differences because preferences may reflect not only value differences, but also the degree to which one good may "substitute" for another (e.g., one food may substitute well for another food, but neither substitutes well for water). We propose scaling the value of food pairs by a third food that is less substitutable for either food offered in preference tests (cross-modal scaling). Here, Cebus monkeys chose between four pairwise alternatives: fruits A versus B; cereal amount X versus fruit A and cereal amount Y versus fruit B where X and Y were adjusted to produce indifference between each cereal amount and each fruit; and cereal amounts X versus Y. When choice was between perfect substitutes (different cereal amounts), preferences were nearly absolute; so too when choice was between close substitutes (fruits); however, when choice was between fruits and cereal amounts, preferences were more modest and less likely due to substitutability. These results suggest that scaling between-good value differences in terms of a third, less-substitutable good may be better than simple preference tests in defining between-good value differences. C1 [Casey, Anna H.; Silberberg, Alan] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Paukner, Annika; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Poolesville, MD USA. RP Casey, AH (reprint author), Amer Univ, Dept Psychol, Washington, DC 20016 USA. EM annahcasey@gmail.com; asilber@american.edu FU Intramural NIH HHS [Z99 HD999999] NR 19 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1435-9448 EI 1435-9456 J9 ANIM COGN JI Anim. Cogn. PD MAR PY 2014 VL 17 IS 2 BP 177 EP 183 DI 10.1007/s10071-013-0650-y PG 7 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA AA2WV UT WOS:000330955800002 PM 23771492 ER PT J AU Tan, S Yao, JH Flynn, JA Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Flynn, John A. Yao, Lawrence Ward, Michael M. TI Quantitative measurement of syndesmophyte volume and height in ankylosing spondylitis using CT SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article DE Ankylosing Spondylitis; Spondyloarthritis; Arthritis ID ABDOMINAL COMPUTED-TOMOGRAPHY; RADIOGRAPHIC PROGRESSION; INFLAMMATORY LESIONS; DOSE REDUCTION; SPINE; INDEX AB Objective Syndesmophyte growth in ankylosing spondylitis can be difficult to measure using radiographs because of poor visualisation and semiquantitative scoring methods. We developed and tested the reliability and validity of a new computer-based method that fully quantifies syndesmophyte volumes and heights on CT scans. Methods In this developmental study, we performed lumbar spine CT scans on 38 patients and used our algorithm to compute syndesmophyte volume and height in four intervertebral disk spaces. To assess reliability, we compared results between two scans performed on the same day in nine patients. To assess validity, we compared computed measures to visual ratings of syndesmophyte volume and height on both CT scans and radiographs by two physician readers. Results Coefficients of variation for syndesmophyte volume and height, based on repeat scans, were 2.05% and 2.40%, respectively. Based on Bland-Altman analysis, an increase in syndesmophyte volume of more than 4% or in height of more than 0.20mm represented a change greater than measurement error. Computed volumes and heights were strongly associated with physician ratings of syndesmophyte volume and height on visual examination of both the CT scans (p<0.0001) and plain radiographs (p<0.002). Syndesmophyte volumes correlated with the Schober test (r=-0.48) and lateral thoracolumbar flexion (r=-0.60). Conclusions This new CT-based method that fully quantifies syndesmophytes in three-dimensional space had excellent reliability and face and construct validity. Given its high precision, this method shows promise for longitudinal clinical studies of syndesmophyte development and growth. C1 [Tan, Sovira; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Yao, Jianhua; Yao, Lawrence] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Flynn, John A.] Johns Hopkins Med Inst, Sch Med, Baltimore, MD 21205 USA. RP Ward, MM (reprint author), NIAMSD, Bldg 10 CRC,Room 4-1339, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; Clinical Center, National Institutes of Health; Johns Hopkins University School of Medicine General Clinical Research Center from the National Center for Research Resources/NIH [M01-RR00052] FX This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and by the Clinical Center, National Institutes of Health, and the Johns Hopkins University School of Medicine General Clinical Research Center (grant number M01-RR00052 from the National Center for Research Resources/NIH). NR 28 TC 8 Z9 9 U1 1 U2 3 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 MAR PY 2014 VL 73 IS 3 BP 544 EP 550 DI 10.1136/annrheumdis-2012-202661 PG 7 WC Rheumatology SC Rheumatology GA AA0VK UT WOS:000330815300015 PM 23345598 ER PT J AU Castri, P Lee, YJ Ponzio, T Maric, D Spatz, M Bembry, J Hallenbeck, J AF Castri, Paola Lee, Yang-ja Ponzio, Todd Maric, Dragan Spatz, Maria Bembry, Joliet Hallenbeck, John TI Poly(ADP-ribose) polymerase-1 and its cleavage products differentially modulate cellular protection through NF-kB-dependent signaling SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE PARP-1; ARTD1; Brain ischemia; OGD; NF-kB ID ADP-RIBOSE POLYMERASE-1; KAPPA-B ACTIVATION; CEREBRAL-ISCHEMIA; DNA-BINDING; INFLAMMATION; APOPTOSIS; TRANSCRIPTION; DISEASE; PARP-1; CELLS AB Poly(ADP-ribose) polymerase-1 (PARP-1) and its cleavage products regulate cell viability and NF-kB activity when expressed in neurons. PARP-1 cleavage generates a 24 kDa (PARP-1(24)) and an 89 kDa fragment (PARP-1(89)). Compared to WT (PARP-1(WT)), the expression of an uncleavable PARP-1 (PARP-1(UNCL)) or of PARP-1(24) conferred protection from oxygen/glucose deprivation (OGD) or OGD/restoration of oxygen and glucose (ROG) damage in vitro, whereas expression of PARP-189 was cytotoxic. Viability experiments were performed in SH-SY5Y, a human neuroblastoma cell line, as well as in rat primary cortical neurons. Following OGD, the higher viability in the presence of PARP-1(UNCL) or PARP-1(24) was not accompanied with decreased formation of poly(ADP-riboses) or higher NAD levels. PARP-1 is a known cofactor for NF-kB, hence we investigated whether PARP-1 cleavage influences the inflammatory response. All PARP-1 constructs mimicked PARP-1(WT) in regard to induction of NF-kB translocation into the nucleus and its increased activation during ischemic challenge. However, expression of PARP-189 construct induced significantly higher NF-kB activity than PARP-1; and the same was true for NF-kB-dependent iNOS promoter binding activity. At a protein level, PARP-1(UNCL) and PARP-1(24) decreased iNOS (and lower levels of iNOS transcript) and COX-2, and increased Bc1-xL. The increased levels of NF-kB and iNOS transcriptional activities, seen with cytotoxic PARP-189, were accompanied by higher protein expression of COX-2 and iNOS (and higher levels of INOS transcript) and lower protein expression of Bc1-xL. Taken together, these findings suggest that PARP-1 cleavage products may regulate cellular viability and inflammatory responses in opposing ways during in vitro models of "ischemia". Published by Elsevier B.V. C1 [Castri, Paola; Lee, Yang-ja; Spatz, Maria; Bembry, Joliet; Hallenbeck, John] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Ponzio, Todd] NINDS, Lab Neurochem, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Castri, P (reprint author), NINDS, Stroke Branch, NIH, Bldg 10,Room 5B06,9000 Rockville Pike, Bethesda, MD 20892 USA. EM castrip@mail.nih.gov FU Intramural Research Program of the NIH, NINDS/NIH FX This research was supported by the Intramural Research Program of the NIH, NINDS/NIH. No conflict of interest to disclose. NR 54 TC 6 Z9 7 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAR PY 2014 VL 1843 IS 3 BP 640 EP 651 DI 10.1016/j.bbamcr.2013.12.005 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AA0XP UT WOS:000330821000014 PM 24333653 ER PT J AU Eichholzer, M Richard, A Nicastro, HL Platz, EA Linseisen, J Rohrmann, S AF Eichholzer, Monika Richard, Aline Nicastro, Holly L. Platz, Elizabeth A. Linseisen, Jakob Rohrmann, Sabine TI Urinary lignans and inflammatory markers in the US National Health and Nutrition Examination Survey (NHANES) 1999-2004 and 2005-2008 SO CANCER CAUSES & CONTROL LA English DT Article DE Mammalian lignans; C-reactive protein; White blood cell count; Cross-sectional study ID C-REACTIVE PROTEIN; HORMONE REPLACEMENT THERAPY; BLOOD-CELL COUNT; CARDIOVASCULAR-DISEASE; PHYTOESTROGEN CONCENTRATIONS; PHYSICAL-ACTIVITY; UNITED-STATES; RISK-FACTORS; CANCER-RISK; POPULATION AB Chronic inflammation has been implicated in the etiology of various chronic diseases. We previously found that certain urinary isoflavones are associated with markers of inflammation. In the present study, we examined the associations of serum C-reactive protein (CRP) and white blood cell (WBC) count with lignans, which are more frequent in the Western diet than isoflavones. Our analysis included 2,028 participants of NHANES 2005-2008 and 2,628 participants of NHANES 1999-2004 aged 18 years and older. The exposures of interest were urinary mammalian lignans (enterodiol and enterolactone). Outcome variables were two inflammatory markers (CRP [a parts per thousand currency sign10 mg/L] and WBC [a parts per thousand yen3.0 and a parts per thousand currency sign11.7 (1,000 cells/mu L)]). Log-transformed CRP concentration and WBC count by log-transformed creatinine-standardized concentrations of mammalian lignans were used for linear regression. Statistically significant inverse associations of urinary lignan, enterodiol, and enterolactone concentrations with circulating CRP and WBC counts were observed in the multivariate-adjusted models: In NHANES 2005-2008, per one-percent increase in lignan concentrations in the urine, CRP concentrations and WBC counts decreased by 8.1 % (95 % CI -11.5, -4.5) and 1.9 % (95 % CI -2.7; -1.2), respectively. Per one-percent increase in enterodiol and enterolactone, WBC counts decreased by 2.1 % (95 % CI -2.8, -1.3) and 1.3 % (95 % CI -1.9, -0.6), respectively. In NHANES 1999-2004, analogous results were 3.0 % (95 % CI -5.6, -0.3), 1.2 % (95 % CI -2.0; -0.4), 1.0 % (95 % CI -1.8, -0.2), and 0.8 % (95 % CI -1.4, 0.2). Mammalian lignans were inversely associated with markers of chronic inflammation. Due to the cross-sectional design, our findings require confirmation in prospective studies. C1 [Eichholzer, Monika; Richard, Aline; Rohrmann, Sabine] Univ Zurich, Inst Social & Prevent Med, Div Canc Epidemiol & Prevent, CH-8001 Zurich, Switzerland. [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Platz, Elizabeth A.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Linseisen, Jakob] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. RP Eichholzer, M (reprint author), Univ Zurich, Inst Social & Prevent Med, Div Canc Epidemiol & Prevent, Hirschengraben 84, CH-8001 Zurich, Switzerland. EM monika.eichholzer@ifspm.uzh.ch FU Swiss Foundation for Nutrition Research (SFEFS; Zurich, Switzerland) FX This work was supported by the Swiss Foundation for Nutrition Research (SFEFS; Zurich, Switzerland). We thank all individuals at the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention who were responsible for the planning and administering of NHANES. NR 56 TC 4 Z9 4 U1 0 U2 7 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 MAR PY 2014 VL 25 IS 3 BP 395 EP 403 DI 10.1007/s10552-014-0340-3 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AA2ZU UT WOS:000330963500012 PM 24463788 ER PT J AU Kar, AN Sun, CY Reichard, K Gervasi, NM Pickel, J Nakazawa, K Gioio, AE Kaplan, BB AF Kar, Amar N. Sun, Ching-Yu Reichard, Kathryn Gervasi, Noreen M. Pickel, James Nakazawa, Kazu Gioio, Anthony E. Kaplan, Barry B. TI Dysregulation of the Axonal Trafficking of Nuclear-Encoded Mitochondrial mRNA Alters Neuronal Mitochondrial Activity and Mouse Behavior SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE axonal mRNAs; mitochondrial mRNAs; intra-axonal protein synthesis; energy metabolism; ROS generation; anxiety-like behavior ID MEDIAL PREFRONTAL CORTEX; LOCAL PROTEIN-SYNTHESIS; ANXIETY-LIKE BEHAVIORS; ELEVATED PLUS-MAZE; SYMPATHETIC NEURONS; OXIDATIVE-PHOSPHORYLATION; NADPH-OXIDASE; LOCALIZATION; STRESS; TRANSLATION AB Local translation of nuclear-encoded mitochondrial mRNAs is essential for mitochondrial activity, yet there is little insight into the role that axonal trafficking of these transcripts play in neuronal function and behavior. Previously, we identified a 38 nucleotide stem-loop structure (zipcode) in the 3' untranslated region of the Cytochrome C oxidase IV (COXIV) mRNA that directs the transport of a reporter mRNA to the axon of superior cervical ganglion neurons (SCG). Overexpression of a chimeric reporter mRNA with the COXIV zipcode competed with the axonal trafficking of endogenous COXIV mRNA, and led to attenuated axon growth in SCG neurons. Here, we show that exogenous expression of the COXIV zipcode in cultured SCG neurons also results in the reduction of local ATP levels and increases levels of reactive oxygen species (ROS) in the axon. We took advantage of this competition phenotype to investigate the in vivo significance of axonal transport of COXIV mRNA. Toward this end, we generated transgenic mice expressing a fluorescent reporter fused to COXIV zipcode under a forebrain-specific promoter. Immunohistological analyses and RT-PCR analyses of RNA from the transgenic mouse brain showed expression of the reporter in the deep layer neurons in the pre-frontal and frontal cortex. Consistent with the in vitro studies, we observed increased ROS levels in neurons of these transgenic animals. A battery of behavioral tests on transgenic mice expressing the COXIV zipcode revealed an anxiety-like behavioral phenotype, suggesting an important role for axonal trafficking of nuclear-encoded mitochondrial mRNAs in neuronal physiology and animal behavior. (c) 2013 Wiley Periodicals, Inc. *Develop Neurobiol 74: 333-350, 2014 C1 [Kar, Amar N.; Sun, Ching-Yu; Reichard, Kathryn; Gervasi, Noreen M.; Gioio, Anthony E.; Kaplan, Barry B.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. [Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Bethesda, MD 20892 USA. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kaplanb@mail.nih.gov RI Nakazawa, Kazutoshi/J-6195-2015; OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Kar, Amar/0000-0003-2380-7504 FU Division of Intramural Research Programs of the National Institute of Mental Health [ZIAMH002768] FX Contract grant sponsor: Division of Intramural Research Programs of the National Institute of Mental Health; contract grant number: ZIAMH002768. NR 42 TC 8 Z9 9 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAR PY 2014 VL 74 IS 3 SI SI BP 333 EP 350 DI 10.1002/dneu.22141 PG 18 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA AA1KG UT WOS:000330854500012 PM 24151253 ER PT J AU Calliari, A Farias, J Puppo, A Canclini, L Mercer, JA Munroe, D Sotelo, JR Sotelo-Silveira, JR AF Calliari, Aldo Farias, Joaquina Puppo, Agostina Canclini, Lucia Mercer, John A. Munroe, David Sotelo, Jose R. Sotelo-Silveira, Jose R. TI Myosin Va Associates With mRNA in Ribonucleoprotein Particles Present in Myelinated Peripheral Axons and in the Central Nervous System SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE RNA transport; ribonucleoprotein complexes; RNP; myosin Va; axon ID PERIAXOPLASMIC RIBOSOMAL PLAQUES; ZIPCODE-BINDING-PROTEIN; GROWTH CONES; SYMPATHETIC NEURONS; NEURITE OUTGROWTH; PC12 CELLS; FRAGILE-X; LOCALIZATION; ACTIN; TRANSLATION AB Sorting of specific mRNAs to particular cellular locations and regulation of their translation is an essential mechanism underlying cell polarization. The transport of RNAs by kinesins and dyneins has been clearly established in several cell models, including neurons in culture. A similar role appears to exist in higher eukaryotes for the myosins. Myosin Va (Myo5a) has been described as a component of ribonucleoprotein particles (RNPs) in the adult rat nervous system and associated to ZBP1 and ribosomes in ribosomal periaxoplasmic plaques (PARPs), making it a likely candidate for mediating some aspects of RNA transport in neurons. To test this hypothesis, we have characterized RNPs containing Myo5a in adult brains of rats and mice. Microarray analysis of RNAs co-immunoprecipitated with Myo5a indicates that this motor may associate with a specific subpopulation of neuronal mRNAs. We found mRNAs encoding -synuclein and several proteins with functions in translation in these RNPs. Immunofluorescence analyses of RNPs showed apparent co-localization of Myo5a with ribosomes, mRNA and RNA-binding proteins in discrete structures present both in axons of neurons in culture and in myelinated fibers of medullary roots. Our data suggest that PARPs include RNPs bearing the mRNA coding for Myo5a and are equipped with kinesin and Myo5a molecular motors. In conclusion, we suggest that Myo5a is involved in mRNA trafficking both in the central and peripheral nervous systems. (c) 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 382-396, 2014 C1 [Calliari, Aldo; Puppo, Agostina; Canclini, Lucia; Sotelo, Jose R.] Inst Invest Biol Clemente Estable, Dept Prot & Nucle Acids, Montevideo, Uruguay. [Calliari, Aldo] UdelaR, Sch Vet, Dept Mol & Cellular Biol, Montevideo, Uruguay. [Farias, Joaquina; Sotelo-Silveira, Jose R.] Inst Invest Biol Clemente Estable, Dept Genet, Montevideo, Uruguay. [Mercer, John A.] McLaughlin Res Inst, Great Falls, MT USA. [Mercer, John A.] Natl Ctr Biol Sci, Inst Stem Cell Biol & Regenerat Med, Bangalore, Karnataka, India. [Munroe, David] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Sotelo-Silveira, Jose R.] UdelaR, Sch Sci, Dept Cell & Mol Biol, Montevideo, Uruguay. RP Sotelo-Silveira, JR (reprint author), Inst Invest Biol Clemente Estable, Dept Genet, Montevideo, Uruguay. EM jsotelosilveira@iibce.edu.uy OI Mercer, John/0000-0003-0307-4438 FU University of the Republic (CSIC- UdelaR, Uruguay); Program for the Development of Basic Sciences (PEDECIBA, Uruguay); National Agency for Research and Innovation (ANII, Uruguay) FX Contract grant sponsor: I+D Grants of the University of the Republic (CSIC- UdelaR, Uruguay), the Program for the Development of Basic Sciences (PEDECIBA, Uruguay), and the National Agency for Research and Innovation (ANII, Uruguay). NR 61 TC 3 Z9 3 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAR PY 2014 VL 74 IS 3 SI SI BP 382 EP 396 DI 10.1002/dneu.22155 PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA AA1KG UT WOS:000330854500015 PM 24272908 ER PT J AU Brooks, PJ Zakhari, S AF Brooks, Philip J. Zakhari, Samir TI Acetaldehyde and the Genome: Beyond Nuclear DNA Adducts and Carcinogenesis SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE Fanconi anemia; alcochol metabolism; protein adducts; mitochondria; epigenetics ID ALDEHYDE DEHYDROGENASE; HUMAN-CELLS; TRANSLESION SYNTHESIS; HUMAN CANCER; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; MEDIATED CARCINOGENESIS; CHEMICAL CARCINOGENESIS; XERODERMA-PIGMENTOSUM; MOLECULAR-MECHANISMS; ETHANOL-CONSUMPTION AB The designation of acetaldehyde associated with the consumption of alcoholic beverages as carcinogenic to humans (Group 1) by the International Agency for Research on Cancer (IARC) has brought renewed attention to the biological effects of acetaldehyde, as the primary oxidative metabolite of alcohol. Therefore, the overall focus of this review is on acetaldehyde and its direct and indirect effects on the nuclear and mitochondrial genome. We first consider different acetaldehyde-DNA adducts, including a critical assessment of the evidence supporting a role for acetaldehyde-DNA adducts in alcohol related carcinogenesis, and consideration of additional data needed to make a conclusion. We also review recent data on the role of the Fanconi anemia DNA repair pathway in protecting against acetaldehyde genotoxicity and carcinogenicity, as well as teratogenicity. We also review evidence from the older literature that acetaldehyde may impact the genome indirectly, via the formation of adducts with proteins that are themselves critically involved in the maintenance of genetic and epigenetic stability. Finally, we note the lack of information regarding acetaldehyde effects on the mitochondrial genome, which is notable since aldehyde dehydrogenase 2 (ALDH2), the primary acetaldehyde metabolic enzyme, is located in the mitochondrion, and roughly 30% of East Asian individuals are deficient in ALDH2 activity due to a genetic variant in the ALDH2 gene. In summary, a comprehensive understanding of all of the mechanisms by which acetaldehyde impacts the function of the genome has implications not only for alcohol and cancer, but types of alcohol related pathologies as well. Environ. Mol. Mutagen. 55:77-91, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Brooks, Philip J.; Zakhari, Samir] NIAAA, Div Metab & Hlth Effects, Bethesda, MD 20892 USA. RP Brooks, PJ (reprint author), NIAAA, Div Metab & Hlth Effects, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. EM pjbrooks@mail.nih.gov NR 106 TC 24 Z9 27 U1 1 U2 54 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD MAR PY 2014 VL 55 IS 2 BP 77 EP 91 DI 10.1002/em.21824 PG 15 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA AA6QO UT WOS:000331223200001 PM 24282063 ER PT J AU Laudisio, A Milaneschi, Y Bandinelli, S Gemma, A Ferrucci, L Incalzi, RA AF Laudisio, Alice Milaneschi, Yuri Bandinelli, Stefania Gemma, Antonella Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Chewing problems are associated with depression in the elderly: results from the InCHIANTI study SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE chewing problems; depression; elderly; epidemiology ID QUALITY-OF-LIFE; OLDER-ADULTS; MASTICATORY DYSFUNCTION; ABILITY; SYMPTOMS; HEALTH; HOSPITALIZATION; REPRODUCIBILITY; MORTALITY; FREQUENCY AB ObjectiveDepression is increasingly recognized in older populations and associated with undernutrition, disability, and increased mortality. Chewing problems (CPs) share with depression these associations. The aim of the study was to evaluate the association, if any, between CPs and depression in older subjects. MethodsWe assessed 927 participants aged 65years and older, derived from the InCHIANTI' study. Mood was evaluated using the CES-D scale and defined depressed by a CES-D score 20. CPs were self-reported. Logistic regression was performed to assess the adjusted association between depression and CPs. The adjusted model was analyzed after stratifying for use of complete, partial dentures and edentulism. ResultsChewing problems were reported by 293/927 (31.6%) participants. Depression was present in 188/927(20.3%) participants. In multivariable logistic regression, CPs were associated with depression (OR=1.81, 95% CI=1.26-2.58; p=0.001). No significant association was found among subjects who used complete dentures (OR=1.12, 95% CI=0.80-1.58, p=0.515). Up to 27.8% of prevalent depression might be attributed to CPs. ConclusionsChewing problems are associated with depression in elderly population. Use of complete dentures hinder this association. Older depressed subjects should be screened for the presence of CPs; further studies are needed to evaluate the impact of early detection and correction of CPs on the development of depression. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Laudisio, Alice; Incalzi, Raffaele Antonelli] Campus Biomed Univ, Area Geriatria, Rome, Italy. [Milaneschi, Yuri; Ferrucci, Luigi] Natl Inst Aging, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD USA. [Milaneschi, Yuri] Vrije Univ Amsterdam, GGZ inGeest, Ctr Med, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri] Vrije Univ Amsterdam, GGZ inGeest, Ctr Med, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Rehabil Unit, Florence, Italy. [Gemma, Antonella] Azienda Sanitaria Locale Roma E, UOS Accesso & Presa Car Assistenziale, Rome, Italy. RP Laudisio, A (reprint author), Campus Biomed Univ, Area Geriatria, Rome, Italy. EM lavoralice@gmail.com OI Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging [263 MD 9164, 263 MD 821336] FX 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 US National Institute on Aging (Contracts 263 MD 9164 and 263 MD 821336). NR 35 TC 4 Z9 4 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 29 IS 3 BP 236 EP 244 DI 10.1002/gps.3995 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AA2EJ UT WOS:000330907600003 PM 23852611 ER PT J AU Wu, LT Brady, KT Mannelli, P Killeen, TK AF Wu, Li-Tzy Brady, Kathleen T. Mannelli, Paolo Killeen, Therese K. CA NIDA AAPI Workgrp TI Cannabis use disorders are comparatively prevalent among nonwhite racial/ethnic groups and adolescents: A national study SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Asian Americans; Cannabis use disorder; Mixed race; Native Americans; Pacific Islanders ID SUBSTANCE USE DISORDERS; NATIVE HAWAIIANS/PACIFIC ISLANDERS; AGE-OF-ONSET; MARIJUANA USE; MEDICAL MARIJUANA; PSYCHIATRIC-DISORDERS; DRUG-USE; NICOTINE DEPENDENCE; ASIAN-AMERICANS; UNITED-STATES AB The racial/ethnic composition of the US population is shifting, with the nonwhite population growing faster than whites. We examined cannabis use disorder (CUD) prevalences and correlates in seven racial/ethnic groups. We included cannabis use (CU) prevalence as a comparison. Data were from the 2005-2011 National Surveys on Drug Use and Health (N = 394,400). Substance use among respondents aged >= 12 years was assessed by computer-assisted, self-interviewing methods. The following were included as control variables: age, sex, family income, government assistance, county type, residential stability, major depressive episode history, arrest history, nicotine dependence, alcohol disorder, and survey year. Past-year CU prevalence increased significantly from 10.45% in 2005 to 11.41-11.54% during 2009-2011. Compared with whites, mixed-race individuals had higher odds of CU; Asian Americans and Hispanics had lower odds of CU. There were no significant yearly changes in CUD prevalence in the sample during 2005-2011 (1.58-1.73%). Compared with whites, individuals who were mixed-race, black, and Native American had higher odds of CUD; Asian Americans had lower odds. In aggregate, 15.35% of past-year cannabis users met criteria for a CUD in the 12-month period. Past-year cannabis users who were black, Native American, Hispanic, or Asian American had higher odds of CUD than white users. In each racial/ethnic group, adolescent cannabis users generally showed greater odds of CUD than adult users. Behavioral health indicators (major depressive episode, arrest history, nicotine dependence, alcohol disorder) were associated with CU and CUD. In conclusion, CUD disproportionally affects nonwhite groups and youth. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Wu, Li-Tzy; Mannelli, Paolo] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27710 USA. [Brady, Kathleen T.] Med Univ S Carolina, South Carolina Clin & Translat Res Inst, Charleston, SC 29425 USA. [Killeen, Therese K.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Clin Neurosci Div, Charleston, SC 29425 USA. [NIDA AAPI Workgrp] NIDA, Asian Amer & Pacific Islander Researchers & Schol, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Med Ctr, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institutes of Health [R01MD007658, HHSN271200900499P, R01DA019623, R01DA019901, R33DA027503, U10DA013727]; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine FX This work was made possible by research support from the U.S. National Institutes of Health (R01MD007658, HHSN271200900499P, R01DA019623, R01DA019901, R33DA027503 to Li-Tzy Wu; U10DA013727 to Kathleen T. Brady) and Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors. NR 57 TC 13 Z9 13 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAR PY 2014 VL 50 BP 26 EP 35 DI 10.1016/j.jpsychires.2013.11.010 PG 10 WC Psychiatry SC Psychiatry GA AA5SV UT WOS:000331160800004 PM 24342767 ER PT J AU de Sousa, RT Zarate, CA Zanetti, MV Costa, AC Talib, LL Gattaz, WF Machado-Vieira, R AF de Sousa, Rafael T. Zarate, Carlos A., Jr. Zanetti, Marcus V. Costa, Alana C. Talib, Leda L. Gattaz, Wagner F. Machado-Vieira, Rodrigo TI Oxidative stress in early stage Bipolar Disorder and the association with response to lithium SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Oxidative stress; Lithium; Bipolar; Disorder; Depression; Neuroprotection ID LIPID-PEROXIDATION; I DISORDER; RAT-BRAIN; MITOCHONDRIAL DYSFUNCTION; SUPEROXIDE-DISMUTASE; ANTIOXIDANT ENZYMES; PARKINSONS-DISEASE; GLUTAMATE UPTAKE; DOPAMINE; CELLS AB Background: Several studies have described increased oxidative stress (OxS) parameters and imbalance of antioxidant enzymes in Bipolar Disorder (BD) but few is know about the impact of treatment at these targets. However, no study has evaluated OxS parameters in unmedicated early stage BD and their association with lithium treatment in bipolar depression. Methods: Patients with BD I or II (n = 29) in a depressive episode were treated for 6 weeks with lithium. Plasma samples were collected at baseline and endpoint, and were also compared to age-matched controls (n = 28). The thiobarbituric acid reactive substances (TBARS), and the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were measured. Results: Subjects with BD depression at baseline presented a significant increase in CAT (p = 0.005) and GPx (p < 0.001) levels, with lower SOD/CAT ratio (p = 0.001) and no changes on SOD or TBARS compared to healthy controls. Regarding therapeutics, lithium only induced a decrease in TBARS (p = 0.023) and SOD (p = 0.029) levels, especially in BDII. Finally, TBARS levels were significantly lower at endpoint in lithium responders compared to non-responders (p = 0.018) with no difference in any biomarker regarding remission. Conclusion: The present findings suggest a reactive increase in antioxidant enzymes levels during depressive episodes in early stage BD with minimal prior treatment. Also, decreased lipid peroxidation (TBARS) levels were observed, associated with lithium's clinical efficacy. Overall, these results reinforce the role for altered oxidative stress in the pathophysiology of BD and the presence of antioxidant effects of lithium in the prevention of illness progression and clinical efficacy. Published by Elsevier Ltd. C1 [de Sousa, Rafael T.; Zanetti, Marcus V.; Costa, Alana C.; Talib, Leda L.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Lab Neurosci, LIM 27, BR-05508 Sao Paulo, Brazil. [Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, ETPB, NIH, Bethesda, MD 20892 USA. [Zanetti, Marcus V.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, BR-05508 Sao Paulo, Brazil. RP Machado-Vieira, R (reprint author), Sch Med, Inst & Dept Psychiat, Rua Ovidio Pires de Campos 785, BR-01060970 Sao Paulo, Brazil. EM machadovieirar@gmail.com RI Gattaz, Wagner/C-4456-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Sao Paulo Research Foundation (Fapesp) FX Sao Paulo Research Foundation (Fapesp) funded the study, but had no role in study design or analysis. NR 66 TC 43 Z9 44 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAR PY 2014 VL 50 BP 36 EP 41 DI 10.1016/j.jpsychires.2013.11.011 PG 6 WC Psychiatry SC Psychiatry GA AA5SV UT WOS:000331160800005 PM 24332923 ER PT J AU Yang, JL Lin, YT Chuang, PC Bohr, VA Mattson, MP AF Yang, Jenq-Lin Lin, Yu-Ting Chuang, Pei-Chin Bohr, Vilhelm A. Mattson, Mark P. TI BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1 SO NEUROMOLECULAR MEDICINE LA English DT Article DE Running; Base excision repair; Exercise; Alzheimer; Oxidative stress; Akt kinase; Synaptic plasticity; Comet assay ID BASE EXCISION-REPAIR; NEUROTROPHIC FACTOR; CELL-DEATH; NEURODEGENERATIVE DISORDERS; ALZHEIMERS-DISEASE; TRANSCRIPTIONAL REGULATION; CEREBRAL-ISCHEMIA; BRAIN; DAMAGE; NEUROPROTECTION AB Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1. C1 [Yang, Jenq-Lin; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Yang, Jenq-Lin; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Yang, Jenq-Lin; Lin, Yu-Ting] Kaohsiung Chang Gung Mem Hosp, Ctr Translat Res Biomed Sci, Kaohsiung 83301, Taiwan. [Chuang, Pei-Chin] Kaohsiung Chang Gung Mem Hosp, Dept Med Res, Kaohsiung 83301, Taiwan. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov OI Yang, Jenq-Lin/0000-0002-9897-8087 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; Chang Gung Medical Foundation [CLRPG871342, CMRPG8A0781, CRPG8B0051]; National Science Council Taiwan [NSC 101-2320-B-182A-007-, NSC 102-2320-B-182A-012-] FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Chang Gung Medical Foundation Grant No. CLRPG871342, CMRPG8A0781, CRPG8B0051, and research grants NSC 101-2320-B-182A-007- and NSC 102-2320-B-182A-012- from National Science Council Taiwan. NR 49 TC 24 Z9 30 U1 2 U2 24 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2014 VL 16 IS 1 BP 161 EP 174 DI 10.1007/s12017-013-8270-x PG 14 WC Neurosciences SC Neurosciences & Neurology GA AA4YF UT WOS:000331101900016 PM 24114393 ER PT J AU Huynh, N Jeffrey, BG Turriff, A Sieving, PA Cukras, CA AF Huynh, Nancy Jeffrey, Brett G. Turriff, Amy Sieving, Paul A. Cukras, Catherine A. TI Sorting out Co-occurrence of Rare Monogenic Retinopathies: Stargardt Disease Co-existing with Congenital Stationary Night Blindness SO OPHTHALMIC GENETICS LA English DT Article DE ABCA4; congenital stationary night blindness; electronegative ERG; GRM6; Stargardt disease ID CONE-ROD DYSTROPHY; FUNDUS FLAVIMACULATUS; RETINITIS-PIGMENTOSA; FLICKER ELECTRORETINOGRAM; SEQUENCE VARIATIONS; MACULAR DYSTROPHY; GRM6 GENE; MUTATIONS; ABCA4; MGLUR6 AB disorder is rare. Here, we report a case of Stargardt disease and congenital stationary night blindness (CSNB) in the same patient, and the identification of two novel in-frame deletions in the GRM6 gene. Materials and Methods: The patient underwent an ophthalmic exam and visual function testing including: visual acuity, color vision, Goldmann visual field, and electroretinography (ERG). Imaging of the retina included fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence. Genomic DNA was PCR-amplified for analysis of all coding exons and flanking splice sites of both the ABCA4 and GRM6 genes. Results: A 46-year-old woman presented with recently reduced central vision and clinical findings of characteristic yellow flecks consistent with Stargardt disease. However, ERG testing revealed an ERG phenotype unusual for Stargardt disease but consistent with CSNB1. Genetic testing revealed two previously reported mutations in the ABCA4 gene and two novel deletions in the GRM6 gene. Conclusions: Diagnosis of concurrent Stargardt disease and CSNB was made on the ophthalmic history, clinical examination, ERG, and genetic testing. This case highlights that clinical tests need to be taken in context, and that co-existing retinal dystrophies and degenerations should be considered when clinical impressions and objective data do not correlate. C1 [Huynh, Nancy; Jeffrey, Brett G.; Turriff, Amy; Sieving, Paul A.; Cukras, Catherine A.] NEI, NIH, Bethesda, MD 20892 USA. RP Cukras, CA (reprint author), 10 Ctr Dr,Bldg 10,Room 10C438, Bethesda, MD 20892 USA. EM cukrasc@nei.nih.gov FU National Institutes of Health/National Eye Institute [HHS-N-260-2007-00001-C] FX The DNA samples used for the analyses described in this manuscript were obtained from the National Eye Institute - National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (R)) Protocol 06-EI-0236, which has been funded in part from the National Institutes of Health/National Eye Institute, under Contract No. HHS-N-260-2007-00001-C. We would like to thank the eyeGENE (R) participants and the eyeGENE (R) Research Group for their valuable contribution to this research. We would also like to thank Chris Antolik for his discussions on the bioinformatics analysis. NR 32 TC 3 Z9 3 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1381-6810 EI 1744-5094 J9 OPHTHALMIC GENET JI Ophthalmic Genet. PD MAR PY 2014 VL 35 IS 1 BP 51 EP 56 DI 10.3109/13816810.2013.865762 PG 6 WC Genetics & Heredity; Ophthalmology SC Genetics & Heredity; Ophthalmology GA AA1IZ UT WOS:000330851100009 PM 24397708 ER PT J AU Baum, BJ AF Baum, B. J. TI Gene therapy SO ORAL DISEASES LA English DT Review DE gene therapy; mouth; oral diseases ID ADENOVIRAL-MEDIATED TRANSFER; INCREASED FLUID SECRETION; SALIVARY-GLANDS; AQUAPORIN-1 CDNA; SUBMANDIBULAR-GLANDS; NECK-CANCER; DELIVERY; TRIAL; THERAPEUTICS; HYPOFUNCTION AB Applications of gene therapy have been evaluated in virtually every oral tissue, and many of these have proved successful at least in animal models. While gene therapy will not be used routinely in the next decade, practitioners of oral medicine should be aware of the potential of this novel type of treatment that doubtless will benefit many patients with oral diseases. C1 [Baum, B. J.] Natl Inst Dent & Craniofacial Res, Gene Transfer Sect, NIH, Bethesda, MD USA. EM editor@bethesdaoralmed.com FU National Institute of Dental and Craniofacial Research, NIH FX I am very grateful to the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, for its many years of supporting my research related to salivary glands and gene therapy. NR 33 TC 3 Z9 3 U1 5 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD MAR PY 2014 VL 20 IS 2 BP 115 EP 118 DI 10.1111/odi.12211 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AA2EK UT WOS:000330907700001 PM 24372817 ER PT J AU Hinkle, SN Albert, PS Mendola, P Sjaarda, LA Yeung, E Boghossian, NS Laughon, SK AF Hinkle, Stefanie N. Albert, Paul S. Mendola, Pauline Sjaarda, Lindsey A. Yeung, Edwina Boghossian, Nansi S. Laughon, S. Katherine TI The Association between Parity and Birthweight in a Longitudinal Consecutive Pregnancy Cohort SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE pregnancy; birthweight; parity; siblings; birth order ID GESTATIONAL-AGE; PERINATAL-MORTALITY; CHANGING PATERNITY; SURVIVING SIBLINGS; FETAL-GROWTH; RISK; OUTCOMES; PREECLAMPSIA; WOMEN; STANDARDS AB BackgroundNulliparity is associated with lower birthweight, but few studies have examined how within-mother changes in risk factors impact this association. MethodsWe used longitudinal electronic medical record data from a hospital-based cohort of consecutive singleton live births from 2002-2010 in Utah. To reduce bias from unobserved pregnancies, primary analyses were limited to 9484 women who entered nulliparous from 2002-2004, with 23380 pregnancies up to parity 3. Unrestricted secondary analyses used 101225 pregnancies from 45212 women with pregnancies up to parity 7. We calculated gestational age and sex-specific birthweight z-scores with nulliparas as the reference. Using linear mixed models, we estimated birthweight z-score by parity adjusting for pregnancy-specific sociodemographics, smoking, alcohol, prepregnancy body mass index, gestational weight gain, and medical conditions. ResultsCompared with nulliparas', infants of primiparas were larger by 0.20 unadjusted z-score units [95% confidence interval (CI) 0.18, 0.22]; the adjusted increase was similar at 0.18 z-score units [95% CI 0.15, 0.20]. Birthweight continued to increase up to parity 3, but with a smaller difference (parity 3 vs. 0 =0.27 [95% CI 0.20, 0.34]). In the unrestricted secondary sample, there was significant departure in linearity from parity 1 to 7 (P<0.001); birthweight increased only up to parity 4 (parity 4 vs. 0 =0.34 [95% CI 0.31, 0.37]). ConclusionsThe association between parity and birthweight was non-linear with the greatest increase observed between first- and second-born infants of the same mother. Adjustment for changes in weight or chronic diseases did not change the relationship between parity and birthweight. C1 [Hinkle, Stefanie N.; Mendola, Pauline; Sjaarda, Lindsey A.; Yeung, Edwina; Boghossian, Nansi S.; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM laughonsk@mail.nih.gov RI Yeung, Edwina/F-5992-2015; Hinkle, Stefanie/F-8253-2013; OI Yeung, Edwina/0000-0002-3851-2613; Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200800002I, HHSN27500004] FX Financial Disclosure: Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers: HHSN275200800002I, HHSN27500004) NR 43 TC 8 Z9 8 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAR PY 2014 VL 28 IS 2 BP 106 EP 115 DI 10.1111/ppe.12099 PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA AA7JN UT WOS:000331273800005 PM 24320682 ER PT J AU Uhl, GR Drgonova, J Hall, FS AF Uhl, George R. Drgonova, Jana Hall, F. Scott TI Curious cases: Altered dose-response relationships in addiction genetics SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Cell adhesion molecule; Knockout mouse; Genome wide association; Cocaine; Alcohol; Smoking; caffeine ID GENOME-WIDE ASSOCIATION; SMOKING-CESSATION SUCCESS; CELL-ADHESION MOLECULE; TYROSINE-PHOSPHATASE-DELTA; T-CADHERIN; NICOTINE DEPENDENCE; NEUROTROPHIC FACTOR; ALCOHOL DEPENDENCE; PTP-DELTA; TRANSSYNAPTIC INTERACTION AB Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2) > p > 10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the alpha 5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Delta and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics. Published by Elsevier Inc. C1 [Uhl, George R.; Drgonova, Jana; Hall, F. Scott] NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU NIH IRP (NIDA) FX We acknowledge support from the NIH IRP (NIDA). Likewise, we thank Drs Barbara Ranscht, Noriko Uetani, Yoichiro Iwakura and Martin Grumet for their generous supply of mice used in the experiments, and also gratefully acknowledge Drs Amy Hart and Abraham Palmer for the unpublished results. We are grateful to numerous clinical collaborators and to research volunteers at sites including the NIDA IRP, PIRC and Duke Center for Nicotine and Smoking Research. NR 105 TC 10 Z9 11 U1 4 U2 19 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 MAR PY 2014 VL 141 IS 3 BP 335 EP 346 DI 10.1016/j.pharmthera.2013.10.013 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AA2IA UT WOS:000330917100007 PM 24189489 ER PT J AU Eisenberg, DP Berman, KF AF Eisenberg, Daniel Paul Berman, Karen F. TI Catechol-O-Methyltransferase and Genetic Variation Under Hemizygosity SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID MESSENGER-RNA; SCHIZOPHRENIA; GENOTYPE; PROTEIN; BRAIN; COMT C1 [Eisenberg, Daniel Paul; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Intramural Res Program,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, NIH, Bldg 10,Room 3C109,10 Ctr Dr,MSC 1365, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov RI Eisenberg, Daniel/S-4342-2016 FU Intramural NIH HHS [Z01 MH002652-15] NR 10 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2014 VL 75 IS 5 BP 346 EP 347 DI 10.1016/j.biopsych.2013.12.011 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 304CQ UT WOS:000330724100004 PM 24507568 ER PT J AU Gothelf, D Law, AJ Frisch, A Chen, J Zarchi, O Michaelovsky, E Ren-Patterson, R Lipska, BK Carmel, M Kolachana, B Weizman, A Weinberger, DR AF Gothelf, Doron Law, Amanda J. Frisch, Amos Chen, Jingshan Zarchi, Omer Michaelovsky, Elena Ren-Patterson, Renee Lipska, Barbara K. Carmel, Miri Kolachana, Bhaskar Weizman, Abraham Weinberger, Daniel R. TI Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome SO BIOLOGICAL PSYCHIATRY LA English DT Article DE COMT; DiGeorge; gene expression; haplotype; psychosis; velocardiofacial syndrome ID CATECHOL-O-METHYLTRANSFERASE; CARDIO-FACIAL SYNDROME; VELOCARDIOFACIAL SYNDROME; ENZYME-ACTIVITY; HUMAN BRAIN; PSYCHIATRIC-DISORDERS; PROTEIN EXPRESSION; PREFRONTAL CORTEX; GENETIC-VARIATION; MESSENGER-RNA AB Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Methods: Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing control subjects. We measured COMT messenger (m) RNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. Results: There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3' untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3' untranslated region single nucleotide polymorphism, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 "T" mutation is associated with absent soluble COMT expression and very low COMT activity in two 22q11.2DS individuals. Conclusions: Our findings confirma robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone. C1 [Gothelf, Doron; Zarchi, Omer] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Behav Neurogenet Ctr, Tel Hashomer, Israel. [Gothelf, Doron; Frisch, Amos; Zarchi, Omer; Weizman, Abraham] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Law, Amanda J.] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO USA. [Law, Amanda J.] Univ Colorado, Sch Med, Dept Cell & Dev Biol, Aurora, CO USA. [Law, Amanda J.; Chen, Jingshan; Ren-Patterson, Renee; Lipska, Barbara K.; Kolachana, Bhaskar; Weinberger, Daniel R.] NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Frisch, Amos; Michaelovsky, Elena; Carmel, Miri; Weizman, Abraham] Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Weinberger, Daniel R.] Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Dept Neurol, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Weinberger, DR (reprint author), Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, 855 Wolfe St, Baltimore, MD 21205 USA. EM drweinberger@libd.org RI Lipska, Barbara/E-4569-2017; OI Law, Amanda/0000-0002-2574-1564 FU March of Dimes [5-FY06-590]; Weinberger Lab at the National Institute of Mental Health Intramural Research Program FX This work was supported by grants from the March of Dimes (Grant No. 5-FY06-590 to DG) and direct funding of the Weinberger Lab at the National Institute of Mental Health Intramural Research Program. NR 40 TC 22 Z9 22 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2014 VL 75 IS 5 BP 406 EP 413 DI 10.1016/j.biopsych.2013.07.021 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 304CQ UT WOS:000330724100012 PM 23992923 ER PT J AU Shockley, KR AF Shockley, Keith R. TI Using Weighted Entropy to Rank Chemicals in Quantitative High-Throughput Screening Experiments SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE quantitative high-throughput screening; information theory; concentration response; Tox21 ID SHANNON ENTROPY; NONLINEAR-REGRESSION; ANDROGEN RECEPTORS; GENE-EXPRESSION; ESTROGEN AB Quantitative high-throughput screening (qHTS) experiments can simultaneously produce concentration-response profiles for thousands of chemicals. In a typical qHTS study, a large chemical library is subjected to a primary screen to identify candidate hits for secondary screening, validation studies, or prediction modeling. Different algorithms, usually based on the Hill equation logistic model, have been used to classify compounds as active or inactive (or inconclusive). However, observed concentration-response activity relationships may not adequately fit a sigmoidal curve. Furthermore, it is unclear how to prioritize chemicals for follow-up studies given the large uncertainties that often accompany parameter estimates from nonlinear models. Weighted Shannon entropy can address these concerns by ranking compounds according to profile-specific statistics derived from estimates of the probability mass distribution of response at the tested concentration levels. This strategy can be used to rank all tested chemicals in the absence of a prespecified model structure, or the approach can complement existing activity call algorithms by ranking the returned candidate hits. The weighted entropy approach was evaluated here using data simulated from the Hill equation model. The procedure was then applied to a chemical genomics profiling data set interrogating compounds for androgen receptor agonist activity. C1 [Shockley, Keith R.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Shockley, KR (reprint author), NIEHS, Biostat Branch, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM shockleykr@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [ZIA ES102865] FX The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES102865). NR 32 TC 3 Z9 3 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD MAR PY 2014 VL 19 IS 3 BP 344 EP 353 DI 10.1177/1087057113505325 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA AA0AD UT WOS:000330756600002 PM 24056003 ER PT J AU Chai, TC Richter, HE Moalli, P Keay, S Biggio, J Zong, WJ Curto, T Kim, HY Stoddard, AM Kusek, JW AF Chai, Toby C. Richter, Holly E. Moalli, Pamela Keay, Susan Biggio, Joseph Zong, Wenjun Curto, Teresa Kim, Hae-Young Stoddard, Anne M. Kusek, John W. TI Inflammatory and Tissue Remodeling Urinary Biomarkers before and after Mid Urethral Sling Surgery for Stress Urinary Incontinence SO JOURNAL OF UROLOGY LA English DT Article DE biological markers; urinary incontinence, stress; surgical procedures, operative; prognosis; treatment outcome ID NERVE GROWTH-FACTOR; BURCH COLPOSUSPENSION; OVERACTIVE BLADDER; BONE TURNOVER; WOMEN; PREDICTORS; OSTEOPOROSIS; CONTINENCE; MARKERS AB Purpose: Urinary biomarkers were measured in women at baseline and 1 year after surgery for stress urinary incontinence, and associations with clinicodemographic covariates and outcomes were analyzed. Materials and Methods: Preoperative and postoperative urine specimens from 150 women were assayed for inflammatory biomarkers (tumor necrosis factor-alpha, interferon-gamma, interleukin-1 beta, interleukin-6, interleukin-10, interleukin-12p70, interleukin-17 and nerve growth factor) and tissue remodeling biomarkers (collagenase activity, matrix metalloproteinases-1, 2, 9 and 13, and NTx [N-telopeptide cross-linked collagen], epidermal growth factor and heparin-binding epidermal growth factor-like growth factor). Paired t-tests were used to compare changes in biomarkers during 1 year (significance p < 0.05). Linear regression models correlated baseline and changes in biomarker levels with covariates (significance p <= 0.001). Logistic regression models, controlling for age, were used to analyze associations of baseline and changes in biomarker levels with surgical failure (significance p < 0.05). Results: During 1 year interleukin-12p70 decreased (mean +/- SD 0.53 +/- 1.4 to 0.28 +/- 0.62 pg/mg creatinine, p = 0.04) and nerve growth factor increased (0.034 +/- 0.046 to 0.044 +/- 0.060 pg/ml/mOsm, p = 0.03). Baseline NTx level per mg creatinine was positively associated with age and postmenopausal status (p = 0.001), and negatively associated with current estrogen use (p = 0.0001). Baseline collagenase activity per mg creatinine was positively associated with age (p = 0.001). Epidermal growth factor per mOsm, NTx per mOsm and interferon-g per mOsm were negatively correlated with age, current estrogen use and UDI (Urogenital Distress Inventory)-irritative subscale score, respectively (p <= 0.001). Subjects with lower baseline NTx per mg creatinine were less likely to experience surgical failure (OR 0.49, 95% CI 0.26-0.93, p = 0.03). Changes in biomarker levels were not associated with any covariates or surgical failure. Conclusions: Stress urinary incontinence surgery was significantly less likely to fail in women with lower baseline NTx levels. Studies are needed to validate NTx as a possible independent biomarker for stress urinary incontinence surgery outcomes. C1 [Chai, Toby C.; Keay, Susan] Univ Maryland, Baltimore, MD 21201 USA. [Keay, Susan] VA Maryland Hlth Care Syst, Baltimore, MD USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Richter, Holly E.; Biggio, Joseph] Univ Alabama Birmingham, Birmingham, AL USA. [Moalli, Pamela; Zong, Wenjun] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Curto, Teresa; Kim, Hae-Young; Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Chai, TC (reprint author), Yale Univ, Dept Urol, Sch Med, 789 Howard Ave,FMP 309,POB 208058, New Haven, CT 06520 USA. EM toby.chai@yale.edu RI maiza, marisa/L-6168-2013 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases [3U01DK060397-08S2] FX Supported by National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases Grant 3U01DK060397-08S2. NR 30 TC 7 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD MAR PY 2014 VL 191 IS 3 BP 703 EP 709 DI 10.1016/j.juro.2013.10.051 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AA5GF UT WOS:000331123400049 PM 24140551 ER PT J AU Pierson, TM Yuan, H Marsh, ED Fuentes-Fajardo, K Adams, DR Markello, T Golas, G Simeonov, DR Holloman, C Tankovic, A Karamchandani, MM Schreiber, JM Mullikin, JC Tifft, CJ Toro, C Boerkoel, CF Traynelis, SF Gahl, WA AF Pierson, Tyler Mark Yuan, Hongjie Marsh, Eric D. Fuentes-Fajardo, Karin Adams, David R. Markello, Thomas Golas, Gretchen Simeonov, Dimitre R. Holloman, Conisha Tankovic, Anel Karamchandani, Manish M. Schreiber, John M. Mullikin, James C. Tifft, Cynthia J. Toro, Camilo Boerkoel, Cornelius F. Traynelis, Stephen F. Gahl, William A. TI GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objective: Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. Methods: Three modern translational medicine tools were utilized: (1) high-throughput sequencing technology to identify a novel de novo mutation; (2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and (3) screening of existing drug libraries to identify potential therapeutic compounds. Results: A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by N-methyl-D-aspartate receptors (NMDAs) containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden. Interpretation: This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease. C1 [Pierson, Tyler Mark; Fuentes-Fajardo, Karin; Adams, David R.; Markello, Thomas; Golas, Gretchen; Simeonov, Dimitre R.; Holloman, Conisha; Tifft, Cynthia J.; Toro, Camilo; Boerkoel, Cornelius F.; Gahl, William A.] NIH Off Rare Dis Res, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Pierson, Tyler Mark; Fuentes-Fajardo, Karin; Adams, David R.; Markello, Thomas; Golas, Gretchen; Simeonov, Dimitre R.; Holloman, Conisha; Tifft, Cynthia J.; Toro, Camilo; Boerkoel, Cornelius F.; Gahl, William A.] NHGRI, Bethesda, MD 20892 USA. [Pierson, Tyler Mark] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Pediat & Neurol, 8700 Beverly Blvd,AHSP 8401, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Regenerat Med Inst, Los Angeles, CA 90048 USA. [Yuan, Hongjie; Tankovic, Anel; Karamchandani, Manish M.; Traynelis, Stephen F.] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Marsh, Eric D.; Tifft, Cynthia J.; Toro, Camilo; Boerkoel, Cornelius F.; Gahl, William A.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Marsh, Eric D.; Tifft, Cynthia J.; Toro, Camilo; Boerkoel, Cornelius F.; Gahl, William A.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Adams, David R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Markello, Thomas; Golas, Gretchen; Holloman, Conisha] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Schreiber, John M.] NINDS, EEG Sect, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Pierson, TM (reprint author), Cedars Sinai Med Ctr, Dept Pediat & Neurol, 8700 Beverly Blvd,AHSP 8401, Los Angeles, CA 90048 USA. EM tyler.pierson@cshs.org FU Intramural NIH HHS [Z01 HG000215-05]; NINDS NIH HHS [R37 NS036654, R01 NS036654] NR 29 TC 39 Z9 41 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 MAR PY 2014 VL 1 IS 3 BP 190 EP 198 DI 10.1002/acn3.39 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KF UT WOS:000209814800005 PM 24839611 ER PT J AU Abulaban, K Brunner, H Nelson, SL Bennett, M Ying, J Song, HJ Kimmel, P Kusek, J Feldman, H Ramachandran, V Rovin, BH AF Abulaban, Khalid Brunner, Hermine Nelson, Shannen L. Bennett, Michael Ying, Jun Song, Huijuan Kimmel, Paul Kusek, John Feldman, Harold Ramachandran, Vasan Rovin, Brad H. TI Urine Biomarkers Role in Predicting the Future Development of Renal Functional Loss With Lupus Nephritis in Children and Adults SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Abulaban, Khalid; Nelson, Shannen L.; Bennett, Michael] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Ying, Jun] Univ Cincinnati, Cincinnati, OH USA. [Song, Huijuan; Rovin, Brad H.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Kimmel, Paul; Kusek, John] NIDDK, NIH, Bethesda, MD USA. [Feldman, Harold] Univ Penn, Philadelphia, PA 19104 USA. [Ramachandran, Vasan] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 2 Z9 2 U1 0 U2 3 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 MAR PY 2014 VL 66 SU 3 SI SI MA A78 BP S111 EP S111 DI 10.1002/art.38494 PG 1 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900079 ER PT J AU Canna, S de Jesus, AA Deng, ZM Gouni, S Marrero, B Brooks, S Dimattia, M Liu, Y Huang, Y Plass, N Chapelle, DC Montealegre, G Benseler, S Laxer, RM Goldbach-Mansky, R AF Canna, Scott de Jesus, Adriana Almeida Deng, Zuoming Gouni, Sushanth Marrero, Bernadette Brooks, Stephen Dimattia, Michael Liu, Yin Huang, Yan Plass, Nicole Chapelle, Dawn C. Montealegre, Gina Benseler, Susanne Laxer, Ronald M. Goldbach-Mansky, Raphaela TI Macrophage Activation Syndrome-like Illness Due to an Activating Mutation in NLRC4 SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Canna, Scott; de Jesus, Adriana Almeida; Deng, Zuoming; Gouni, Sushanth; Marrero, Bernadette; Brooks, Stephen; Dimattia, Michael; Liu, Yin; Huang, Yan; Plass, Nicole; Montealegre, Gina] NIAMS, NIH, Bethesda, MD USA. [Chapelle, Dawn C.; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Benseler, Susanne] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. [Laxer, Ronald M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NR 1 TC 2 Z9 2 U1 1 U2 1 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 MAR PY 2014 VL 66 SU 3 SI SI MA A157 BP S203 EP S203 DI 10.1002/art.38583 PG 1 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900159 ER PT J AU Habers, GEA Huber, AM Mamyrova, G O'Hanlon, TP Adams, S Pandey, JP Miller, FW Boonacker, C van Royen-Kerkhof, A Rider, LG AF Habers, G. Esther A. Huber, Adam M. Mamyrova, Gulnara O'Hanlon, Terrance P. Adams, Sharon Pandey, Janardan P. Miller, Frederick W. Boonacker, Chantal van Royen-Kerkhof, Annet Rider, Lisa G. TI The Association of Immunogenetic and Environmental Factors with Disease Course in Patients with Juvenile Idiopathic Inflammatory Myopathies SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Habers, G. Esther A.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Child Dev & Exercise Ctr, Utrecht, Netherlands. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS, Canada. [Mamyrova, Gulnara] George Washington Univ Sch Med, Div Rheumatol, Dept Med, Washington, DC USA. [O'Hanlon, Terrance P.; Miller, Frederick W.; Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. [Adams, Sharon] Dept Transfus Med, Bethesda, MD USA. [Pandey, Janardan P.] Med Univ S Carolina, Charleston, SC 29425 USA. [Boonacker, Chantal] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [van Royen-Kerkhof, Annet] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, Netherlands. OI Miller, Frederick/0000-0003-2831-9593 NR 0 TC 1 Z9 1 U1 0 U2 2 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 MAR PY 2014 VL 66 SU 3 SI SI MA A25 BP S39 EP S40 DI 10.1002/art.38441 PG 2 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900026 ER PT J AU Kim, H Sanchez, GAM Chapelle, DC Plass, N Dwyer, A Goldbach-Mansky, R Hill, S AF Kim, Hanna Sanchez, Gina A. Montealegre Chapelle, Dawn C. Plass, Nicole Dwyer, Andrew Goldbach-Mansky, Raphaela Hill, Suvimol TI Skeletal Features of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) on Anakinra Treatment: Long-Term Follow-up SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Kim, Hanna; Sanchez, Gina A. Montealegre; Chapelle, Dawn C.; Plass, Nicole; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Dwyer, Andrew; Hill, Suvimol] NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2014 VL 66 SU 3 SI SI MA A80 BP S113 EP S113 DI 10.1002/art.38496 PG 1 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900081 ER PT J AU Pilkington, C Tjarnlund, A Bottai, M Rider, LG Werth, VP de Visser, M Alfredsson, L Amato, AA Barohn, RJ Liang, MH Singh, JA Miller, FW Lundberg, IE AF Pilkington, Clarissa Tjarnlund, Anna Bottai, Matteo Rider, Lisa G. Werth, Victoria P. de Visser, Marianne Alfredsson, Lars Amato, Anthony A. Barohn, Richard J. Liang, Matthew H. Singh, Jasvinder A. Miller, Frederick W. Lundberg, Ingrid E. CA IMCCP International Myositis TI Progress Report on the Development of New Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract ID DERMATOMYOSITIS; POLYMYOSITIS C1 [Pilkington, Clarissa] Great Ormond St Hosp Sick Children, Dept Rheumatol, London WC1N 3JH, England. [Tjarnlund, Anna; Lundberg, Ingrid E.; IMCCP International Myositis] Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Bottai, Matteo; Alfredsson, Lars] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD USA. [Werth, Victoria P.] Philadelphia VAMC, Dept Dermatol, Philadelphia, PA USA. [Werth, Victoria P.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [de Visser, Marianne] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Amato, Anthony A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Barohn, Richard J.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, MO USA. [Liang, Matthew H.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Singh, Jasvinder A.] VA Med Ctr, Birmingham, AL USA. [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. OI Miller, Frederick/0000-0003-2831-9593 NR 6 TC 3 Z9 3 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 MAR PY 2014 VL 66 SU 3 SI SI MA A47 BP S70 EP S71 DI 10.1002/art.38463 PG 2 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900048 ER PT J AU Rider, LG Faiq, A Farhadi, PN Bayat, N Itert, L Chase, M Ulrey, R Malley, K Wilkerson, J Johnson, A Rose, K Morris, R Parks, C Giannini, EH Brunner, H Goldberg, B Miller, FW AF Rider, Lisa G. Faiq, Abdullah Farhadi, Payam Noroozi Bayat, Nastaran Itert, Lukasz Chase, Mikaela Ulrey, Robert Malley, Karen Wilkerson, Jesse Johnson, Anne Rose, Kathryn Morris, Richard Parks, Christine Giannini, Edward H. Brunner, Hermine Goldberg, Bob Miller, Frederick W. TI Demographics, Clinical Features and Therapies of Patients with Juvenile Dermatomyositis Participating in a National Myositis Patient Registry SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Rider, Lisa G.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD USA. [Faiq, Abdullah; Farhadi, Payam Noroozi; Bayat, Nastaran; Chase, Mikaela] NIEHS, NIH, Bethesda, MD USA. [Itert, Lukasz; Johnson, Anne; Giannini, Edward H.; Brunner, Hermine] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Ulrey, Robert; Goldberg, Bob] Myositis Assoc, Alexandria, VA USA. [Malley, Karen] Malley Res Programming Inc, Bethesda, MD USA. [Wilkerson, Jesse; Rose, Kathryn; Morris, Richard] Social & Sci Syst Inc, Durham, NC USA. [Parks, Christine] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. OI Miller, Frederick/0000-0003-2831-9593 NR 0 TC 3 Z9 3 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 MAR PY 2014 VL 66 SU 3 SI SI MA A58 BP S86 EP S87 DI 10.1002/art.38474 PG 2 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900059 ER PT J AU Rodriguez-Smith, J Lin, Y Kim, H Sanchez, GAM Chapelle, DC Plass, N Tsai, WX Huang, Y Gadina, M Bielekova, B Goldbach-Mansky, R AF Rodriguez-Smith, Jackeline Lin, Yenchih Kim, Hanna Sanchez, Gina A. Montealegre Chapelle, Dawn C. Plass, Nicole Tsai, Wanxia Huang, Yan Gadina, Massimo Bielekova, Bibiana Goldbach-Mansky, Raphaela TI Cerebrospinal Fluid Cytokines Correlate With Innate Immune Cells in Neonatal Onset Multisystem Inflammatory Disease (NOMID) Patients in Clinical Remission Treated With Anakinra SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Rodriguez-Smith, Jackeline; Kim, Hanna; Sanchez, Gina A. Montealegre; Chapelle, Dawn C.; Plass, Nicole; Tsai, Wanxia; Huang, Yan; Gadina, Massimo; Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Lin, Yenchih; Bielekova, Bibiana] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 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 MAR PY 2014 VL 66 SU 3 SI SI MA A173 BP S226 EP S226 DI 10.1002/art.38599 PG 1 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900175 ER PT J AU Barrett, A Jain, N Ito, S Lu, K Muranski, P Childs, R Hourigan, C Haggerty, J Ramos, C Cook, L Battiwalla, M AF Barrett, A. Jain, N. Ito, S. Lu, K. Muranski, P. Childs, R. Hourigan, C. Haggerty, J. Ramos, C. Cook, L. Battiwalla, M. TI THE CLINICAL AND FINANCIAL BURDEN OF PREEMPTIVE MANAGEMENT OF CMV DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Barrett, A.; Jain, N.; Ito, S.; Lu, K.; Muranski, P.; Childs, R.; Hourigan, C.; Haggerty, J.; Ramos, C.; Cook, L.; Battiwalla, M.] NHLBI, Hematol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P483 BP S331 EP S331 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901482 ER PT J AU Barrett, A Amarnath, S Salem, B Laurence, A Eckhaus, M Melenhorst, JJ Rose, JJ Sabatino, M Stroncek, D Fowler, DH AF Barrett, A. Amarnath, S. Salem, B. Laurence, A. Eckhaus, M. Melenhorst, J. J. Rose, J. J. Sabatino, M. Stroncek, D. Fowler, D. H. TI BONE MARROW DERIVED MESENCHYMAL STROMAL CELLS (BMSC) ARE EFFICIENT MODULATORS OF XENOGENEIC GRAFT VERSUS HOST DISEASE SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Barrett, A.] NHLBI, Hematol, NIH, Bethesda, MD 20892 USA. [Amarnath, S.; Salem, B.; Rose, J. J.; Fowler, D. H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Laurence, A.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Eckhaus, M.] NIH, Div Vet Serv, Off Res Serv, Bethesda, MD 20892 USA. [Melenhorst, J. J.] Univ Penn, Dept Pathol & Lab Med, Clin Cell & Vaccine Prod Facil, Philadelphia, PA USA. [Sabatino, M.; Stroncek, D.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P445 BP S314 EP S314 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901444 ER PT J AU Bollard, C Kennedy-Nasser, A Barrett, AJ Ito, S Yvon, E Krance, R Leung, K Heslop, HE Brenner, K AF Bollard, C. Kennedy-Nasser, A. Barrett, A. J. Ito, S. Yvon, E. Krance, R. Leung, K. Heslop, H. E. Brenner, K. TI ULTRA LOW-DOSE IL-2 MEDIATED EXPANSION OF REGULATORY T CELLS AS GVHD PROPHYLAXIS FOR RECIPIENTS OF ALLOGENEIC HEMATOPOIETIC STEM CELLS SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Bollard, C.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bollard, C.] GW Univ, Washington, DC USA. [Kennedy-Nasser, A.; Krance, R.; Leung, K.; Heslop, H. E.; Brenner, K.] Baylor Coll Med, Houston, TX 77030 USA. [Barrett, A. J.] NIH, Bethesda, MD 20892 USA. [Yvon, E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 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 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P298 BP S242 EP S242 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901298 ER PT J AU Fujiwara, H Ochi, F Tanimoto, K Asai, H Miyazaki, Y Okamoto, S Mineno, J Kuzushima, K Barrett, J Ishii, E Yasukawa, M AF Fujiwara, H. Ochi, F. Tanimoto, K. Asai, H. Miyazaki, Y. Okamoto, S. Mineno, J. Kuzushima, K. Barrett, J. Ishii, E. Yasukawa, M. TI GENE-MODIFIED HUMAN ALPHA/BETA-T CELLS EXPRESSING A CHIMERIC CD16-CD3ZETA RECEPTOR AS ADOPTIVELY TRANSFERABLE EFFECTOR CELLS FOR ANTICANCER MONOCLONAL ANTIBODY THERAPY SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Fujiwara, H.; Miyazaki, Y.; Yasukawa, M.] Ehime Univ, Grad Sch Med, Dept Hematol Clin Immunol & Infect Dis, Toon, Japan. [Ochi, F.] Ehime Univ, Dept Pediat, Toon, Japan. [Tanimoto, K.; Asai, H.] Ehime Univ, Dept Hematol Clin Immunol & Infect Dis, Toon, Japan. [Okamoto, S.; Mineno, J.] Takara Bio Inc, Ctr Cell & Gene Therapy, Otsu, Shiga, Japan. [Kuzushima, K.] Aichi Canc Ctr, Div Immunol, Nagoya, Aichi 464, Japan. [Barrett, J.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Ishii, E.] Ehime Univ, Grad Sch Med, Dept Pediat, Toon, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-O029 BP S16 EP S17 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941900030 ER PT J AU Grkovic, L Pulanic, D Serventi-Seiwerth, R Matic, N Mravak-Stipetic, M Bilic, E Ceovic, R Ljubas, D Rajic, L Bilic, E Durakovic, N Peric, Z Pulanic, TK Kovac, K Dusek, D Bojanic, I Grce, M Batinic, D Vrhovac, R Pavletic, SZ Nemet, D AF Grkovic, L. Pulanic, D. Serventi-Seiwerth, R. Matic, N. Mravak-Stipetic, M. Bilic, E. Ceovic, R. Ljubas, D. Rajic, L. Bilic, E. Durakovic, N. Peric, Z. Pulanic, T. Klepac Kovac, K. Dusek, D. Bojanic, I. Grce, M. Batinic, D. Vrhovac, R. Pavletic, S. Z. Nemet, D. TI IMPLEMENTATION AND DISSEMINATION OF CHRONIC GRAFT-VERSUS-HOST DISEASE NIH CRITERIA AND RECOMMENDATIONS - FORMATION OF A MULTIDISCIPLINARY TEAM AND PROGRAM AT THE UNIVERSITY HOSPITAL CENTER ZAGREB, CROATIA SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Grkovic, L.; Pulanic, D.; Serventi-Seiwerth, R.; Matic, N.; Durakovic, N.; Peric, Z.; Vrhovac, R.; Nemet, D.] UHC Zagreb, Hematol, Zagreb, Croatia. [Mravak-Stipetic, M.] UHC Zagreb, Dental Med, Zagreb, Croatia. [Bilic, E.] UHC Zagreb, Neurol, Zagreb, Croatia. [Ceovic, R.] UHC Zagreb, Dermatol, Zagreb, Croatia. [Ljubas, D.] UHC Zagreb, Nutr, Zagreb, Croatia. [Rajic, L.; Bilic, E.] UHC Zagreb, Pediat Hematol, Zagreb, Croatia. [Pulanic, T. Klepac] UHC Zagreb, Gynecol, Zagreb, Croatia. [Kovac, K.] UHC Zagreb, Rehabil Med, Zagreb, Croatia. [Dusek, D.] Univ Hosp Infect Dis Dr Fran Mihaljevic, Infect Dis, Zagreb, Croatia. [Bojanic, I.] UHC Zagreb, Transfusiol, Zagreb, Croatia. [Grce, M.] Rudjer Boskovic Inst, Zagreb, Croatia. [Batinic, D.] UHC Zagreb, Immunol, Zagreb, Croatia. [Pavletic, S. Z.] NCI, Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P419 BP S301 EP S302 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901418 ER PT J AU Kuzmina, Z Hakim, F Gounden, V Rose, J Cowen, EW Naik, HB Hasni, SA Mays, J Curtis, L Cole, K Avila, D Taylor, T Mitchell, S Baruffaldi, J Baird, K Steinberg, S Pavletic, SZ AF Kuzmina, Z. Hakim, F. Gounden, V. Rose, J. Cowen, E. W. Naik, H. B. Hasni, S. A. Mays, J. Curtis, L. Cole, K. Avila, D. Taylor, T. Mitchell, S. Baruffaldi, J. Baird, K. Steinberg, S. Pavletic, S. Z. TI LARGE SCALE CLINICAL CHARACTERIZATION OF AUTOANTIBODIES IN PATIENTS WITH CHRONIC GVHD SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Kuzmina, Z.; Hakim, F.; Rose, J.; Curtis, L.; Cole, K.; Avila, D.; Taylor, T.; Baruffaldi, J.; Pavletic, S. Z.] NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD USA. [Gounden, V.] NCI, Clin Chem, Dept Lab Med, Bethesda, MD 20892 USA. [Cowen, E. W.; Naik, H. B.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Hasni, S. A.] NIAMSD, Bethesda, MD 20892 USA. [Mays, J.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Mitchell, S.] NCI, Res & Practice Dev Serv, Bethesda, MD 20892 USA. [Baird, K.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Steinberg, S.] Ctr Canc Res, Biostat & Data Management Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P421 BP S303 EP S303 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901420 ER PT J AU Lugli, E Roberto, A Castagna, L Roederer, M Zanon, V Gandolfi, S Tentorio, P Mavilio, D AF Lugli, E. Roberto, A. Castagna, L. Roederer, M. Zanon, V. Gandolfi, S. Tentorio, P. Mavilio, D. TI HIGH FREQUENCY OF T MEMORY STEM CELLS PRECEDES T CELL IMMUNE-RECONSTITUTION FOLLOWING HUMAN BONE MARROW TRANSPLANTATION SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Lugli, E.; Roberto, A.; Zanon, V.; Tentorio, P.; Mavilio, D.] Fdn Humanitas Ric, Lab Clin & Expt Immunol, Rozzano, MI, Italy. [Castagna, L.; Gandolfi, S.] Fdn Humanitas Ric, Hematol & Bone Marrow Transplant Unit, Humanitas Canc Ctr, Rozzano, MI, Italy. [Roederer, M.] NIH, ImmunoTechnol Sect, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Mavilio, D.] Univ Milan, Dept Med Biotechnol & Translat Med BioMeTra, Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-O043 BP S24 EP S24 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941900044 ER PT J AU Mravak-Stipetic, M Grkovic, L Pulanic, D Sabol, I Grce, M Nemet, D Pavletic, SZ AF Mravak-Stipetic, M. Grkovic, L. Pulanic, D. Sabol, I. Grce, M. Nemet, D. Pavletic, S. Z. TI COMPREHENSIVE EVALUATION OF ORAL CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) IN A COHORT OF CROATIAN PATIENTS SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Mravak-Stipetic, M.] UHC Zagreb, Dent Med, Zagreb, Croatia. [Grkovic, L.] UHC Zagreb, Zagreb, Croatia. [Pulanic, D.; Nemet, D.] UHC Zagreb, Hematol, Zagreb, Croatia. [Sabol, I.; Grce, M.] Rudjer Boskovic Inst, Zagreb, Croatia. [Pavletic, S. Z.] NCI, Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Sabol, Ivan/B-7455-2012 OI Sabol, Ivan/0000-0002-5753-8528 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-AB242 BP S541 EP S542 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941902361 ER PT J AU Trlen, J Ringden, O Le-Rademacher, J Battiwalla, M Chen, J Ho, VT Kebriaei, P Keever-Taylor, CA Kindwall-Keller, TL Lazarus, HM Laughlin, M Lill, MC Brien, TO Perales, MA Rocha, V Savani, BN Szwajcer, D Valcarcel, D Eapen, M AF Trlen, J. Ringden, O. Le-Rademacher, J. Battiwalla, M. Chen, J. Ho, V. T. Kebriaei, P. Keever-Taylor, C. A. Kindwall-Keller, T. L. Lazarus, H. M. Laughlin, M. Lill, M. C. Brien, T. O' Perales, M. -A. Rocha, V. Savani, B. N. Szwajcer, D. Valcarcel, D. Eapen, M. CA Ctr Int Blood Marrow Transplant TI LOW CD34 CELL DOSE IS ASSOCIATED WITH HIGHER NON-RELAPSE AND OVERALL MORTALITY AFTER REDUCED INTENSITY CONDITIONING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Trlen, J.] Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Ringden, O.] Karolinska Inst, Div Therapeut Immunol, Stockholm, Sweden. [Le-Rademacher, J.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplantat Res, Milwaukee, WI 53226 USA. [Battiwalla, M.] NIH, Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD 20892 USA. [Chen, J.; Eapen, M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ho, V. T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kebriaei, P.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Keever-Taylor, C. A.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Kindwall-Keller, T. L.] Univ Virginia, Med Ctr, Charlottesville, VA USA. [Lazarus, H. M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Laughlin, M.] Cleveland Cord Blood Ctr, Cleveland, OH USA. [Lill, M. C.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Brien, T. O'] Sydney Childrens Hosp, Ctr Childrens Canc & Blood Disorders, Sydney, NSW, Australia. [Perales, M. -A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rocha, V.] Churchill Hosp, Canc & Haematol Ctr, Oxford OX3 7LJ, England. [Savani, B. N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Szwajcer, D.] Univ Manitoba, CancerCare Manitoba, Winnipeg, MB, Canada. [Valcarcel, D.] Hosp Infantil Vall dHebron, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P269 BP S229 EP S230 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901269 ER PT J AU Williams, KM Chakrabarty, JLH Lindenberg, L Gea-Banacloche, J Schuver, BB Hickstein, D Kochenderfer, J Wilder, J Kurdziel, K Steinberg, S Khuu, H Fowler, DH Halverson, D Avila, DN Selby, G Taylor, TN Mann, J Hsu, J Pavletic, SZ Bollard, CM Choyke, P Gress, RE AF Williams, K. M. Chakrabarty, J. L. Holter Lindenberg, L. Gea-Banacloche, J. Schuver, B. Blacklock Hickstein, D. Kochenderfer, J. Wilder, J. Kurdziel, K. Steinberg, S. Khuu, H. Fowler, D. H. Halverson, D. Avila, D. N. Selby, G. Taylor, T. N. Mann, J. Hsu, J. Pavletic, S. Z. Bollard, C. M. Choyke, P. Gress, R. E. TI NOVEL IMAGING REVEALS EARLY ENGRAFTMENT AND STEM CELL HOMING AFTER HSCT SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Williams, K. M.] NCI, BMT, Childrens Natl Med Ctr, ETIB,NIH, Washington, DC USA. [Chakrabarty, J. L. Holter; Selby, G.] Univ Oklahoma, BMT, Norman, OK 73019 USA. [Lindenberg, L.; Kurdziel, K.; Choyke, P.] Mol Imaging Branch, Bethesda, MD USA. [Gea-Banacloche, J.; Schuver, B. Blacklock; Hickstein, D.; Kochenderfer, J.; Wilder, J.; Fowler, D. H.; Halverson, D.; Avila, D. N.; Taylor, T. N.; Mann, J.; Hsu, J.; Pavletic, S. Z.; Gress, R. E.] NCI, ETIB, NIH, Bethesda, MD 20892 USA. [Steinberg, S.] NCI, Biostat & Data Management Sect, OCD, CCR,NIH, Bethesda, MD 20892 USA. [Khuu, H.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Bollard, C. M.] Childrens Natl Med Ctr, BMT, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P299 BP S242 EP S243 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901299 ER PT J AU Prasad, V AF Prasad, Vinay TI But how many people died? Health outcomes in perspective SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Editorial Material ID ALL-CAUSE MORTALITY; PANCREATIC-CANCER; MEDICAL-PRACTICES; END-POINTS; RISK; TRIALS; CALCIUM; DISEASE; STATINS; ASPIRIN C1 [Prasad, Vinay] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, NIH, 10 Ctr Dr,101-2N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 37 TC 1 Z9 1 U1 1 U2 1 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD MAR PY 2014 VL 82 IS 3 BP 146 EP 150 DI 10.3949/ccjm.82a.14058 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA CE9JR UT WOS:000352160700005 ER PT J AU Davis, SK Gebreab, S Quarells, R Gibbons, GH AF Davis, Sharon K. Gebreab, Samson Quarells, Rakale Gibbons, Gary H. TI SOCIAL DETERMINANTS OF CARDIOVASCULAR HEALTH AMONG BLACK AND WHITE WOMEN RESIDING IN STROKE BELT AND BUCKLE REGIONS OF THE SOUTH SO ETHNICITY & DISEASE LA English DT Article DE Black; White; Women; Cardiovascular Risk Factor; Social Determinants; Stroke; South ID DISEASE RISK-FACTORS; UNITED-STATES; AFRICAN-AMERICANS; ATHEROSCLEROSIS RISK; HYPERTENSION; DISCRIMINATION; INEQUALITIES; ASSOCIATION; COMMUNITIES; RELIABILITY AB Objective: To assess the associations of social determinants on cardiovascular health among White and Black residing in Stroke Belt (urban) and Stroke Buckle (rural) regions of the South. Design: A cross-sectional observational analysis based on a random digit-dial telephone survey of a representative sample of White and Black adults residing in urban and rural Georgia conducted from 2004-2005. Separate logistic regression analyses examined the effects of social determinants on cardiovascular health within and between White and Black women and within and between urban and rural residential location. The main outcome measure was poor cardiovascular health defined as >= 2 self-reported clinical cardiovascular disease risk factors (hypertension, diabetes, elevated cholesterol, overweight or obese). Social determinants were defined as socioeconomic status (SES), general daily stress, racial discrimination, and stress due to exposure to racial discrimination. Significance was established as a two-tailed P<.05. Results: A total of 674 White and Black women aged 18-90 years were included in the sample. Results showed Black women with lower SES had worse cardiovascular health than White women in both rural and urban areas (rural odds ratio [OR] 2.68; confidence interval [CI] 1.44, 4.90; P=.001; urban OR=2.92; CI=1.62, 5.23; P=.0003). White women reporting high or very high exposure to general daily stress where more likely to have worse cardiovascular health than White women reporting very little to no daily stress (OR=2.85; CI=1.49, 5.44; P=.001). Conclusion: Our findings demonstrate the importance of social determinants associated with cardiovascular health. Tailored cardiovascular risk reduction intervention is needed among lower SES Black women in Stroke Belt and Buckle regions of the South, as well as stress-reduction intervention among White women in the South. C1 [Gibbons, Gary H.] NHGRI, Inherited Dis Branch, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Gibbons, Gary H.] NHLBI, Bethesda, MD USA. RP Davis, SK (reprint author), NHGRI, Inherited Dis Branch, Ctr Res Genom & Global Hlth, Social Epidemiol Unit, 10 Ctr Dr,Room 7N320,MSC 1644, Bethesda, MD 20892 USA. EM sharon.davis@nih.gov FU National Institute on Minority Health and Health Disparities [5P20MD00272] FX We would like to thank the respondents who participated in this study. Research was supported by a grant (5P20MD00272) from the National Institute on Minority Health and Health Disparities. NR 35 TC 6 Z9 6 U1 0 U2 3 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SPR PY 2014 VL 24 IS 2 BP 133 EP 143 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CU7KS UT WOS:000363717200001 PM 24804357 ER PT J AU Allen, AJ McNeely, JM Waldstein, SR Evans, MK Zonderman, AB AF Allen, Allyssa J. McNeely, Jessica M. Waldstein, Shari R. Evans, Michele K. Zonderman, Alan B. TI SUBJECTIVE SOCIOECONOMIC STATUS PREDICTS FRAMINGHAM CARDIOVASCULAR DISEASE RISK FOR WHITES, NOT BLACKS SO ETHNICITY & DISEASE LA English DT Article DE Health Disparities; Socioeconomic Status; Cardiovascular Disease Risk ID SOCIAL-STATUS; HEART-DISEASE; HEALTH; RACE AB Background: Higher rates of cardiovascular disease (CVD) and its risk factors are well documented among those with objective indicators of lower socioeconomic status (SES), such as income, education, and occupation. However, relatively little is known about the relationship of subjective SES to CVD risk, particularly within different racial groups. Methods: Subjective SES and Framingham 10-year CVD risk profile were examined in 1,722 socioeconomically diverse Black and White adults enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. The sample had a mean age of 47.7 years, was 57% female, 56% African American, and 39% living in poverty. Results: Subjective SES was associated with greater CVD risk after adjustment for poverty status, substance use, BMI, depression, antihypertensives, and co-morbidities (B=-.059, t[1,1711]=-2.44, P=.015). However, when the analysis was race-stratified, subjective SES was associated with CVD risk in Whites (B=-.074, F[1,787]=-2.01, P=.045), but not Blacks. Conclusions: These results suggest that subjective SES may aid in predicting CVD risk in Whites, but not Blacks. It is important to note that these analyses were adjusted for poverty status, a potent indicator of objective SES. Thus, these findings further suggest that for Whites, subjective SES may influence CVD risk beyond that associated with objective SES. These findings highlight the potential importance of patients' subjective SES in CVD risk detection. C1 [Allen, Allyssa J.; McNeely, Jessica M.; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21250 USA. [McNeely, Jessica M.; Evans, Michele K.; Zonderman, Alan B.] NIA, Baltimore, MD 21224 USA. RP Allen, AJ (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM allyssa1@umbc.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH); NIH grant [1 RO1AG034161] FX This work was supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH) and NIH grant 1 RO1AG034161. NR 17 TC 3 Z9 3 U1 1 U2 3 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SPR PY 2014 VL 24 IS 2 BP 150 EP 154 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CU7KS UT WOS:000363717200003 PM 24804359 ER PT J AU Grigsby, TJ Kent, EE Montoya, MJ Sender, LS Morris, RA Ziogas, A Anton-Culver, H AF Grigsby, Timothy J. Kent, Erin E. Montoya, Michael J. Sender, Leonard S. Morris, Rebecca A. Ziogas, Argyrios Anton-Culver, Hoda TI Attitudes Toward Cancer Clinical Trial Participation in Young Adults with a History of Cancer and a Healthy College Student Sample: A Preliminary Investigation SO JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY LA English DT Article DE beliefs; attitudes; recruitment; clinical trials ID RANDOMIZED CONTROLLED-TRIALS; CHILDRENS ONCOLOGY; ADOLESCENT; RACE; AGE; DIAGNOSIS; LITERACY; OUTCOMES; QUALITY; CONSENT AB Purpose: Adolescents and young adults (AYAs) aged 15-39 at diagnosis have very low cancer clinical trial accrual rates. To date, no studies have examined attitudes toward clinical trial participation in this age range to determine if certain individuals are less likely to enroll if offered participation. The current study assessed attitudes toward participation using the Cancer Treatment Subscale of the Attitudes toward Cancer Trials Scales. Methods: Data were collected from a sample of leukemia and lymphoma survivors (n = 99) and a healthy college student sample (n = 397). Following a principal components analysis, two subscales-Personal Barriers/Safety and Personal Benefits-were retained for analysis. Results: In the cancer survivor group, only 14 (13.3%) reported being offered participation in a cancer clinical trial, and only 8 of those 14 (7.6% of survivors) participated. Responses from leukemia and lymphoma survivors revealed no significant relationships between age, gender, race/ethnicity, clinical trial participation, insurance status, or social class with Personal Benefits or Personal Barriers/Safety. Healthy college females had more negative Personal Barriers/Safety attitudes compared to males after adjusting for race/ethnicity and social class (p = 0.01), but no associations were present when examining Personal Benefits as an outcome. Conclusion: This preliminary investigation suggests that drivers of attitudes toward clinical trial participation in AYAs are not well understood and may impact cancer trial participation. Future work should focus on defining attitudes toward cancer clinical trials in the AYA population and developing interventions to increase awareness, knowledge, and positive attitudes toward participating in cancer research. C1 [Grigsby, Timothy J.] Univ So Calif, Dept Prevent Med, Inst Hlth Promot & Dis Prevent, Los Angeles, CA 90089 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Montoya, Michael J.] Univ Calif Irvine, Dept Anthropol, Irvine, CA USA. [Montoya, Michael J.] Univ Calif Irvine, Dept Chicano Latino Studies, Irvine, CA USA. [Montoya, Michael J.] Univ Calif Irvine, Dept Publ Hlth, Irvine, CA USA. [Sender, Leonard S.; Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Sender, Leonard S.; Anton-Culver, Hoda] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Genet Epidemiol Res Inst, Irvine, CA USA. [Sender, Leonard S.; Morris, Rebecca A.] CHOC Childrens Hosp, Hyundai Canc Inst, Orange, CA USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM erin.kent@nih.gov FU UC MEXUS dissertation grant; Centers for Disease Control and Prevention R36 Public Health Dissertation [R36DP002012-01]; T32 fellowship from National Institutes of Health [CA009492] FX This project was carried out as part of Erin Kent's doctoral dissertation at the University of California, Irvine. Support for this work was provided by a UC MEXUS dissertation grant and a Centers for Disease Control and Prevention R36 Public Health Dissertation (Grant R36DP002012-01). Support for Timothy Grigsby is provided by a T32 fellowship from the National Institutes of Health (Grant CA009492). The authors thank undergraduate research assistants Marym Mohammady and Priyanka Saxena and clinical research coordinator Isabel Guzman for their assistance with study recruitment and coordination. NR 26 TC 5 Z9 5 U1 2 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2156-5333 EI 2156-535X J9 J ADOLESC YOUNG ADUL JI J. Adolesc. Young Adult Oncol. PD MAR PY 2014 VL 3 IS 1 BP 20 EP 27 DI 10.1089/jayao.2013.0030 PG 8 WC Oncology SC Oncology GA CC1UG UT WOS:000350129300004 ER PT J AU Ramasamy, A Trabzuni, D Forabosco, P Smith, C Walker, R Dillman, A Sveinbjornsdottir, S Hardy, J Weale, ME Ryten, M AF Ramasamy, Adaikalavan Trabzuni, Daniah Forabosco, Paola Smith, Colin Walker, Robert Dillman, Allissa Sveinbjornsdottir, Sigurlaug Hardy, John Weale, Michael E. Ryten, Mina CA NABEC UKBEC TI Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis SO MULTIPLE SCLEROSIS AND RELATED DISORDERS LA English DT Article DE Multiple sclerosis; Genetics; Vitamin D; CYP24A1; Expression quantitative trait loci; Genome-wide association studies ID NETWORK ANALYSIS; CYP27B1 GENE; HUMAN BRAIN; NO EVIDENCE; EXPRESSION; GENOTYPE; ASSOCIATION; CONCORDANCE; IMPUTATION; PATHOLOGY AB Background: Multiple sclerosis (MS) is a common disease of the central nervous system and a major cause of disability amongst young adults. Genome-wide association studies have identified many novel susceptibility loci including rs2248359. We hypothesized that genotypes of this locus could increase the risk of MS by regulating expression of neighboring gene, CYP24A1 which encodes the enzyme responsible for initiating degradation of 1,25-dihydroxyvitamin D3. Methods: We investigated this hypothesis using paired gene expression and genotyping data from three independent datasets of neurologically healthy adults of European descent. The UK Brain Expression Consortium (UKBEC) consists of post-mortem samples across 10 brain regions originating from 134 individuals (1231 samples total). The North American Brain Expression Consortium (NABEC) consists of cerebellum and frontal cortex samples from 304 individuals (605 samples total). The brain dataset from Heinzen and colleagues consists of prefrontal cortex samples from 93 individuals. Additionally, we used gene network analysis to analyze UKBEC expression data to understand CYP24A1 function in human brain. Findings: The risk allele, rs2248359-C, is strongly associated with increased expression of CYP24A1 in frontal cortex (p-value= 1.45 x 10(-13)), but not white matter. This association was replicated using data from NABEC (p-value=7.2 x 10(-6)) and Heinzen and colleagues (p-value= 1.2 x 10(-4)) Network analysis shows a significant enrichment of terms related to immune response in eight out of the 10 brain regions. Interpretation: The known MS risk allele rs2248359-C increases CYP24A1 expression in human brain providing a genetic link between MS and vitamin D metabolism, and predicting that the physiologically active form of vitamin D3 is protective. Vitamin D3's involvement in MS may relate to its immunomodulatory functions in human brain. (C) 2013 The Authors. Published by Elsevier B.V. Open access under CC BY license. C1 [Ramasamy, Adaikalavan; Weale, Michael E.; Ryten, Mina] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England. [Ramasamy, Adaikalavan; Trabzuni, Daniah; Hardy, John; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, Reta Lila Weston Res Labs, London WC1N 3BG, England. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Forabosco, Paola] Ist Genet Popolaz CNR, Sassari, Italy. [Smith, Colin; Walker, Robert] Univ Edinburgh, Dept Neuropathol, MRC Sudden Death Brain Bank Project, Edinburgh EH8 9AG, Midlothian, Scotland. [Dillman, Allissa] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Sveinbjornsdottir, Sigurlaug] Broomfield Hosp, MEHT, Dept Neurol, Chelmsford CM1 7ET, Essex, England. [Sveinbjornsdottir, Sigurlaug] Univ London, Dept Neurol, Queen Mary Coll, London WC1E 7HU, England. RP Weale, ME (reprint author), Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England. EM michael.weale@kcl.ac.uk; mina.ryten@ucl.ac.uk RI Weale, Michael/F-2587-2010 OI Weale, Michael/0000-0003-4593-1186 FU MRC through the MRC Sudden Death Brain Bank; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; National Institute on Aging, National Institutes of Health part of the US Department of Health and Human Services [ZIA AG000932-04]; National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]; National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]; Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]; Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]; Michael J. Fox Foundation for Parkinson's Research; [G0901254]; [G0802462] FX This work was supported by the MRC through the MRC Sudden Death Brain Bank (C.S.) and by a Project Grant (G0901254 to J.H. and M.W.) and Training Fellowship (G0802462 to M.R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia.; The work performed by the North American Brain Expression Consortium was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services; Project number ZIA AG000932-04.; We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human biospecimens. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. NR 30 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-0348 EI 2211-0356 J9 MULT SCLER RELAT DIS JI Mult. Scler. Relat. Disord. PD MAR PY 2014 VL 3 IS 2 BP 211 EP 219 DI 10.1016/j.msard.2013.08.009 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CB5KA UT WOS:000349664700011 PM 25568836 ER PT J AU Ashe, K Liu, P Reed, MN Kotilinek, LA Grant, MKO Forster, CL Qiang, W Reich, J Cleary, JP Zahs, KR AF Ashe, Karen Liu, P. Reed, M. N. Kotilinek, L. A. Grant, M. K. O. Forster, C. L. Qiang, W. Reich, J. Cleary, J. P. Zahs, K. R. TI THE RELEVANCE OF QUATERNARY STRUCTURE TO THE FUNCTIONAL EFFECTS OF AMYLOID-beta OLIGOMERS IN THE BRAIN SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 13th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy CY MAR 26-29, 2014 CL Geneva, SWITZERLAND DE Amyloid; Oligomers; Alzheimer C1 [Ashe, Karen; Liu, P.; Reed, M. N.; Kotilinek, L. A.; Grant, M. K. O.; Forster, C. L.; Reich, J.; Cleary, J. P.; Zahs, K. R.] Univ Minnesota, Minneapolis, MN USA. [Qiang, W.] NIH, Bethesda, MD 20892 USA. EM hsiao005@umn.edu 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2014 VL 35 SU 1 BP S2 EP S2 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CP6PW UT WOS:000360011100006 ER PT J AU Launer, LJ AF Launer, Lenore J. TI STUDYING LIFE-LONG VASCULAR RISK FOR LATE LIFE DEMENTIA SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 13th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy CY MAR 26-29, 2014 CL Geneva, SWITZERLAND DE Life-course; Brain aging; Epidemiology C1 [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2014 VL 35 SU 1 BP S13 EP S14 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CP6PW UT WOS:000360011100051 ER PT J AU Rosenblatt, E Abdel-Wahab, M El-Gantiry, M Elattar, I Bourque, JM Afiane, M Benjaafar, N Abubaker, S Chansilpa, Y Vikram, B Levendag, P AF Rosenblatt, Eduardo Abdel-Wahab, May El-Gantiry, Mahmoud Elattar, Inas Bourque, Jean Marc Afiane, M'hamed Benjaafar, Nouredine Abubaker, Shahid Chansilpa, Yaowalak Vikram, Bhadrasain Levendag, Peter TI Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency SO RADIATION ONCOLOGY LA English DT Article DE Nasopharynx; Nasopharyngeal carcinoma; Brachytherapy boost AB Background: The purpose was to determine whether a brachytherapy boost improves outcomes in patients with advanced nasopharyngeal carcinoma treated with standard chemo-radiotherapy. Methods: Patients with nasopharyngeal carcinoma WHO grades I-III and TNM stages III or non-metastatic stage IV were eligible for this phase III study. Patients were randomized to either arm (A) induction chemotherapy, followed by external beam radiotherapy (EBRT) with concomitant cisplatin (n = 139) or arm (B), the same schedule plus a brachytherapy boost to the nasopharynx (n = 135). The EBRT doses given were 70 Gy to the primary tumour and positive lymph nodes and 46 Gy to the negative neck. The additional brachytherapy boost in arm (B) was given by either low dose-rate (LDR - 11 Gy) or high dose-rate (HDR - 3 fractions of 3.0 Gy) brachytherapy. The primary endpoint was 3-year overall survival (OS) and secondary endpoints were: local control, regional control, distant metastasis and grade 3-4 adverse events. Results: 274 patients were randomized between September 2004 and December 2008. The two arms were comparable with regard to age, gender, stage and grade. 273 patients completed treatment. Median follow-up was 29 months (0.2-67 months). The effect of treatment arm, country, age, gender, WHO pathology, stage (T3-4, N2-3 versus other) and chemotherapy on overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS) was studied. Stage significantly affected OS (p = 0.024) and DFS (p = 0.018) while age significantly affected OS (p = 0.014). None of the other factors studied were significant. The 3-year LRFS was 60.5% and 54.4% in arms A and B respectively (p = 0.647). The 3-year regional control rate in the neck was 59.7% and 54.3% respectively (p = 0.7). Distant metastasis developed in 59.7% of patients in arm A and 55.4% in arm B (p = 0.377). Patients with T1/T2 N + had a 3 year LRFS of 51.8% in Arm A (62 patients) versus 57.9% in Arm B (67 patients) (p = 0.343). The grade 3-4 toxicity rate was 21.6% (30/139) and 24.4% (33/135) respectively (p = 0.687). Conclusions: The addition of a brachytherapy boost to external beam radiotherapy and chemotherapy did not improve outcome in loco-regionally advanced nasopharyngeal carcinoma. C1 [Rosenblatt, Eduardo; Abdel-Wahab, May; Bourque, Jean Marc] IAEA, A-1400 Vienna, Austria. [Abdel-Wahab, May] Cleveland Clin, Taussig Comprehens Canc Ctr, Cleveland, OH 44106 USA. [El-Gantiry, Mahmoud; Elattar, Inas] Cairo Univ, Natl Canc Inst, Cairo, Egypt. [Afiane, M'hamed] Ctr Hosp Univ Mustafa CHU, Ctr Pierre & Marie Curie, Dept Radiotherapie, Algiers, Algeria. [Benjaafar, Nouredine] Inst Natl Oncol, Rabat, Morocco. [Abubaker, Shahid] PAEC, Inst Nucl Med & Oncol, Lahore, Pakistan. [Chansilpa, Yaowalak] Mahidol Univ, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. [Vikram, Bhadrasain] NCI, Bethesda, MD 20892 USA. [Levendag, Peter] Erasmus Univ, Rotterdam, Netherlands. [Bourque, Jean Marc] Univ Western Ontario, London Reg Canc Program, London, ON, Canada. RP Rosenblatt, E (reprint author), IAEA, A-1400 Vienna, Austria. EM e.rosenblatt@iaea.org NR 26 TC 6 Z9 6 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD MAR 1 PY 2014 VL 9 AR 67 DI 10.1186/1748-717X-9-67 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA V42LG UT WOS:000209614700001 PM 24581393 ER PT J AU Azrin, ST Chambers, DA AF Azrin, Susan T. Chambers, David A. TI News from the NIH: improving health and reducing premature mortality in people with serious mental illnesses SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT News Item ID SCHIZOPHRENIA; CATIE C1 [Azrin, Susan T.; Chambers, David A.] NIMH, Bethesda, MD 20892 USA. RP Azrin, ST (reprint author), NIMH, Bethesda, MD 20892 USA. EM susan.azrin@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 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 MAR PY 2014 VL 4 IS 1 BP 1 EP 3 DI 10.1007/s13142-013-0238-8 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PH UT WOS:000356786000001 PM 24653770 ER PT J AU Glasgow, RE Fisher, L Strycker, LA Hessler, D Toobert, DJ King, DK Jacobs, T AF Glasgow, Russell E. Fisher, Lawrence Strycker, Lisa A. Hessler, Danielle Toobert, Deborah J. King, Diane K. Jacobs, Tom TI Minimal intervention needed for change: definition, use, and value for improving health and health research SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Intervention; Costs; Research methods; Comparative effectiveness ID SELF-MANAGEMENT; PUBLIC-HEALTH; OUTCOMES; QUESTIONNAIRE; DEPRESSION; DISTRESS; SUPPORT; DIETARY; DESIGNS AB Much research focuses on producing maximal intervention effects. This has generally not resulted in interventions being rapidly or widely adopted or seen as feasible given resources, time, and expertise constraints in the majority of real-world settings. We present a definition and key characteristics of a minimum intervention needed to produce change (MINC). To illustrate use of a MINC condition, we describe a computer-assisted, interactive minimal intervention, titled Healthy Habits, used in three different controlled studies and its effects. This minimal intervention produced modest to sizable health behavior and psychosocial improvements, depending on the intensity of personal contacts, producing larger effects at longer-term assessments. MINC comparison conditions could help to advance both health care and health research, especially comparative effectiveness research. Policy and funding implications of requiring an intervention to be demonstrated more effective than a simpler, less costly MINC alternative are discussed. C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fisher, Lawrence; Hessler, Danielle] Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94143 USA. [Strycker, Lisa A.; Toobert, Deborah J.] Oregon Res Inst, Eugene, OR 97403 USA. [King, Diane K.] Univ Alaska Anchorage, Ctr Behav Hlth Res & Serv, Anchorage, AK USA. [Jacobs, Tom] InterVis Media, Eugene, OR USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM glasgowre@mail.nih.gov FU NIDDK R01 [DK35524, DK035524, DK061937] FX The opinions expressed are those of the authors and do not necessarily represent those of the National Cancer Institute. We thank Drs. Barbara Rimer and Robert Croyle for first bringing the MINC concept to our attention. Partial support was provided by NIDDK R01 grants: DK35524, DK035524, and DK061937. NR 38 TC 8 Z9 8 U1 3 U2 8 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 MAR PY 2014 VL 4 IS 1 BP 26 EP 33 DI 10.1007/s13142-013-0232-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PH UT WOS:000356786000005 PM 24653774 ER PT J AU Tesauro, GM Seger, YR DiJoseph, L Schnell, JD Klein, WMP AF Tesauro, Gina M. Seger, Yvette R. DiJoseph, Leo Schnell, Joshua D. Klein, William M. P. TI Assessing the value of a Small Grants Program for behavioral research in cancer control SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Small grants; Behavioral research; Program evaluation AB In 1999, the National Cancer Institute (NCI) issued the first Small Grants Program (SGP) for Behavioral Research in Cancer Control (R03) funding opportunity announcement for investigators new to behavioral cancer prevention and control research. We explored whether the SGP was successful in its goals to encourage new investigators from a variety of disciplines to apply their skills to and promote career development in behavioral cancer prevention and control research. A quasi-experimental design examined applicant characteristics and outcome data by award status. Propensity score matching was used to compare awardees and non-awardees with similar impact scores as a control for application quality. Awardees were more likely than non-awardees to pursue and receive subsequent funding from the NCI and publish their research. Tailored small grant programs create benefit for both promoting and retaining new investigators. C1 [Tesauro, Gina M.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Seger, Yvette R.; DiJoseph, Leo; Schnell, Joshua D.] Thomson Reuters, New York, NY USA. NCI, Rockville, MD USA. RP Tesauro, GM (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, Room 3E634,9609 Med Ctr Dr,MSC 9761, Bethesda, MD 20892 USA. EM tesaurog@mail.nih.gov RI Schnell, Joshua/J-4000-2012; Seger, Yvette/A-5423-2010 OI Schnell, Joshua/0000-0001-9241-7441; Seger, Yvette/0000-0003-2099-4244 FU National Cancer Institute, NIH; [HHSN263201000058B] FX We would like to acknowledge Veronica Chollette (NCI) for her assistance and helpful comments in the preparation of this manuscript. We thank Laure Haak (Open Researcher and Contributor ID, ORCID) and other NCI colleagues who served as members of the BRP-SGP evaluation advisory committee including Kara Hall, Julie Mason, Richard Moser, Lawrence Solomon, and Amanda Vogel for their role and insights during the early stages of this evaluation. We are also grateful to the National Science Foundation, the International Cancer Research Portfolio, and the Livestrong Foundation for sharing their data. This work was supported by contract number HHSN263201000058B and funded with federal funds from the National Cancer Institute, NIH. NR 2 TC 1 Z9 1 U1 0 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 MAR PY 2014 VL 4 IS 1 BP 79 EP 85 DI 10.1007/s13142-013-0236-x PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CL2PH UT WOS:000356786000009 PM 24653778 ER PT J AU Weigel, B Malempati, S Reid, JM Voss, SD Cho, SY Chen, HX Krailo, M Villaluna, D Adamson, PC Blaney, SM AF Weigel, Brenda Malempati, Suman Reid, Joel M. Voss, Stephan D. Cho, Steven Y. Chen, Helen X. Krailo, Mark Villaluna, Doojduen Adamson, Peter C. Blaney, Susan M. TI Phase 2 Trial of Cixutumumab in Children, Adolescents, and Young Adults With Refractory Solid Tumors: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE insulin-like growth factor-I receptor; investigational agents; monoclonal antibody; pediatric cancer ID FACTOR-I RECEPTOR; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; DOWN-REGULATION; WILMS-TUMOR; INSULIN; CANCER; VIVO; PROLIFERATION AB PurposeThis phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. Patients and MethodsPatients with relapsed or refractory solid tumors were treated with 9mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. ResultsOne hundred sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. ConclusionCixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway. Pediatr Blood Cancer 2014;61:452-456. (c) 2013 Wiley Periodicals, Inc. C1 [Weigel, Brenda] Univ Minnesota, Minneapolis, MN 55455 USA. [Malempati, Suman] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Reid, Joel M.] Mayo Clin & Mayo Fdn, Rochester, MN USA. [Voss, Stephan D.] Childrens Hosp, Boston, MA 02115 USA. [Voss, Stephan D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cho, Steven Y.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Chen, Helen X.] NCI, Rockville, MD USA. [Krailo, Mark] USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Villaluna, Doojduen] Childrens Oncol Grp Operat Ctr, Monrovia, CA USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. RP Weigel, B (reprint author), Univ Minnesota, Dept Pediat, Div Pediat Hematol Oncol, MMC 366,420 Delaware St SE, Minneapolis, MN 55455 USA. EM weige007@umn.edu FU National Cancer Institute [U01 CA97452, U10 CA98543]; GCRC [M01-RR00188-46] FX Grant sponsor: National Cancer Institute; Grant numbers: U01 CA97452, U10 CA98543; Grant sponsor: GCRC; Grant number: M01-RR00188-46 NR 34 TC 40 Z9 42 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2014 VL 61 IS 3 BP 452 EP 456 DI 10.1002/pbc.24605 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288AZ UT WOS:000329585300011 PM 23956055 ER PT J AU Linsalata, AE Chen, XB Winters, CA Reese, TS AF Linsalata, Alexander E. Chen, Xiaobing Winters, Christine A. Reese, Thomas S. TI Electron Tomography on gamma-Aminobutyric Acid-ergic Synapses Reveals a Discontinuous Postsynaptic Network of Filaments SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE inhibitory synapse; postsynaptic density; gephyrin; -aminobutyric acid receptor; glycine receptor ID RAT SPINAL-CORD; CLUSTERING PROTEIN GEPHYRIN; VESICULAR GABA TRANSPORTER; TUBULIN LINKER PROTEIN; GLYCINE RECEPTOR; INHIBITORY SYNAPSES; GLUTAMATE-DECARBOXYLASE; HIPPOCAMPAL-NEURONS; CRYSTAL-STRUCTURE; CEREBRAL-CORTEX AB The regulation of synaptic strength at -aminobutyric acid (GABA)-ergic synapses is dependent on the dynamic capture, retention, and modulation of GABA A-type receptors by cytoplasmic proteins at GABAergic postsynaptic sites. How these proteins are oriented and organized in the postsynaptic cytoplasm is not yet established. To better understand these structures and gain further insight into the mechanisms by which they regulate receptor populations at postsynaptic sites, we utilized electron tomography to examine GABAergic synapses in dissociated rat hippocampal cultures. GABAergic synapses were identified and selected for tomography by using a set of criteria derived from the structure of immunogold-labeled GABAergic synapses. Tomography revealed a complex postsynaptic network composed of filaments that extend approximate to 100 nm into the cytoplasm from the postsynaptic membrane. The distribution of these postsynaptic filaments was strikingly similar to that of the immunogold label for gephyrin. Filaments were interconnected through uniform patterns of contact, forming complexes composed of 2-12 filaments each. Complexes did not link to form an integrated, continuous scaffold, suggesting that GABAergic postsynaptic specializations are less rigidly organized than glutamatergic postsynaptic densities. J. Comp. Neurol. 522:921-936, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Linsalata, Alexander E.; Chen, Xiaobing; Winters, Christine A.; Reese, Thomas S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Linsalata, AE (reprint author), 330 E Kingsley Rd, Ann Arbor, MI 48104 USA. EM latalinsa@gmail.com FU Intramural Program; National Institute of Neurological Disorders and Stroke; National Institutes of Health FX Grant sponsor: Intramural Program; Grant sponsor: National Institute of Neurological Disorders and Stroke; Grant sponsor: National Institutes of Health. NR 73 TC 6 Z9 6 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD MAR PY 2014 VL 522 IS 4 BP 921 EP 936 DI 10.1002/cne.23453 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 288BH UT WOS:000329586400010 PM 23982982 ER PT J AU Choi, H Yang, HC Shung, KK AF Choi, Hojong Yang, Hao-Chung Shung, K. Kirk TI Bipolar-power-transistor-based limiter for high frequency ultrasound imaging systems SO ULTRASONICS LA English DT Article DE Ultrasonic transducer; Limiter; Bipolar power transistor ID ARRAY AB High performance limiters are described in this paper for applications in high frequency ultrasound imaging systems. Limiters protect the ultrasound receiver from the high voltage (HV) spikes produced by the transmitter. We present a new bipolar power transistor (BPT) configuration and compare its design and performance to a diode limiter used in traditional ultrasound research and one commercially available limiter. Limiter performance depends greatly on the insertion loss (IL), total harmonic distortion (THD) and response time (RT), each of which will be evaluated in all the limiters. The results indicated that, compared with commercial limiter, BPT-based limiter had less IL (-7.7 dB), THD (-74.6 dB) and lower RT (43 ns) at 100 MHz. To evaluate the capability of these limiters, they were connected to a 100 MHz single element transducer and a two-way pulse-echo test was performed. It was found that the -6 dB bandwidth and sensitivity of the transducer using BPT-based limiter were better than those of the commercial limiter by 22% and 140%, respectively. Compared to the commercial limiter, BPT-based limiter is shown to be capable of minimizing signal attenuation, RT and THD at high frequencies and is thus suited for high frequency ultrasound applications. (C) 2013 Elsevier B.V. All rights reserved. C1 [Choi, Hojong] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA USA. RP Choi, H (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM hojongch@usc.edu FU National Institutes of Health [P41-EB002182] FX The authors thank Mr. Thomas Cummins and for his editing contribution. This research was supported by National Institutes of Health Grant # P41-EB002182. NR 10 TC 2 Z9 2 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0041-624X EI 1874-9968 J9 ULTRASONICS JI Ultrasonics PD MAR PY 2014 VL 54 IS 3 BP 754 EP 758 DI 10.1016/j.ultras.2013.10.010 PG 5 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 281VW UT WOS:000329130100002 PM 24199954 ER PT J AU Mohanty, JG Nagababu, E Rifkind, JM AF Mohanty, Joy G. Nagababu, Enika Rifkind, Joseph M. TI Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE red blood cells; oxidative Stress; deformability; heme degradation; cellular aging ID HEME DEGRADATION-PRODUCTS; ERYTHROCYTE-MEMBRANE; HYDROGEN-PEROXIDE; TYROSINE PHOSPHORYLATION; GLUTATHIONE-PEROXIDASE; LIPID-PEROXIDATION; LIFE-SPAN; HEMOGLOBIN; DEFORMABILITY; TRANSPORT AB Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Decreased deformability of RBCs is, therefore, one of the factors that can contribute to the elimination of aged or damaged RBCs from the circulation. This process can also cause impaired oxygen delivery, which contributes to the pathology of a number of diseases. Studies from our laboratory have shown that oxidative stress plays a significant role in damaging the RBC membrane and impairing its deformability. RBCs are continuously exposed to both endogenous and exogenous sources of reactive oxygen species (ROS) like superoxide and hydrogen peroxide (H2O2). The bulk of the ROS are neutralized by the RBC antioxidant system consisting of both non-enzymatic and enzymatic antioxidants including catalase, glutathione peroxidase and peroxiredoxin-2. However, the autoxidation of hemoglobin (Hb) bound to the membrane is relatively inaccessible to the predominantly cytosolic RBC antioxidant system. This inaccessibility becomes more pronounced under hypoxic conditions when Hb is partially oxygenated, resulting in an increased rate of autoxidation and increased affinity for the RBC membrane. We have shown that a fraction of peroxyredoxin-2 present on the RBC membrane may play a major role in neutralizing these ROS. H2O2 that is not neutralized by the R BC antioxidant system can react with the heme producing fluorescent heme degradation products (HDPs). We have used the level of these HDP as a measure of RBC oxidative Stress. Increased levels of HDP are detected during cellular aging and various diseases. The negative correlation (p < 0.0001) between the level of HDP and RBC deformability establishes a contribution of RBC oxidative stress to impaired deformability and cellular stiffness. While decreased deformability contributes to the removal of RBCs from the circulation, oxidative stress also contributes to the uptake of RBCs by macrophages, which plays a major role in the removal of RBCs from circulation. The contribution of oxidative stress to the removal of RBCs by macrophages involves caspase-3 activation, which requires oxidative stress. RBC oxidative stress, therefore, plays a significant role in inducing RBC aging. C1 [Mohanty, Joy G.; Nagababu, Enika; Rifkind, Joseph M.] NIA, Mol Dynam Sect, Lab Mol Gerontol, Bethesda, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, Lab Mol Gerontol, 251 Bayview Blvd, Bethesda, MD 21224 USA. EM rifkindj@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging, NIH FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging, NIH. NR 68 TC 34 Z9 37 U1 10 U2 22 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD FEB 28 PY 2014 VL 5 AR UNSP 84 DI 10.3389/fphys.2014.00084 PG 6 WC Physiology SC Physiology GA AX3HT UT WOS:000346831400001 PM 24616707 ER PT J AU Seo, K Rainer, PP Lee, DI Hao, S Bedja, D Birnbaumer, L Cingolani, OH Kass, DA AF Seo, Kinya Rainer, Peter P. Lee, Dong-ik Hao, Scarlett Bedja, Djahida Birnbaumer, Lutz Cingolani, Oscar H. Kass, David A. TI Hyperactive Adverse Mechanical Stress Responses in Dystrophic Heart Are Coupled to Transient Receptor Potential Canonical 6 and Blocked by cGMP-Protein Kinase G Modulation SO CIRCULATION RESEARCH LA English DT Article DE cardiac; stress mechanics; pharmacology; muscular dystrophy; Duchenne; muscle contraction; myocytes; cardiac ID DUCHENNE MUSCULAR-DYSTROPHY; PATHOLOGICAL CARDIAC-HYPERTROPHY; MDX MOUSE MODEL; CATION CHANNELS; ANGIOTENSIN-II; TRPC6 CHANNELS; STRETCH; MUSCLE; SILDENAFIL; MICE AB Rationale: The heart is exquisitely sensitive to mechanical stimuli to adapt rapidly to physiological demands. In muscle lacking dystrophin, such as Duchenne muscular dystrophy, increased load during contraction triggers pathological responses thought to worsen the disease. The relevant mechanotransducers and therapies to target them remain unclear. Objectives: We tested the role of transient receptor potential canonical (TRPC) channels TRPC3 and TRPC6 and their modulation by protein kinase G (PKG) in controlling cardiac systolic mechanosensing and determined their pathophysiological relevance in an experimental model of Duchenne muscular dystrophy. Methods and Results: Contracting isolated papillary muscles and cardiomyocytes from controls and mice genetically lacking either TRPC3 or TRPC6 were subjected to auxotonic load to induce stress-stimulated contractility (SSC, gradual rise in force and intracellular Ca2+). Incubation with cGMP (PKG activator) markedly blunted SSC in controls and Trpc3(-/-); whereas in Trpc6(-/-), the resting SSC response was diminished and cGMP had no effect. In Duchenne muscular dystrophy myocytes (mdx/utrophin deficient), the SSC was excessive and arrhythmogenic. Gene deletion or selective drug blockade of TRPC6 or cGMP/PKG activation reversed this phenotype. Chronic phosphodiesterase 5A inhibition also normalized abnormal mechanosensing while blunting progressive chamber hypertrophy in Duchenne muscular dystrophy mice. Conclusions: PKG is a potent negative modulator of cardiac systolic mechanosignaling that requires TRPC6 as the target effector. In dystrophic hearts, excess SSC and arrhythmia are coupled to TRPC6 and are ameliorated by its targeted suppression or PKG activation. These results highlight novel therapeutic targets for this disease. C1 [Seo, Kinya; Rainer, Peter P.; Lee, Dong-ik; Hao, Scarlett; Bedja, Djahida; Cingolani, Oscar H.; Kass, David A.] Johns Hopkins Med Inst, Div Cardiol, Dept Med, Baltimore, MD 21205 USA. [Kass, David A.] Johns Hopkins Med Inst, Dept Biomed Engn, Baltimore, MD 21205 USA. [Rainer, Peter P.] Med Univ Graz, Div Cardiol, Graz, Austria. [Birnbaumer, Lutz] NIEHS, Res Triangle Pk, NC 27709 USA. RP Kass, DA (reprint author), Johns Hopkins Med Inst, Div Cardiol, Ross Bldg,Room 858,720 Rutland Ave, Baltimore, MD 21205 USA. EM dkass@jhmi.edu RI Rainer, Peter/M-2145-2016 OI Rainer, Peter/0000-0002-2840-6454 FU Muscular Dystrophy Association [186454]; Fondation Leducq TransAtlantic Network of Excellence; National Institutes of Health [HL 59480]; American Heart Association; Max Kade Fellowship, Austrian Academy of Sciences; Intramural Research Program of the National Institutes of Health [Z01-ES-101864]; Abraham and Virginia Weiss Professorship and Peter Belfer Endowment FX This research was supported by a grant from Muscular Dystrophy Association (186454), Fondation Leducq TransAtlantic Network of Excellence, and National Institutes of Health Grant-HL 59480 (D. A. Kass), American Heart Association Fellowship Grant (K. Seo), Max Kade Fellowship, Austrian Academy of Sciences (P.P. Rainer), Intramural Research Program of the National Institutes of Health (Project Z01-ES-101864, L. Birnbaumer), and the Abraham and Virginia Weiss Professorship and Peter Belfer Endowment (D.A. Kass). NR 51 TC 19 Z9 19 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD FEB 28 PY 2014 VL 114 IS 5 BP 823 EP 832 DI 10.1161/CIRCRESAHA.114.302614 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AG7GS UT WOS:000335586900014 PM 24449818 ER PT J AU Desai, SS Modali, SD Parekh, VI Kebebew, E Agarwal, SK AF Desai, Shruti S. Modali, Sita D. Parekh, Vaishali I. Kebebew, Electron Agarwal, Sunita K. TI GSK-3 beta Protein Phosphorylates and Stabilizes HLXB9 Protein in Insulinoma Cells to Form a Targetable Mechanism of Controlling Insulinoma Cell Proliferation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Differentiation; Neuroendocrinology; Pancreatic Islets; Proliferation; Tumor; GSK-3; HLXB9; Insulinoma; MEN1; Menin ID MULTIPLE-ENDOCRINE-NEOPLASIA; GLYCOGEN-SYNTHASE KINASE-3-BETA; TUMOR-SUPPRESSOR GENE; MOLECULAR PATHOGENESIS; NEUROENDOCRINE TUMORS; CANCER-CELLS; MEN1; TYPE-1; EXPRESSION; MICE AB Background: Germ line heterozygous loss of the MEN1 tumor suppressor gene causes tissue-specific tumors such as insulinomas. Results: GSK-3 and GSK-3-mediated phosphorylation of HLXB9, a -cell differentiation factor, is elevated in insulinomas, and GSK-3 inhibition blocks insulinoma cell proliferation. Conclusion: GSK-3 and phospho-HLXB9 form a targetable mechanism of insulinoma pathogenesis. Significance: Reactivation of a tissue-specific differentiation factor accounts for tumor tissue specificity. Insulinomas (pancreatic islet cell tumors) are the most common type of functioning pancreatic neuroendocrine tumors that occur sporadically or as a part of the MEN1 syndrome that is caused by germ line mutations in MEN1. Tissue-specific tumor predisposition from germ line mutations in ubiquitously expressed genes such as MEN1 could occur because of functional consequences on tissue-specific factors. We previously reported the proapoptotic cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3 inactivates the proapoptotic activity of HLXB9 by phosphorylating HLXB9 at Ser-78/Ser-80 (pHLXB9). Although HLXB9 is found in the nucleus and cytoplasm, pHLXB9 is predominantly nuclear. Both pHLXB9 and active GSK-3 are elevated in cells with menin knockdown, in MEN1-associated cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3 blocked cell proliferation in three different rodent insulinoma cell lines by arresting the cells in G(2)/M phase and caused apoptosis. Taken together, these data suggest that the combination of GSK-3 and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3 and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with cell proliferation. C1 [Desai, Shruti S.; Modali, Sita D.; Parekh, Vaishali I.; Agarwal, Sunita K.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIH, Bldg 10,Rm 8C-101, Bethesda, MD 20892 USA. EM sunitaa@mail.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU NIDDK, National Institutes of Health [1ZIADK07503503]; NCI, National Institutes of Health [1ZIABC01127503] FX This work was supported by NIDDK, National Institutes of Health Intramural Program Grant 1ZIADK07503503 (to S. K. A.) and NCI, National Institutes of Health Grant 1ZIABC01127503 (to E. K.). NR 40 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 28 PY 2014 VL 289 IS 9 BP 5386 EP 5398 DI 10.1074/jbc.M113.533612 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB8BQ UT WOS:000332015500004 PM 24425879 ER PT J AU Hasenour, CM Ridley, DE Hughey, CC James, FD Donahue, EP Shearer, J Viollet, B Foretz, M Wasserman, DH AF Hasenour, Clinton M. Ridley, D. Emerson Hughey, Curtis C. James, Freyja D. Donahue, E. Patrick Shearer, Jane Viollet, Benoit Foretz, Marc Wasserman, David H. TI 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE AMP; AMP Kinase; AMP-activated Kinase (AMPK); Energy Metabolism; Liver Metabolism; AICAR; Fat Metabolism; In Vivo ID ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; ISOLATED RAT HEPATOCYTES; NUCLEAR RECEPTOR SHP; INSULIN-RESISTANCE; GLUCOKINASE TRANSLOCATION; GLUCAGON RECEPTOR; GENE-EXPRESSION; SHORT-TERM; COMPLEX I AB Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR; 8 mg center dot kg(-1)min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (alpha 1 alpha 2(lox/lox)) and liver-specific AMPK knock-out mice (alpha 1 alpha 2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted alpha 1 alpha 2(lox/lox) and alpha 1 alpha 2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by approximate to 20% in alpha 1 alpha 2(lox/lox), which was exacerbated by approximate to 2-fold in alpha 1 alpha 2(lox/lox) + Albcre. This corresponded to a approximate to 6-fold rise in AMP/ATP in alpha 1 alpha 2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was approximate to 30% lower in alpha 1 alpha 2(lox/lox) + Albcre than alpha 1 alpha 2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration. C1 [Hasenour, Clinton M.; Ridley, D. Emerson; James, Freyja D.; Donahue, E. Patrick; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Wasserman, David H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. [Viollet, Benoit; Foretz, Marc] Inst Cochin, INSERM, U1016, F-75014 Paris, France. [Viollet, Benoit; Foretz, Marc] CNRS, UMR 8104, F-75014 Paris, France. [Viollet, Benoit; Foretz, Marc] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France. [Shearer, Jane] Univ Calgary, Fac Kinesiol, Calgary, AB T2N 1N4, Canada. [Hughey, Curtis C.; Shearer, Jane] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. RP Hasenour, CM (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 823 Light Hall,2215 Garland Ave, Nashville, TN 37232 USA. EM clinton.m.hasenour@vanderbilt.edu FU National Institutes of Health [U24 DK59637, R37 DK50277, DK20593]; Molecular Endocrinology Training Program at Vanderbilt FX This work was supported, in whole or in part, by National Institutes of Health Grants U24 DK59637 and R37 DK50277 (to D. H. W.) and DK20593 (the Diabetes Research and Training Center). This work was also supported by the Molecular Endocrinology Training Program at Vanderbilt. NR 63 TC 15 Z9 15 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 28 PY 2014 VL 289 IS 9 BP 5950 EP 5959 DI 10.1074/jbc.M113.528232 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB8BQ UT WOS:000332015500051 PM 24403081 ER PT J AU Bojjireddy, N Botyanszki, J Hammond, G Creech, D Peterson, R Kemp, DC Snead, M Brown, R Morrison, A Wilson, S Harrison, S Moore, C Balla, T AF Bojjireddy, Naveen Botyanszki, Janos Hammond, Gerald Creech, Donald Peterson, Richard Kemp, Daniel C. Snead, Mark Brown, Randy Morrison, Alastair Wilson, Steve Harrison, Steve Moore, Chris Balla, Tamas TI Pharmacological and Genetic Targeting of the PI4KA Enzyme Reveals Its Important Role in Maintaining Plasma Membrane Phosphatidylinositol 4-Phosphate and Phosphatidylinositol 4,5-Bisphosphate Levels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Angiotensin II; G Protein-coupled Receptors; Phosphatidylinositol; Phosphatidylinositol Kinase; Phospholipase C ID C VIRUS-REPLICATION; III-ALPHA; 4-KINASE; PHOSPHOINOSITIDES; DOMAINS; KINASE; POOLS; PTDINS(4,5)P-2; TRAFFICKING; ACTIVATION AB Background: PI4KA is a critical host factor for replication of hepatitis C virus in liver and a potential therapeutic target. Results: PI4KA inhibitors prevent the maintenance of PtdIns(4,5)P-2 pools during strong PLC activation. Conclusion: PI4KA plays a critical role in maintaining plasma membrane phosphoinositide pools. Significance: Safe pharmacological targeting of PI4KA is not feasible. Phosphatidylinositol 4-kinase type III (PI4KA) is a host factor essential for hepatitis C virus replication and hence is a target for drug development. PI4KA has also been linked to endoplasmic reticulum exit sites and generation of plasma membrane phosphoinositides. Here, we developed highly specific and potent inhibitors of PI4KA and conditional knock-out mice to study the importance of this enzyme in vitro and in vivo. Our studies showed that PI4KA is essential for the maintenance of plasma membrane phosphatidylinositol 4,5-bisphosphate pools but only during strong stimulation of receptors coupled to phospholipase C activation. Pharmacological blockade of PI4KA in adult animals leads to sudden death closely correlating with the drug's ability to induce phosphatidylinositol 4,5-bisphosphate depletion after agonist stimulation. Genetic inactivation of PI4KA also leads to death; however, the cause in this case is due to severe intestinal necrosis. These studies highlight the risks of targeting PI4KA as an anti-hepatitis C virus strategy and also point to important distinctions between genetic and pharmacological studies when selecting host factors as putative therapeutic targets. C1 [Bojjireddy, Naveen; Hammond, Gerald; Balla, Tamas] Eunice Kennedy Shriver NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Botyanszki, Janos; Creech, Donald; Moore, Chris] GlaxoSmithKline, Infect Dis Discovery Performance Unit, Res Triangle Pk, NC 27709 USA. [Peterson, Richard; Kemp, Daniel C.; Brown, Randy] GlaxoSmithKline, Safety Assessment, Res Triangle Pk, NC 27709 USA. [Snead, Mark; Morrison, Alastair; Wilson, Steve; Harrison, Steve] GlaxoSmithKline, Lab Anim Serv, Res Triangle Pk, NC 27709 USA. RP Moore, C (reprint author), GlaxoSmithKline, Infect Dis Discovery Performance Unit, Rm 3-3245,5 Moore Dr, Res Triangle Pk, NC 27709 USA. EM christopher.b.moore@gsk.com; ballat@mail.nih.gov RI Hammond, Gerald/A-5759-2016; OI Hammond, Gerald/0000-0002-6660-3272; Balla, Tamas/0000-0002-9077-3335 FU National Institutes of Health from the Intramural Research Program of the Eunice Kennedy Shriver NICHD FX This work was supported, in whole or in part, by National Institutes of Health grants from the Intramural Research Program of the Eunice Kennedy Shriver NICHD (to N. B., G. H., and T. B.). NR 43 TC 34 Z9 34 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 28 PY 2014 VL 289 IS 9 BP 6120 EP 6132 DI 10.1074/jbc.M113.531426 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB8BQ UT WOS:000332015500066 PM 24415756 ER PT J AU Kim, SJ Cheresh, P Williams, D Cheng, Y Ridge, K Schumacker, PT Weitzman, S Bohr, VA Kamp, DW AF Kim, Seok-Jo Cheresh, Paul Williams, David Cheng, Yuan Ridge, Karen Schumacker, Paul T. Weitzman, Sigmund Bohr, Vilhelm A. Kamp, David W. TI Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE DNA Damage; DNA Repair; Epithelial Cell; Fibrosis; Oxidative Stress; Lung Fibrosis; Mitochondrial DNA Damage; Mitochondrial Aconitase; Mitochondrial hOgg1 ID RETICULUM STRESS-RESPONSE; ARTERY ENDOTHELIAL-CELLS; OXIDATIVE STRESS; PULMONARY-FIBROSIS; SIGNALING PATHWAY; INDUCED APOPTOSIS; REACTIVE OXYGEN; MTDNA DAMAGE; LUNG-CANCER; NUCLEAR-DNA AB Background: Mitochondrial Ogg1 prevents oxidant (H2O2 and asbestos)-induced Aco-2 degradation and apoptosis. Results: Oxidant stress caused preferential AEC mtDNA > nuclear DNA damage, mt-p53 translocation, and apoptosis; effects were blocked by mt-hOgg1 or Aco-2. Conclusion: mt-hOgg1 and Aco-2 preserve AEC mtDNA, preventing oxidant-induced p53 activation and apoptosis. Significance: mt-hOgg1/Aco-2 effects on mtDNA may be an innovative target for preventing degenerative diseases. Mitochondria-targeted human 8-oxoguanine DNA glycosylase (mt-hOgg1) and aconitase-2 (Aco-2) each reduce oxidant-induced alveolar epithelial cell (AEC) apoptosis, but it is unclear whether protection occurs by preventing AEC mitochondrial DNA (mtDNA) damage. Using quantitative PCR-based measurements of mitochondrial and nuclear DNA damage, mtDNA damage was preferentially noted in AEC after exposure to oxidative stress (e.g. amosite asbestos (5-25 g/cm(2)) or H2O2 (100-250 m)) for 24 h. Overexpression of wild-type mt-hOgg1 or mt-long / 317-323 hOgg1 mutant incapable of DNA repair (mt-hOgg1-Mut) each blocked A549 cell oxidant-induced mtDNA damage, mitochondrial p53 translocation, and intrinsic apoptosis as assessed by DNA fragmentation and cleaved caspase-9. In contrast, compared with controls, knockdown of Ogg1 (using Ogg1 shRNA in A549 cells or primary alveolar type 2 cells from ogg1(-/-) mice) augmented mtDNA lesions and intrinsic apoptosis at base line, and these effects were increased further after exposure to oxidative stress. Notably, overexpression of Aco-2 reduced oxidant-induced mtDNA lesions, mitochondrial p53 translocation, and apoptosis, whereas siRNA for Aco-2 (siAco-2) enhanced mtDNA damage, mitochondrial p53 translocation, and apoptosis. Finally, siAco-2 attenuated the protective effects of mt-hOgg1-Mut but not wild-type mt-hOgg1 against oxidant-induced mtDNA damage and apoptosis. Collectively, these data demonstrate a novel role for mt-hOgg1 and Aco-2 in preserving AEC mtDNA integrity, thereby preventing oxidant-induced mitochondrial dysfunction, p53 mitochondrial translocation, and intrinsic apoptosis. Furthermore, mt-hOgg1 chaperoning of Aco-2 in preventing oxidant-mediated mtDNA damage and apoptosis may afford an innovative target for the molecular events underlying oxidant-induced toxicity. C1 [Kim, Seok-Jo; Cheresh, Paul; Williams, David; Cheng, Yuan; Ridge, Karen; Kamp, David W.] Jesse Brown Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Dept Med, Chicago, IL 60611 USA. [Kim, Seok-Jo; Cheresh, Paul; Williams, David; Cheng, Yuan; Ridge, Karen; Kamp, David W.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Schumacker, Paul T.] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Weitzman, Sigmund] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Kamp, DW (reprint author), Northwestern Univ, Feinberg Sch Med, McGaw M-330,240 E Huron St, Chicago, IL 60611 USA. EM d-kamp@northwestern.edu FU National Institutes of Health [RO1 ES020357, P01HL071643]; Veterans Affairs Merit Award FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1 ES020357 (to D. W. K.) and P01HL071643 (to K. R.). This work was also supported by a Veterans Affairs Merit Award (to D. W. K.). NR 60 TC 17 Z9 19 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 28 PY 2014 VL 289 IS 9 BP 6165 EP 6176 DI 10.1074/jbc.M113.515130 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB8BQ UT WOS:000332015500070 PM 24429287 ER PT J AU Groft, SC AF Groft, Stephen C. TI A past with uncertainty, a future with hope - rare disease day 2014 from a USA perspective SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Editorial Material DE Rare disease; Orphan product; Translational research resources; Undiagnosed disease; Rare disease day 2014 AB We reflect on the worldwide research accomplishments, orphan product approvals, and the commitments by the rare diseases community. Major collaborative efforts by the public and private sectors increased interventions and diagnostics for rare diseases. We marvel at the impact of safe and effective treatments when they become available. Hope remains for the rare diseases community with a renewed commitment and acceptance of collaborative public-private partnerships of government translational research and regulatory programs, the biopharmaceutical, devices and diagnostics industries, academic investigators, and patient advocacy groups. The global rare diseases community remains strong and responsive to the voices and needs of patients, families, and clinicians awaiting diagnosis and treatment for their disease. We anticipate even greater successes in 2014 to reflect on Rare Disease Day 2015. C1 NIH, Off Rare Dis Res, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. RP Groft, SC (reprint author), NIH, Off Rare Dis Res, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. EM Stephen.Groft@nih.gov NR 0 TC 2 Z9 2 U1 1 U2 2 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 FEB 28 PY 2014 VL 9 AR 31 DI 10.1186/1750-1172-9-31 PG 3 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA AG2NO UT WOS:000335253400002 PM 24580809 ER PT J AU Okello, E Beaton, A Mondo, CK Kruszka, P Kiwanuka, N Odoi-Adome, R Freers, J AF Okello, Emmy Beaton, Andrea Mondo, Charles K. Kruszka, Paul Kiwanuka, Noah Odoi-Adome, Richard Freers, Juergen TI Rheumatic heart disease in Uganda: the association between MHC class II HLA DR alleles and disease: a case control study SO BMC CARDIOVASCULAR DISORDERS LA English DT Article DE Rheumatic heart disease; HLA-DR1; HLA-DRB11; MHC- major histocompatibility complex ID PRIMERS PCR-SSP; SUSCEPTIBILITY; FEVER; AMPLIFICATION; HAPLOTYPES; DIVERSITY; ANTIGENS; CHILDREN AB Background: Rheumatic heart disease (RHD), the only long term consequence of acute rheumatic fever, remains a leading cause of morbidity and mortality among young adults in Uganda. An inherited susceptibility to acute rheumatic fever centers around the major histocompatibility class II human leucocyte antigens. However, there is paucity of data from sub-Saharan Africa. This study compares the frequency of HLA class II DR alleles between RHD cases and normal controls in Uganda. Methods: One hundred ninety-nine participants including 96 established RHD cases aged 5-60 years and 103 age and sex matched normal controls were recruited for participation. DNA was manually extracted from buffy coat samples and HLA analysis was performed. HLA-DR allelic frequency comparison between cases and controls were estimated using conditional logistic regression with 95% confidence intervals. P -values were corrected for multiple hypothesis testing. Results: 199 participants (103 female, 51.8%) completed the study. The mean (SD) age in years for cases and controls were 29.6 (10.2) and 29(18), respectively. After conditional logistic regression and multiple hypothesis testing, HLA-DR1 was associated with a decreased risk of RHD (OR = 0.42, CI 0.21-085, P = 0.01, Corrected P value (PC) = 0.09,) while HLA-DR11 was associated with increased risk of RHD (OR = 3.31, CI 1.57-6.97, P = <0.001, Pc < 0.001). No other significant associations were found. Conclusion: In this first study of HLA genetic susceptibility to RHD in Uganda, HLA-DR1 was more common in normal controls while HLA-DR11 was more common among RHD cases suggesting a disease susceptibility association. In future studies, high resolution HLA analysis and genome wide studies should be carried out to confirm this pattern. C1 [Okello, Emmy; Mondo, Charles K.; Freers, Juergen] Makerere Univ, Dept Med, Uganda Heart Inst, Kampala, Uganda. [Okello, Emmy] Uganda Heart Inst, Kampala, Uganda. [Beaton, Andrea] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. [Kruszka, Paul] NHGRI, NIH, Bethesda, MD 20892 USA. [Kiwanuka, Noah] Makerere Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Kampala, Uganda. [Odoi-Adome, Richard] Makerere Univ, Sch Pharm, Kampala, Uganda. RP Okello, E (reprint author), Makerere Univ, Dept Med, Uganda Heart Inst, Ward 1C,Mulago Hosp Complex,POB 7051, Kampala, Uganda. EM emmkol@hotmail.com FU Millennium Science Initiative (MSI); Fogarty International Center; National Heart Lung and Blood Institute; Common Fund of the National Institutes of Health [R24 TW008861] FX This study was funded by the Millennium Science Initiative (MSI) and the Fogarty International Center, the National Heart Lung and Blood Institute, and the Common Fund of the National Institutes of Health under Award Number R24 TW008861. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 25 TC 7 Z9 7 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD FEB 28 PY 2014 VL 14 AR 28 DI 10.1186/1471-2261-14-28 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AF2JG UT WOS:000334537800001 PM 24581333 ER PT J AU Barrios, B Baez, NS Reynolds, D Iribarren, P Cejas, H Young, HA Rodriguez-Galan, MC AF Barrios, Bibiana Baez, Natalia S. Reynolds, Della Iribarren, Pablo Cejas, Hugo Young, Howard A. Cecilia Rodriguez-Galan, Maria TI Abrogation of TNF alpha Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12 SO PLOS ONE LA English DT Article ID PHASE-I TRIAL; RECOMBINANT HUMAN INTERLEUKIN-12; TUMOR-NECROSIS-FACTOR; RENAL-CELL CANCER; IFN-GAMMA; GENE-THERAPY; INTERFERON-GAMMA; NITRIC-OXIDE; TOXICITY; MICE AB For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with other drugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of this cytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome this toxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors that are difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine still remains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 in the treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work we demonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce different types of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished and survival of mice enhanced in the absence of tumor necrosis factor alpha (TNF alpha). This observation is in contrast to several murine models and clinical trials that postulate interferon gamma (IFN gamma) as the main cytokine responsible for IL-12 toxicity. Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with a low dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNF alpha are almost completely abrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNF alpha signaling does not affect the strong anti-tumor activity of IL-12. Thus, neutralizing TNF alpha with antagonists already approved for human use offers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer. C1 [Barrios, Bibiana; Baez, Natalia S.; Iribarren, Pablo; Cejas, Hugo; Cecilia Rodriguez-Galan, Maria] Univ Nacl Cordoba, CIBICI CONICET, Fac Ciencias Quim, RA-5000 Cordoba, Argentina. [Reynolds, Della; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Rodriguez-Galan, MC (reprint author), Univ Nacl Cordoba, CIBICI CONICET, Fac Ciencias Quim, RA-5000 Cordoba, Argentina. EM crodri@bioclin.fcq.unc.edu.ar FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health; Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina); Secretaria de Ciencia y Tecnica de la Universidad Nacional de Cordoba (SeCyT-UNC, Argentina) FX This project has been funded in part with federal funds from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and also by Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina) and Secretaria de Ciencia y Tecnica de la Universidad Nacional de Cordoba (SeCyT-UNC, Argentina). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 1 Z9 1 U1 0 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 FEB 28 PY 2014 VL 9 IS 2 AR e90116 DI 10.1371/journal.pone.0090116 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200130 PM 24587231 ER PT J AU Dema, B Pellefigues, C Hasni, S Gault, N Jiang, C Ricks, TK Bonelli, MM Scheffel, J Sacre, K Jablonski, M Gobert, D Papo, T Daugas, E Illei, G Charles, N Rivera, J AF Dema, Barbara Pellefigues, Christophe Hasni, Sarfaraz Gault, Nathalie Jiang, Chao Ricks, Tiffany K. Bonelli, Michael M. Scheffel, Joerg Sacre, Karim Jablonski, Mathieu Gobert, Delphine Papo, Thomas Daugas, Eric Illei, Gabor Charles, Nicolas Rivera, Juan TI Autoreactive IgE Is Prevalent in Systemic Lupus Erythematosus and Is Associated with Increased Disease Activity and Nephritis SO PLOS ONE LA English DT Article ID ANTI-DSDNA ANTIBODIES; CLINICAL-SIGNIFICANCE; REVISED CRITERIA; DNA ANTIBODIES; AUTOANTIBODIES; BASOPHILS; DEPOSITS; CLASSIFICATION; MECHANISMS; CELLS AB The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5 +/- 12.7 and 43.6 +/- 15.3 years and disease duration of 13.5 +/- 8.5 and 16.6 +/- 11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE's and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) >= 4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease. C1 [Dema, Barbara; Jiang, Chao; Ricks, Tiffany K.; Scheffel, Joerg; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Pellefigues, Christophe; Sacre, Karim; Papo, Thomas; Daugas, Eric; Charles, Nicolas] Univ Paris Diderot, INSERM, U699, Paris, France. [Hasni, Sarfaraz] NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Sacre, Karim; Gobert, Delphine; Papo, Thomas] Univ Paris Diderot, Fac Med Site Bichat, Hop Bichat, AP HP,Dept Internal Med, Paris, France. [Jablonski, Mathieu; Daugas, Eric] Univ Paris Diderot, Fac Med Site Bichat, Hop Bichat, AP HP,Dept Nephrol, Paris, France. [Gault, Nathalie] Univ Paris Diderot, Fac Med Site Bichat, Hop Bichat, AP HP,Clin Res Unit, Paris, France. [Illei, Gabor] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, NIH, Bethesda, MD USA. [Bonelli, Michael M.] NIAMSD, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Charles, N (reprint author), Univ Paris Diderot, INSERM, U699, Paris, France. EM nicolas.charles@inserm.fr; juan_rivera@nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH); French Institut National de la Sante Et de la Recherche Medicale (INSERM); Assistance Publique - Hopitaux de Paris (AP-HP); Mairie de Paris; ANR JCJC SVSE1 BASILE; French Kidney Foundation (Fondation du Rein); AP-HP (CHRT) FX This work was supported by the Intramural Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH), by the French Institut National de la Sante Et de la Recherche Medicale (INSERM), by the Assistance Publique - Hopitaux de Paris (AP-HP) and by grants from the Mairie de Paris (Emergences 2010), ANR JCJC SVSE1 2011 BASILE and the French Kidney Foundation (Fondation du Rein) to NC. NC is under a translational research contract with the AP-HP (CHRT). The authors wish to acknowledge the invaluable support of the Office of the Clinical Director, NIAMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 27 Z9 27 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2014 VL 9 IS 2 AR e90424 DI 10.1371/journal.pone.0090424 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200192 PM 24587356 ER PT J AU Francischetti, IMB Gordon, E Bizzarro, B Gera, N Andrade, BB Oliveira, F Ma, DY Assumpcao, TCF Ribeiro, JMC Pena, M Qi, CF Diouf, A Moretz, SE Long, CA Ackerman, HC Pierce, SK Sa-Nunes, A Waisberg, M AF Francischetti, Ivo M. B. Gordon, Emile Bizzarro, Bruna Gera, Nidhi Andrade, Bruno B. Oliveira, Fabiano Ma, Dongying Assumpcao, Teresa C. F. Ribeiro, Jose M. C. Pena, Mirna Qi, Chen-Feng Diouf, Ababacar Moretz, Samuel E. Long, Carole A. Ackerman, Hans C. Pierce, Susan K. Sa-Nunes, Anderson Waisberg, Michael TI Tempol, an Intracellular Antioxidant, Inhibits Tissue Factor Expression, Attenuates Dendritic Cell Function, and Is Partially Protective in a Murine Model of Cerebral Malaria SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; FACTOR-KAPPA-B; HUMAN ENDOTHELIAL-CELLS; BLOOD-BRAIN-BARRIER; OXYGEN-RADICAL PRODUCTION; INNATE IMMUNE-RESPONSE; OXIDATIVE STRESS; INFECTED ERYTHROCYTES; PARKINSONS-DISEASE; MITOCHONDRIAL MYOPATHY AB Background: The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood. Methods and Findings: We undertook testing Tempol-a superoxide dismutase (SOD) mimetic and pleiotropic intracellular antioxidant-in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol inhibited LPS-induced production of TNF-alpha, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants-such as a-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ) and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (gp91(phox-/-)) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium) did not show protection or exacerbation for CM. Conclusion: Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic targeting of intracellular ROS in CM is discussed. C1 [Francischetti, Ivo M. B.; Oliveira, Fabiano; Ma, Dongying; Assumpcao, Teresa C. F.; Ribeiro, Jose M. C.; Diouf, Ababacar; Moretz, Samuel E.; Long, Carole A.; Ackerman, Hans C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Gordon, Emile; Gera, Nidhi; Pena, Mirna; Qi, Chen-Feng; Pierce, Susan K.; Waisberg, Michael] NIAID, Immunogenet Lab, NIH, Rockville, MD USA. [Bizzarro, Bruna; Sa-Nunes, Anderson] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Expt Immunol Lab, Sao Paulo, Brazil. [Andrade, Bruno B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Waisberg, Michael] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. RP Francischetti, IMB (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM ifrancischetti@niaid.nih.gov; waisberg@gmail.com RI Andrade, Bruno/J-9111-2012; ma, dongying/D-8623-2012; Sa-Nunes, Anderson/D-8667-2012; Ribeiro, Jose/J-7011-2015; Bizzarro, Bruna/K-4778-2016; OI Andrade, Bruno/0000-0001-6833-3811; Sa-Nunes, Anderson/0000-0002-1859-4973; Bizzarro, Bruna/0000-0001-6315-0549; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Brazilian Malaria Network (MCT/CNPq/MS/SCTIE/DECIT/PRONEX) [555648/2009-5]; Research Network on Bioactive Molecules from Arthropod Vectors (NAP-MOBIARVE, University of Sao Paulo); PATH/Malaria Vaccine Initiative FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Dr. Anderson Sa-Nunes is recipient of grants from Brazilian Malaria Network (MCT/CNPq/MS/SCTIE/DECIT/PRONEX - 555648/2009-5) and from the Research Network on Bioactive Molecules from Arthropod Vectors (NAP-MOBIARVE, University of Sao Paulo). GIA Reference Center is supported by the PATH/Malaria Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 142 TC 9 Z9 10 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2014 VL 9 IS 2 AR e87140 DI 10.1371/journal.pone.0087140 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200011 PM 24586264 ER PT J AU Hoskins, LM Werner-Lin, A Greene, MH AF Hoskins, Lindsey M. Werner-Lin, Allison Greene, Mark H. TI In Their Own Words: Treating Very Young BRCA1/2 Mutation-Positive Women with Care and Caution SO PLOS ONE LA English DT Article ID OVARIAN-CANCER RISK; BREAST-CANCER; CARRIERS; COHORT; TAMOXIFEN; METAANALYSIS; MULTICENTER; MASTECTOMY; PREVENTION; MANAGEMENT AB Purpose: Young women who have been identified as carrying a deleterious mutation in BRCA1 or BRCA2 face a unique set of challenges related to managing cancer risk during a demographically-dense stage of life. They may struggle with decision-making in the absence of clear age-specific guidelines for medical management and because they have not yet fully developed the capacity to make life-altering decisions confidently. This study sought a patient-centered perspective on the dilemmas faced by 18-24 year olds who completed BRCA1/2 gene mutation testing prior to their 25th birthdays. Patients and Method: This study integrated qualitative data from three independent investigations of BRCA1/2-positive women recruited through cancer risk clinics, hospital-based research centers, and online organizations. All 32 participants were women aged 21-25 who tested positive for a BRCA1/2 gene mutation between 2 and 60 months prior to data collection. Investigators used techniques of grounded theory and interpretive description to conduct both within and cross-study analysis. Results: Participants expressed needs for (1) greater clarity in recommendations for screening and prevention before age 25, especially with consideration of early and regular exposure to radiation associated with mammography or to hormones used in birth control, and (2) ongoing contact with providers to discuss risk management protocols as they become available. Conclusions: Health care needs during the young adult years evolve with the cognitive capacity to address abrupt and pressing change. Specific needs of women in this population include a desire to balance autonomous decision-making with supportive guidance, a need for clear, accurate and consistent medical recommendations. Optimally, these women are best cared for by a team of genetically-oriented providers as part of a sustained program of ongoing support, rather than seen in an episodic, crisis-driven fashion. A discussion of insurance issues and provider-patient cultural differences is presented. C1 [Hoskins, Lindsey M.; Greene, Mark H.] NCI, Clin Genet Branch, Bethesda, MD 20892 USA. [Werner-Lin, Allison] Univ Penn, Philadelphia, PA 19104 USA. RP Werner-Lin, A (reprint author), Univ Penn, Philadelphia, PA 19104 USA. EM awer@sp2.upenn.edu FU intramural program of the National Cancer Institute, Division of Cancer Genetics and Epidemiology, Clinical Genetics Branch FX This study was funded through the intramural program of the National Cancer Institute, Division of Cancer Genetics and Epidemiology, Clinical Genetics Branch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 4 Z9 4 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2014 VL 9 IS 2 AR e87696 DI 10.1371/journal.pone.0087696 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200014 PM 24586286 ER PT J AU Miozzi, L Napoli, C Sardo, L Accotto, GP AF Miozzi, Laura Napoli, Chiara Sardo, Luca Accotto, Gian Paolo TI Transcriptomics of the Interaction between the Monopartite Phloem-Limited Geminivirus Tomato Yellow Leaf Curl Sardinia Virus and Solanum lycopersicum Highlights a Role for Plant Hormones, Autophagy and Plant Immune System Fine Tuning during Infection SO PLOS ONE LA English DT Article ID TOBACCO-MOSAIC-VIRUS; ARABIDOPSIS-THALIANA; DIFFERENTIAL EXPRESSION; CYTOSINE METHYLATION; DISEASE RESISTANCE; VIRAL-INFECTION; L2 PROTEINS; CELL-CYCLE; SMALL RNAS; RESPONSES AB Tomato yellow leaf curl Sardinia virus (TYLCSV), a DNA virus belonging to the genus Begomovirus, causes severe losses in tomato crops. It infects only a limited number of cells in the vascular tissues, making difficult to detect changes in host gene expression linked to its presence. Here we present the first microarray study of transcriptional changes induced by the phloem-limited geminivirus TYLCSV infecting tomato, its natural host. The analysis was performed on the midrib of mature leaves, a material naturally enriched in vascular tissues. A total of 2206 genes were up-regulated and 1398 were down-regulated in infected plants, with an overrepresentation of genes involved in hormone metabolism and responses, nucleic acid metabolism, regulation of transcription, ubiquitin-proteasome pathway and autophagy among those up-regulated, and in primary and secondary metabolism, phosphorylation, transcription and methylation-dependent chromatin silencing among those down-regulated. Our analysis showed a series of responses, such as the induction of GA- and ABA-responsive genes, the activation of the autophagic process and the fine tuning of the plant immune system, observed only in TYLCSV-tomato compatible interaction so far. On the other hand, comparisons with transcriptional changes observed in other geminivirus-plant interactions highlighted common host responses consisting in the deregulation of biotic stress responsive genes, key enzymes in the ethylene biosynthesis and methylation cycle, components of the ubiquitin proteasome system and DNA polymerases II. The involvement of conserved miRNAs and of solanaceous-and tomato-specific miRNAs in geminivirus infection, investigated by integrating differential gene expression data with miRNA targeting data, is discussed. C1 [Miozzi, Laura; Napoli, Chiara; Sardo, Luca; Accotto, Gian Paolo] Natl Res Council CNR, Ist Virol Vegetale, Turin, Italy. [Sardo, Luca] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Accotto, GP (reprint author), Natl Res Council CNR, Ist Virol Vegetale, Turin, Italy. EM g.accotto@ivv.cnr.it OI Accotto, Gian Paolo/0000-0002-3825-1097 FU CISIA Project (CNR, Italy); "GenoPom" Project (MIUR, Italy); Fondazione CRT-Progetto Lagrange (Torino, Italy) FX This work was supported by the CISIA Project (CNR, Italy), the "GenoPom" Project (MIUR, Italy) to GPA and LM, and the Fondazione CRT-Progetto Lagrange (Torino, Italy) with a fellowship to LS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 12 Z9 12 U1 2 U2 45 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 FEB 28 PY 2014 VL 9 IS 2 AR e89951 DI 10.1371/journal.pone.0089951 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200099 PM 24587146 ER PT J AU Suzuki, R Leach, S Liu, WH Ralston, E Scheffel, J Zhang, WG Lowell, CA Rivera, J AF Suzuki, Ryo Leach, Sarah Liu, Wenhua Ralston, Evelyn Scheffel, Joerg Zhang, Weiguo Lowell, Clifford A. Rivera, Juan TI Molecular Editing of Cellular Responses by the High-Affinity Receptor for IgE SO SCIENCE LA English DT Article ID FC-EPSILON-RI; MAST-CELLS; ACTIVATION; MICE AB Cellular responses elicited by cell surface receptors differ according to stimulus strength. We investigated how the high-affinity receptor for immunoglobulin E (IgE) modulates the response of mast cells to a high-or low-affinity stimulus. Both high-and low-affinity stimuli elicited similar receptor phosphorylation; however, differences were observed in receptor cluster size, mobility, distribution, and the cells' effector responses. Low-affinity stimulation increased receptor association with the Src family kinase Fgr and shifted signals from the adapter LAT1 to the related adapter LAT2. LAT1-dependent calcium signals required for mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced, altering immune cell recruitment at the site of inflammation. These findings uncover how receptor discrimination of stimulus strength can be interpreted as distinct in vivo outcomes. C1 [Suzuki, Ryo; Leach, Sarah; Scheffel, Joerg; Rivera, Juan] NIAMSD, Lab Mol Immunogenet, Bethesda, MD 20892 USA. [Liu, Wenhua; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, Bethesda, MD 20892 USA. [Zhang, Weiguo] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. [Lowell, Clifford A.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. RP Rivera, J (reprint author), NIAMSD, Lab Mol Immunogenet, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases and its Laboratory Animal Care and Use Section; Flow Cytometry Group, Office of Science and Technology FX Supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by its Laboratory Animal Care and Use Section and Flow Cytometry Group, Office of Science and Technology. All data are provided in the main paper and supplementary materials. The authors declare no conflicts of interest. NR 20 TC 23 Z9 23 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 28 PY 2014 VL 343 IS 6174 BP 1021 EP 1025 DI 10.1126/science.1246976 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC2DZ UT WOS:000332309600045 PM 24505132 ER PT J AU Wolf, CJ Rider, CV Lau, C Abbott, BD AF Wolf, Cynthia J. Rider, Cynthia V. Lau, Christopher Abbott, Barbara D. TI Evaluating the additivity of perfluoroalkyl acids in binary combinations on peroxisome proliferator-activated receptor-a activation SO TOXICOLOGY LA English DT Article DE Perfluoroalkyl acids; PFOA; Mixtures; Additivity; PPAR alpha ID EXPOSED MOUSE FETUSES; SPRAGUE-DAWLEY RATS; PPAR-ALPHA; PERFLUOROOCTANOIC ACID; NUCLEAR RECEPTORS; CELL-PROLIFERATION; DIETARY EXPOSURE; POTASSIUM PERFLUOROOCTANESULFONATE; HEPATOCELLULAR HYPERTROPHY; TRANSCRIPTIONAL ACTIVATION AB Perfluoroalkyl acids (PFAAs) are found globally in the environment, detected in humans and wildlife, and are typically present as mixtures of PFAA congeners. Mechanistic studies have found that responses to PFAAs are mediated in part by PPAR alpha. Our previous studies showed that individual PFAAs activate PPAR alpha transfected into COS-1 cells. The goal of the current study was to determine if binary combinations of perfluorooctanoic acid (PFOA) and another PFAA act in an additive fashion to activate PPAR alpha in the mouse one-hybrid in vitro model. COS-1 cells were transiently transfected with mouse PPAR alpha luciferase reporter construct and exposed to either vehicle control (0.1% DMSO or water), PPAR alpha agonist (VVY14643, 10 mu M), PFOA at 1-128 mu M, perfluorononanoic acid (PFNA) at 1-128 mu M, perfluorohexanoic acid (PFHxA) at 8-1024 mu M, perfluorooctane sulfonate (PFOS) at 4-384 mu M or perfluorohexane sulfonate (PFHxS) at 8-2048 mu M to generate sigmoidal concentration-response curves. In addition, cells were exposed to binary combinations of PFOA + either PFNA, PFHxA, PFOS or PFHxS in an 8 x 8 factorial design. The concentration-response data for individual chemicals were fit to sigmoidal curves and analyzed with nonlinear regression to generate EC(50)s and Hillslopes, which were used in response-addition and concentration-addition models to calculate predicted responses for mixtures in the same plate. All PFOA + PFAA combinations produced concentration-response curves that were closely aligned with the predicted curves for both response addition and concentration addition at low concentrations. However, at higher concentrations of all chemicals, the observed response curves deviated from the predicted models of additivity. We conclude that binary combinations of PFAAs behave additively at the lower concentration ranges in activating PPAR alpha in this in vitro system. Published by Elsevier Ireland Ltd. C1 [Wolf, Cynthia J.; Lau, Christopher; Abbott, Barbara D.] US EPA, Dev Toxicol Branch, Toxic Assessment Div, Natl Hlth & Environm Effects Res Lab,ORD, Res Triangle Pk, NC 27711 USA. [Rider, Cynthia V.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Wolf, CJ (reprint author), US EPA, NHEERL, TAD, MD-67,109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM wolf.cynthiaj@epa.gov NR 52 TC 7 Z9 7 U1 7 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 28 PY 2014 VL 316 BP 43 EP 54 DI 10.1016/j.tox.2013.12.002 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AC3SG UT WOS:000332440900006 PM 24374136 ER PT J AU Krashes, MJ Kravitz, AV AF Krashes, Michael J. Kravitz, Alexxai V. TI Optogenetic and chemogenetic insights into the food addiction hypothesis SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Review DE obesity; addiction; optogenetics; food; feeding; arcuate; striatum ID STRESS-INDUCED REINSTATEMENT; DOPAMINE NEURONS ENCODE; VENTRAL TEGMENTAL AREA; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; FEEDING-BEHAVIOR; COCAINE SEEKING; PALATABLE FOOD; RECEPTOR GENE; AGRP NEURONS AB Obesity is clinically diagnosed by a simple formula based on the weight and height of a person (body mass index), but is associated with a host of other behavioral symptoms that are likely neurological in origin. In recent years, many scientists have asked whether similar behavioral and cognitive changes occur in drug addiction and obesity, lending many to discuss the potential for "food addiction". Advances in understanding the circuitry underlying both feeding behaviors and drug addiction may allow us to consider this question from the viewpoint of neural circuits, to complement behavioral perspectives. Here, we review advances in understanding of these circuits and use them to consider whether drawing comparisons to drug addiction is helpful for understanding certain forms of obesity. C1 [Krashes, Michael J.; Kravitz, Alexxai V.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20814 USA. RP Kravitz, AV (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10 CRC,Room5-5932,10 Ctr Dr, Bethesda, MD 20814 USA. EM lex.kravitz@nih.gov NR 125 TC 7 Z9 8 U1 2 U2 26 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD FEB 28 PY 2014 VL 8 AR 57 DI 10.3389/fnbeh.2014.00057 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AB7WH UT WOS:000332001100001 PM 24616674 ER PT J AU Pothayee, N Pothayee, N Hu, N Zhang, R Kelly, DF Koretsky, AP Riffle, JS AF Pothayee, Nipon Pothayee, Nikorn Hu, Nan Zhang, Rui Kelly, Deborah F. Koretsky, Alan P. Riffle, J. S. TI Manganese graft ionomer complexes (MaGICs) for dual imaging and chemotherapy SO JOURNAL OF MATERIALS CHEMISTRY B LA English DT Article ID POLY(ETHYLENE OXIDE)-BLOCK-POLYMETHACRYLATE ANIONS; NEPHROGENIC SYSTEMIC FIBROSIS; PARAMAGNETIC CONTRAST AGENTS; ENHANCED TUMOR ACCUMULATION; PROLONGED CIRCULATION TIMES; BLOCK-COPOLYMER MICELLES; DRUG-DELIVERY SYSTEMS; POLYMERIC MICELLES; CANCER-THERAPY; BIOLOGICAL SIGNIFICANCE AB Novel manganese graft ionomer complexes (MaGICs) that contain Mn ions complexed with a polyaminobisphosphonate-g-poly(ethylene oxide) (PEO) copolymer were developed for use as T-1-weighted contrast agents for MRI. The complexes exhibited good colloidal stability without release of free manganese and did not result in any in vitro toxicity against mouse hepatocytes. T-1 relaxivities of the MaGICs at physiological pH were 2-10 times higher than that of a commercial manganese-based positive contrast agent. Anticancer drugs including doxorubicin, cisplatin and carboplatin were successfully encapsulated into the MaGICs with high efficiency. Drug release behavior was sustained and depended on pH (faster in acidic environments), drug structures and drug concentration (faster with high concentration). The anticancer drug-loaded manganese nanocarriers exhibited excellent anticancer activity against MCF-7 breast cancer cells together with high relaxivity. Thus, these drug-loaded MaGICs could potentially be utilized for simultaneous diagnosis and treatment of cancer. C1 [Pothayee, Nipon; Hu, Nan; Zhang, Rui; Riffle, J. S.] Virginia Tech, Macromol & Interfaces Inst, Blacksburg, VA 24061 USA. [Pothayee, Nikorn; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Kelly, Deborah F.] Virginia Tech, Virginia Tech Carillon Res Inst, Roanoke, VA USA. RP Riffle, JS (reprint author), Virginia Tech, Macromol & Interfaces Inst, 145 ICTAS 1, Blacksburg, VA 24061 USA. EM judyriffie@aol.com RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NSF [DMR-1106182]; Intramural Research Program (IRP) at NINDS/NIH FX The authors are grateful for the financial support from NSF under contract DMR-1106182. This work was also partially supported by the Intramural Research Program (IRP) at NINDS/NIH. NR 73 TC 2 Z9 2 U1 1 U2 16 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2050-750X EI 2050-7518 J9 J MATER CHEM B JI J. Mat. Chem. B PD FEB 28 PY 2014 VL 2 IS 8 BP 1087 EP 1099 DI 10.1039/c3tb21299h PG 13 WC Materials Science, Biomaterials SC Materials Science GA AB0RW UT WOS:000331500800016 ER PT J AU Stetler-Stevenson, M AF Stetler-Stevenson, Maryalice TI Monoclonal B-cell lymphocytosis in donors SO BLOOD LA English DT Editorial Material ID LEUKEMIA; LYMPHOMA; BLOOD AB In this issue of Blood, Shim et al report that monoclonal B-cell lymphocytosis (MBL), an essential precursor to chronic lymphocytic leukemia (CLL), is a surprisingly common finding in healthy blood donors, thus raising concerns about the potential risk infusion of these blood products may present to recipients. C1 NCI, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 27 PY 2014 VL 123 IS 9 BP 1281 EP 1282 DI 10.1182/blood-2014-01-546739 PG 2 WC Hematology SC Hematology GA AH0VR UT WOS:000335839300001 PM 24578489 ER PT J AU Cortes-Puch, I Wang, D Sun, JF Solomon, SB Remy, KE Fernandez, M Feng, J Kanias, T Bellavia, L Sinchar, D Perlegas, A Solomon, MA Kelley, WE Popovsky, MA Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Cortes-Puch, Irene Wang, Dong Sun, Junfeng Solomon, Steven B. Remy, Kenneth E. Fernandez, Melinda Feng, Jing Kanias, Tamir Bellavia, Landon Sinchar, Derek Perlegas, Andreas Solomon, Michael A. Kelley, Walter E. Popovsky, Mark A. Gladwin, Mark T. Kim-Shapiro, Daniel B. Klein, Harvey G. Natanson, Charles TI Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia SO BLOOD LA English DT Article ID RED-CELL STORAGE; TRANSFERRIN-BOUND IRON; OXIDATIVE STRESS; FREE HEMOGLOBIN; STORED-BLOOD; SEPTIC SHOCK; IN-VITRO; MORTALITY; HEMOLYSIS; QUALITY AB In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n = 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7- or 42-day-old washed or unwashed canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes. C1 [Cortes-Puch, Irene; Wang, Dong; Sun, Junfeng; Solomon, Steven B.; Remy, Kenneth E.; Fernandez, Melinda; Feng, Jing; Solomon, Michael A.; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Kanias, Tamir; Sinchar, Derek; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Bellavia, Landon; Perlegas, Andreas; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Bellavia, Landon; Perlegas, Andreas; Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Solomon, Michael A.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Kelley, Walter E.] Oklahoma Blood Inst, Oklahoma City, OK USA. [Popovsky, Mark A.] Haemonetics Corp, Braintree, MA USA. [Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Cortes-Puch, I (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM irene.cortespuch@nih.gov RI Kanias, Tamir/K-2384-2016; OI Kanias, Tamir/0000-0001-6558-0913; Remy, Kenneth/0000-0001-5222-9884 FU Intramural National Institutes of Health, National Heart, Lung and Blood Institute funds; National Institutes of Health, National Heart, Lung and Blood Institute [HL058091, HL098032]; U.S. government FX This work was supported by Intramural National Institutes of Health, National Heart, Lung and Blood Institute funds and National Institutes of Health, National Heart, Lung and Blood Institute external grants HL058091 and HL098032.; The work by the authors was done as part of U.S. government-funded research; however, the opinions expressed are not necessarily those of the National Institutes of Health. NR 41 TC 21 Z9 21 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 27 PY 2014 VL 123 IS 9 BP 1403 EP 1411 DI 10.1182/blood-2013-11-539353 PG 9 WC Hematology SC Hematology GA AH0VR UT WOS:000335839300023 PM 24366359 ER PT J AU Ciarapica, R Carcarino, E Adesso, L De Salvo, M Bracaglia, G Leoncini, PP Dall'Agnese, A Verginelli, F Milano, GM Boldrini, R Inserra, A Stifani, S Screpanti, I Marquez, VE Valente, S Mai, A Puri, PL Locatelli, F Palacios, D Rota, R AF Ciarapica, Roberta Carcarino, Elena Adesso, Laura De Salvo, Maria Bracaglia, Giorgia Leoncini, Pier Paolo Dall'Agnese, Alessandra Verginelli, Federica Milano, Giuseppe M. Boldrini, Renata Inserra, Alessandro Stifani, Stefano Screpanti, Isabella Marquez, Victor E. Valente, Sergio Mai, Antonello Puri, Pier Lorenzo Locatelli, Franco Palacios, Daniela Rota, Rossella TI Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS SO BMC CANCER LA English DT Article DE EZH2; Histone methyltransferase; rhabdomyosarcoma; Polycomb proteins; Differentiation; DZnep; EZH2 catalytic inhibitors ID SMALL-MOLECULE INHIBITOR; POLYCOMB PROTEIN EZH2; HISTONE METHYLTRANSFERASE; HUMAN RHABDOMYOSARCOMA; CELL-DIFFERENTIATION; PROGNOSTIC-FACTORS; SKELETAL-MUSCLE; TUMOR-CELLS; STEM-CELLS; IN-VITRO AB Background: Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts. Methods: Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo. Results: Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21(Cip1). It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo. Conclusions: These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS. C1 [Ciarapica, Roberta; Adesso, Laura; De Salvo, Maria; Bracaglia, Giorgia; Leoncini, Pier Paolo; Verginelli, Federica; Milano, Giuseppe M.; Locatelli, Franco; Rota, Rossella] IRCCS, Osped Pediat Bambino Gesu, Lab Angiogenesis, Dept Oncohematol, I-00165 Rome, Italy. [Carcarino, Elena; Dall'Agnese, Alessandra; Puri, Pier Lorenzo; Palacios, Daniela] IRCCS Fdn Santa Lucia, Rome, Italy. [Boldrini, Renata] IRCCS, Osped Pediat Bambino Gesu, Dept Pathol, I-00165 Rome, Italy. [Inserra, Alessandro] IRCCS, Osped Pediat Bambino Gesu, Dept Surg, I-00165 Rome, Italy. [Stifani, Stefano] McGill Univ, Montreal Neurol Inst, Ctr Neuronal Survival, Montreal, PQ, Canada. [Screpanti, Isabella] Univ Roma La Sapienza, Dept Mol Med, I-00185 Rome, Italy. [Marquez, Victor E.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, CCR,NIH, Frederick, MD 21701 USA. [Valente, Sergio; Mai, Antonello] Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy. [Puri, Pier Lorenzo] Sanford Burnham Med Res Inst, Muscle Dev & Regenerat Program, La Jolla, CA USA. [Locatelli, Franco] Univ Pavia, Dipartimento Sci Pediat, I-27100 Pavia, Italy. RP Ciarapica, R (reprint author), IRCCS, Osped Pediat Bambino Gesu, Lab Angiogenesis, Dept Oncohematol, Piazza S Onofrio 4, I-00165 Rome, Italy. EM roberta.ciarapica@yahoo.com; rossella.rota@opbg.net RI Valente, Sergio/K-2198-2016; Palacios, Daniela/K-4698-2016; OI Valente, Sergio/0000-0002-2241-607X; Palacios, Daniela/0000-0002-2207-2369; Rota, Rossella/0000-0002-9408-7711; Mai, Antonello/0000-0001-9176-2382; Stifani, Stefano/0000-0002-2376-7701; Leoncini, Pier Paolo/0000-0002-1708-7291 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [10338]; Italian Ministry of Health Ricerca Corrente; Association for International Cancer Research (AICR-UK) [12-0168]; AIRC 5 per mille; NIH Intramural Research Program, National Cancer Institute, CCR; FP7 Project [BLUEPRINT/282510]; [PRIN 2009PX2T2E]; [FIRB RBFR10ZJQT] FX Associazione Italiana per la Ricerca sul Cancro (AIRC, 10338) and Italian Ministry of Health Ricerca Corrente (RR); Association for International Cancer Research (AICR-UK, 12-0168) (DP); AIRC 5 per mille (FL); NIH Intramural Research Program, National Cancer Institute, CCR (VEM); PRIN 2009PX2T2E, FIRB RBFR10ZJQT, and FP7 Project BLUEPRINT/282510 (AM). NR 50 TC 8 Z9 9 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 27 PY 2014 VL 14 AR 139 DI 10.1186/1471-2407-14-139 PG 15 WC Oncology SC Oncology GA AC4YU UT WOS:000332528100001 PM 24575771 ER PT J AU Ernst, A Alkass, K Bernard, S Salehpour, M Perl, S Tisdale, J Possnert, G Druid, H Frisen, J AF Ernst, Aurelie Alkass, Kanar Bernard, Samuel Salehpour, Mehran Perl, Shira Tisdale, John Possnert, Goran Druid, Henrik Frisen, Jonas TI Neurogenesis in the Striatum of the Adult Human Brain SO CELL LA English DT Article ID ENHANCED SYNAPTIC PLASTICITY; ROSTRAL MIGRATORY STREAM; NEWLY GENERATED NEURONS; NEURAL STEM-CELLS; HIPPOCAMPAL NEUROGENESIS; HUNTINGTONS-DISEASE; SUBVENTRICULAR ZONE; PATTERN SEPARATION; MACAQUE MONKEYS; GRANULE CELLS AB In most mammals, neurons are added throughout life in the hippocampus and olfactory bulb. One area where neuroblasts that give rise to adult-born neurons are generated is the lateral ventricle wall of the brain. We show, using histological and carbon-14 dating approaches, that in adult humans new neurons integrate in the striatum, which is adjacent to this neurogenic niche. The neuronal turnover in the striatum appears restricted to interneurons, and postnatally generated striatal neurons are preferentially depleted in patients with Huntington's disease. Our findings demonstrate a unique pattern of neurogenesis in the adult human brain. C1 [Ernst, Aurelie; Alkass, Kanar; Frisen, Jonas] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. [Alkass, Kanar; Druid, Henrik] Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden. [Bernard, Samuel] Univ Lyon, Inst Camille Jordan, CNRS UMR 5208, F-69622 Villeurbanne, France. [Salehpour, Mehran; Possnert, Goran] Uppsala Univ, Dept Phys & Astron Ion Phys, S-75120 Uppsala, Sweden. [Perl, Shira; Tisdale, John] NHLBI, NIH, Bethesda, MD 20892 USA. RP Frisen, J (reprint author), Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. EM jonas.frisen@ki.se RI Bernard, Samuel/A-5623-2009; OI Bernard, Samuel/0000-0002-8442-9968; Druid, Henrik/0000-0002-9198-023X FU NIHR Cambridge Biomedical Research Centre; Swedish Research Council; Swedish Cancer Society; Karolinska Institute; Tobias Stiftelsen; AFA Forsakringar; Strategic Research Programme in Stem Cells and Regenerative Medicine at Karolinska Institutet (StratRegen); ERC; Knut och Alice Wallenbergs Stiftelse; Stockholm County Council; Karolinska Institutet [ALF 20080508]; Torsten Soderbergs Stiftelse FX We thank the Cambridge Brain Bank, Cambridge (UK), and the NICHD Brain and Tissue Bank for Developmental Disorders, Baltimore, Maryland (USA), for providing tissue. The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. The staff at the Swedish National Board of Forensic Medicine is acknowledged for cooperation in tissue donation. We thank Marcelo Toro, Sarantis Giatrellis, and Mathilde Chapuis for help with flow cytometry and evaluation of immunostainings and Helena Lonnqvist for help with DNA extraction. We thank Nenad Bogdanovic for anatomical evaluation of human brain sections, Konstantinos Meletis for discussions, and Karl Hakansson for AMS samples preparation. This study was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Karolinska Institute, Tobias Stiftelsen, AFA Forsakringar, the Strategic Research Programme in Stem Cells and Regenerative Medicine at Karolinska Institutet (StratRegen), the ERC and Knut och Alice Wallenbergs Stiftelse, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet (ALF 20080508) and Torsten Soderbergs Stiftelse. NR 52 TC 209 Z9 217 U1 12 U2 86 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 FEB 27 PY 2014 VL 156 IS 5 BP 1072 EP 1083 DI 10.1016/j.cell.2014.01.044 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AB9BK UT WOS:000332083900022 PM 24561062 ER PT J AU Kiselev, E Sooryakumar, D Agama, K Cushman, M Pommier, Y AF Kiselev, Evgeny Sooryakumar, Dhriti Agama, Keli Cushman, Mark Pommier, Yves TI Optimization of the Lactam Side Chain of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL ANTICANCER AGENTS; CLEAVAGE COMPLEXES; MULTIDRUG-RESISTANCE; MJ-III-65 NSC-706744; DNA-DAMAGE; CAMPTOTHECIN; INDUCTION; CYTOTOXICITY; NITROGEN; UPDATE AB Optimization of the lactam omega-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14-17 and 19 exhibited mean graph midpoint cytotoxicity (GI(50)) values of 21-71 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline-DNA-Top1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone gamma-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA-Top1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development. C1 [Kiselev, Evgeny; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Kiselev, Evgeny; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Sooryakumar, Dhriti; Agama, Keli; Pommier, Yves] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Sooryakumar, Dhriti; Agama, Keli; Pommier, Yves] NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@purdue.edu; pommier@nih.gov FU National Institutes of Health [UO1 CA89566]; Purdue Research Foundation Research Grant FX This work was made possible by the National Institutes of Health through support of this work by Research Grant UO1 CA89566, by a Purdue Research Foundation Research Grant, and by the Center for Cancer Research, Intramural Program of the National Cancer Institute. NR 30 TC 11 Z9 11 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1289 EP 1298 DI 10.1021/jm401471v PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700012 PM 24502276 ER PT J AU Nayak, A Chandra, G Hwang, I Kim, K Hou, X Kim, HO Sahu, PK Roy, KK Yoo, J Lee, Y Cui, M Choi, S Moss, SM Phan, K Gao, ZG Ha, H Jacobson, KA Jeong, LS AF Nayak, Akshata Chandra, Girish Hwang, Inah Kim, Kyunglim Hou, Xiyan Kim, Hea Ok Sahu, Pramod K. Roy, Kuldeep K. Yoo, Jakyung Lee, Yoonji Cui, Minghua Choi, Sun Moss, Steven M. Phan, Khai Gao, Zhan-Guo Ha, Hunjoo Jacobson, Kenneth A. Jeong, Lak Shin TI Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N-6-Substituted-(N)-Methanocarba-nucleosides as A(3) Adenosine Receptor Antagonists and Partial Agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID L-CYCLOPENTENONE DERIVATIVES; CARBOCYCLIC NUCLEOSIDES; SELECTIVE AGONISTS; HIGHLY POTENT; MEDICINAL CHEMISTRY; A(2A); DISCOVERY; LIGANDS; BINDING; N-6-BENZYLADENOSINE-5-URONAMIDES AB Truncated N-6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N-6 and/or C2 substituents were tolerated in A(3)AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA(2A)AR affinity. A small hydrophobic alkyl (4b and 4c) or N-6-cycloalkyl group (4d) showed excellent binding affinity at the hA(3)AR and was better than an unsubstituted free amino group (4a). A(3)AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with K-i values of 7.8-16.0 nM. N-6-Methyl derivative 4b (K-i = 4.9 nM) was a highly selective, low efficacy partial A(3)AR agonist. All compounds were screened for renoprotective effects in human TGF-beta 1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-beta 1-induced collagen I upregulation, and their A(3)AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 mu M), indicating its potential as a good therapeutic candidate for treating renal fibrosis. C1 [Nayak, Akshata; Jeong, Lak Shin] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Nayak, Akshata; Chandra, Girish; Hwang, Inah; Kim, Kyunglim; Hou, Xiyan; Kim, Hea Ok; Sahu, Pramod K.; Roy, Kuldeep K.; Yoo, Jakyung; Lee, Yoonji; Cui, Minghua; Choi, Sun; Ha, Hunjoo; Jeong, Lak Shin] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 120750, South Korea. [Nayak, Akshata; Chandra, Girish; Hwang, Inah; Kim, Kyunglim; Hou, Xiyan; Kim, Hea Ok; Sahu, Pramod K.; Roy, Kuldeep K.; Yoo, Jakyung; Lee, Yoonji; Cui, Minghua; Choi, Sun; Ha, Hunjoo; Jeong, Lak Shin] Ewha Womans Univ, Global Top 5 Res Program, Seoul 120750, South Korea. [Moss, Steven M.; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Jeong, LS (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM lakjeong@snu.ac.kr RI Jacobson, Kenneth/A-1530-2009; OI Ha, Hunjoo/0000-0002-5601-1265; Jacobson, Kenneth/0000-0001-8104-1493; Roy, Kuldeep/0000-0001-9623-0617 FU Midcareer Research Program through the Ministry of Science, ICT & Future Planning (MSIP) [2010-0026203, 370C-20130120]; National Leading Research Lab (NLRL) Program through the Ministry of Science, ICT & Future Planning (MSIP) [2011-0028885]; National Research Foundation, Korea; Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by grants from Midcareer Research Program (2010-0026203 and 370C-20130120) and the National Leading Research Lab (NLRL) Program (2011-0028885) through the Ministry of Science, ICT & Future Planning (MSIP) and the National Research Foundation, Korea and in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. In this study, Schrodinger software was used and the supercomputing resources including technical support were provided by the Supercomputing Center/Korea Institute of Science and Technology Information (KSC-2011-C2-45). NR 56 TC 6 Z9 6 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1344 EP 1354 DI 10.1021/jm4015313 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700015 PM 24456490 ER PT J AU Wang, XF Guan, F Ohkoshi, E Guo, WJ Wang, LL Zhu, DQ Wang, SB Wang, LT Hamel, E Yang, DX Li, LN Qian, KD Morris-Natschke, SL Yuan, SJ Lee, KH Xie, L AF Wang, Xiao-Feng Guan, Fang Ohkoshi, Emika Guo, Wanjun Wang, Lili Zhu, Dong-Qing Wang, Sheng-Biao Wang, Li-Ting Hamel, Ernest Yang, Dexuan Li, Linna Qian, Keduo Morris-Natschke, Susan L. Yuan, Shoujun Lee, Kuo-Hsiung Xie, Lan TI Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TUMOR-CELL LINES; BIOLOGICAL EVALUATION; ANTITUMOR AGENTS; DIVERSE PANEL; BETA-LACTAMS; CANCER-CELLS; BINDING; DESIGN; DISCOVERY; AGONISTS AB The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (la and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (50, the most potent compound, exhibited high in vitro cytotoxic activity (GI(50) 1.9-3.2 nM), significant potency against tubulin assembly (IC50 0.77 mu M), and substantial inhibition of colchicine binding (99% at 5 mu M). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose. C1 [Wang, Xiao-Feng; Guan, Fang; Wang, Lili; Zhu, Dong-Qing; Wang, Sheng-Biao; Xie, Lan] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. [Ohkoshi, Emika; Wang, Sheng-Biao; Qian, Keduo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung] Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. [Guo, Wanjun; Yang, Dexuan; Li, Linna; Yuan, Shoujun] Beijing Inst Radiat Med, Beijing 100850, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Wang, Xiao-Feng] Urumqi Gen Hosp, Dept Pharm, Urumqi 830000, Lanzhou Militar, Peoples R China. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40402, Taiwan. RP Lee, KH (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA. EM khlee@unc.edu; lanxie4@gmail.com FU Natural Science Foundation of China (NSFC) [81120108022, 30930106]; NIH grant from the National Cancer Institute [CA177584]; Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence [DOH100-TD-C-111-005] FX This investigation was supported by grants 81120108022 and 30930106 from the Natural Science Foundation of China (NSFC) awarded to L.X. and NIH grant CA177584-01 from the National Cancer Institute awarded to K.-H.L. This study was also supported in part by the Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence (DOH100-TD-C-111-005). NR 37 TC 9 Z9 9 U1 1 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1390 EP 1402 DI 10.1021/jm4016526 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700019 PM 24502232 ER PT J AU Beck, DE Agama, K Marchand, C Chergui, A Pommier, Y Cushman, M AF Beck, Daniel E. Agama, Keli Marchand, Christophe Chergui, Adel Pommier, Yves Cushman, Mark TI Synthesis and Biological Evaluation of New Carbohydrate-Substituted Indenoisoquinoline Topoisomerase I Inhibitors and Improved Syntheses of the Experimental Anticancer Agents Indotecan (LMP400) and Indimitecan (LMP776) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TYROSYL-DNA PHOSPHODIESTERASE; NITRATED INDENOISOQUINOLINES; COVALENT COMPLEX; IDENTIFICATION; CAMPTOTHECIN; ANALOGS; SERIES; DRUGS; PERSPECTIVES; MECHANISM AB Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined. Twelve of the new indenoisoquinolines exhibit Top1 inhibitory activity equal to or better than that of camptothecin. An advanced synthetic intermediate from this study was also used to efficiently prepare indotecan (LMP400) and indimitecan (LMP776), two anticancer agents currently under investigation in a Phase I clinical trial at the National Institutes of Health. C1 [Beck, Daniel E.; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Beck, Daniel E.; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Agama, Keli; Marchand, Christophe; Chergui, Adel; Pommier, Yves] NCI, Dev Therapeut Program, Ctr Canc Res, Frederick, MD 21702 USA. [Agama, Keli; Marchand, Christophe; Chergui, Adel; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; National Cancer Institute [NO1-CO-56000] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grant UO1 CA89566. In vitro cytotoxicity testing was performed by the Developmental Therapeutics Program at the National Cancer Institute, under Contract NO1-CO-56000. D.E.B. thanks Wei Lv, Martin Conda-Sheridan, Rubayat Khan, and Karl Wood for technical assistance. NR 56 TC 20 Z9 22 U1 0 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1495 EP 1512 DI 10.1021/jm401814y PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700027 PM 24517248 ER PT J AU Zhao, XZ Smith, SJ Metifiot, M Johnson, BC Marchand, C Pommier, Y Hughes, SH Burke, TR AF Zhao, Xue Zhi Smith, Steven J. Metifiot, Mathieu Johnson, Barry C. Marchand, Christophe Pommier, Yves Hughes, Stephen H. Burke, Terrence R., Jr. TI Bicyclic 1-Hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-Containing HIV-1 Integrase Inhibitors Having High Antiviral Potency against Cells Harboring Raltegravir-Resistant Integrase Mutants SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DERIVATIVES; PHARMACOPHORE; DOLUTEGRAVIR; INFECTION; DESIGN AB Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG, and there is extensive cross-resistance to these two drugs. New "2nd-generation" INSTIs are needed that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK's Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K. C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Chem Biol Lab, NIH, Frederick, MD 21702 USA. [Smith, Steven J.; Johnson, Barry C.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Burke, TR (reprint author), NCI, Chem Biol Lab, NIH, Frederick, MD 21702 USA. EM burkete@helix.nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364; FU Intramural Research Program of the NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research; National Cancer Institute, National Institutes of Health; Joint Science and Technology Office of the Department of Defense; Intramural AIDS Targeted Antiviral Program FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research and the National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense, and by funds from the Intramural AIDS Targeted Antiviral Program. NR 38 TC 12 Z9 12 U1 1 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1573 EP 1582 DI 10.1021/jm401902n PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700032 PM 24471816 ER PT J AU Barry, CE AF Barry, Clifton E. TI TUBERCULOSIS Drug discovery goes au naturel SO NATURE LA English DT Editorial Material ID EFFLUX C1 NIAID, TB Res Sect, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [ZIA AI000693-20] NR 6 TC 2 Z9 2 U1 1 U2 13 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 FEB 27 PY 2014 VL 506 IS 7489 BP 436 EP 437 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0DN UT WOS:000332165100023 PM 24572417 ER PT J AU Nottingham, LK Yan, CH Yang, X Si, H Coupar, J Bian, Y Cheng, TF Allen, C Arun, P Gius, D Dang, L Van Waes, C Chen, Z AF Nottingham, L. K. Yan, C. H. Yang, X. Si, H. Coupar, J. Bian, Y. Cheng, T-F Allen, C. Arun, P. Gius, D. Dang, L. Van Waes, C. Chen, Z. TI Aberrant IKK alpha and IKK beta cooperatively activate NF-kappa B and induce EGFR/AP1 signaling to promote survival and migration of head and neck cancer SO ONCOGENE LA English DT Article DE IKK alpha; IKK beta; NF-kappa B; AP1; head and neck cancers ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; INDUCED GENE-EXPRESSION; PROSTATE-CANCER; KINASE-ALPHA; TGF-BETA; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTORS; TUMOR-GROWTH; IN-VIVO AB The inhibitor-kappa B kinase-nuclear factor-kappa B (IKK-NF-kappa B) and epidermal growth factor receptor-activator protein-1 (EGFR-AP1) pathways are often co-activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKK beta or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKK alpha and beta contribute to nuclear activation of canonical and alternate NF-kappa B/REL family transcription factors, and overexpression of signal components that enhance co-activation of the EGFR-AP1 pathway. We observed that IKK alpha and IKK beta exhibit increased protein expression, nuclear localization, and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied among different cell lines, but overexpression of both IKKs induced the strongest NF-kappa B activation. Conversely, siRNA knock down of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and I kappa B alpha and alternative p52 and RELB subunits. Knock down of both IKKs more effectively inhibited NF-kappa B activation, broadly modulated gene expression and suppressed cell proliferation and migration. Global expression profiling revealed that NF-kappa B, cytokine, inflammatory response and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKK alpha and IKK beta together promoted the expression and activity of transforming growth factor a, EGFR and AP1 transcription factors cJun, JunB and Fra1. Knock down of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled and similarly inhibited cell proliferation and migration. Mutations of NF-kappa B and AP1-binding sites abolished or decreased IKK-induced interleukin-8 (IL-8) promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity and geldanomycins that block IKK alpha/beta and EGFR pathways were more active than IKK beta-specific inhibitors in suppressing NF-kappa B activation and proliferation and inducing cell death. We conclude that IKK alpha and IKK beta cooperatively activate NF-kappa B and EGFR/AP1 networks of signaling pathways and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC. C1 [Nottingham, L. K.; Yan, C. H.; Yang, X.; Si, H.; Coupar, J.; Bian, Y.; Cheng, T-F; Allen, C.; Arun, P.; Van Waes, C.; Chen, Z.] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Yan, C. H.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Allen, C.] Clin Res Training Program, Bethesda, MD USA. [Allen, C.] Pfizer Inc, Bethesda, MD USA. [Gius, D.] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN USA. [Dang, L.] Millennium Pharmaceut Inc, Cambridge, MA USA. RP Chen, Z (reprint author), NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10-5D55,MSC-1419, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov; chenz@nidcd.nih.gov FU NIDCD [Z01-DC-00016, Z01-DC-00073, Z01-DC-00074] FX This project is supported by NIDCD Intramural projects Z01-DC-00016, Z01-DC-00073 and Z01-DC-00074. We thank Dr Michael Karin (UC San Diego) and Dr Ulrich Siebenlist (NIH/NIAID) for kindly providing the IKK plasmids; Dr Neil Perkins (Newcastle University, UK) for kindly providing anti-p-p52 antibody; Dr Jialing Zhang for technical assistance; and Dr Michael Karin, Dr Christophe Cataisson (NCI/NIH) and Dr Claire Sauvageot (Millennium Pharmaceuticals, Inc) for critique of the manuscript. NR 58 TC 19 Z9 22 U1 0 U2 5 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 FEB 27 PY 2014 VL 33 IS 9 BP 1135 EP 1147 DI 10.1038/onc.2013.49 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AB6XT UT WOS:000331933800007 PM 23455325 ER PT J AU Han, H Bourboulia, D Jensen-Taubman, S Isaac, B Wei, B Stetler-Stevenson, WG AF Han, H. Bourboulia, D. Jensen-Taubman, S. Isaac, B. Wei, B. Stetler-Stevenson, W. G. TI An endogenous inhibitor of angiogenesis inversely correlates with side population phenotype and function in human lung cancer cells SO ONCOGENE LA English DT Article DE side population; lung cancer; TIMP-2; ABCG2; chemosensitivity; cell migration ID STEM-LIKE CELLS; TUMOR MICROENVIRONMENT; TISSUE INHIBITOR; ABC TRANSPORTERS; RESISTANCE; OVARIAN; TIMP-2; LINES; GROWTH AB The side population (SP) in human lung cancer cell lines and tumors is enriched with cancer stem cells. An endogenous inhibitor of angiogenesis known as tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), characterized for its ability to inhibit matrix metalloproteinases (MMPs), has been shown by several laboratories to impede tumor progression through MMP-dependent or -independent mechanisms. We recently reported that forced expression of TIMP-2, as well as the modified form Ala+TIMP-2 (that lacks MMP inhibitory activity) significantly blocks growth of A549 human lung cancer cells in vivo. However, the mechanisms underlying TIMP-2 antitumor effects are not fully characterized. Here, we examine the hypothesis that the TIMP-2 antitumor activity may involve regulation of the SP in human lung cancer cells. Indeed, using Hoechst dye efflux assay and flow cytometry, as well as quantitative reverse transcriptase-PCR analysis, we found that endogenous TIMP-2 mRNA levels showed a significant inverse correlation with SP fraction size in six non-small cell lung cancer cell lines. In A549 cells expressing increased levels of TIMP-2, a significant decrease in SP was observed, and this decrease was associated with lowered gene expression of ABCG2, ABCB1 and AKR1C1. Functional analysis of A549 cells showed that TIMP-2 overexpression increased chemosensitivity to cytotoxic drugs. The SP isolated from TIMP-2-overexpressing A549 cells also demonstrated impaired migratory capacity compared with the SP from empty vector control. More importantly, our data provide strong evidence that these TIMP-2 functions occur independent of MMP inhibition, as A549 cells overexpressing Ala+TIMP-2 exhibited identical behavior to those overexpressing TIMP-2 alone. Our findings provide the first indication that TIMP-2 modulates SP phenotype and function, and suggests that TIMP-2 may act as an endogenous suppressor of the SP in human lung cancer cells. C1 [Han, H.; Bourboulia, D.; Jensen-Taubman, S.; Isaac, B.; Wei, B.; Stetler-Stevenson, W. G.] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH,Adv Technol Ctr, Bethesda, MD 20892 USA. RP Bourboulia, D (reprint author), NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch,Adv Technol Ctr, Ctr Canc Res,NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM bourmpouliad@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU NCI Center for Cancer Research Intramural Research Grant [ZIA SC009179-22] FX We thank the Laboratory of Molecular Technology, NCI Frederick for the microarray experiment. We also thank the members of the Extracellular Matrix Pathology Section, Radiation Oncology Branch, NCI for critical discussions. This work was supported by the NCI Center for Cancer Research Intramural Research Grant # ZIA SC009179-22. NR 30 TC 6 Z9 6 U1 1 U2 7 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 FEB 27 PY 2014 VL 33 IS 9 BP 1198 EP 1206 DI 10.1038/onc.2013.61 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AB6XT UT WOS:000331933800013 PM 23474755 ER PT J AU McHugh, MJ Demers, CH Salmeron, BJ Devous, MD Stein, EA Adinoff, B AF McHugh, Meredith J. Demers, Catherine H. Salmeron, Betty Jo Devous, Michael D., Sr. Stein, Elliot A. Adinoff, Bryon TI Cortico-amygdala coupling as a marker of early relapse risk in cocaine-addicted individuals SO FRONTIERS IN PSYCHIATRY LA English DT Article DE cocaine; relapse; addiction; amygdala; connectivity; neuroimaging; ventromedial; prefrontal AB Addiction to cocaine is a chronic condition characterized by high rates of early relapse. This study builds on efforts to identify neural markers of relapse risk by studying resting-state functional connectivity (rsFC) in neural circuits arising from the amygdala, a brain region implicated in relapse-related processes including craving and reactivity to stress following acute and protracted withdrawal from cocaine. Whole-brain resting-state functional magnetic resonance imaging connectivity (6?min) was assessed in 45 cocaine-addicted individuals and 22 healthy controls. Cocaine-addicted individuals completed scans in the final week of a residential treatment episode. To approximate preclinical models of relapse-related circuitry, separate seeds were derived for the left and right basolateral (BLA) and corticomedial (CMA) amygdala. Participants also completed the Iowa Gambling Task, Wisconsin Card Sorting Test, Cocaine Craving Questionnaire, Obsessive-Compulsive Cocaine Use Scale and Personality Inventory. Relapse within the first 30?days post-treatment (n = 24) was associated with reduced rsFC between the left CMA and ventromedial prefrontal cortex/rostral anterior cingulate cortex (vmPFC/rACC) relative to cocaine-addicted individuals who remained abstinent (non-relapse, n = 21). Non-relapse participants evidenced reduced rsFC between the bilateral BLA and visual processing regions (lingual gyrus/cuneus) compared to controls and relapsed participants. Early relapse was associated with fewer years of education but unrelated to trait reactivity to stress, neurocognitive and clinical characteristics or cocaine use history. Findings suggest that rsFC within neural circuits implicated in preclinical models of relapse may provide a promising marker of relapse risk in cocaine-addicted individuals. Future efforts to replicate the current findings and alter connectivity within these circuits may yield novel interventions and improve treatment outcomes. C1 [McHugh, Meredith J.; Demers, Catherine H.; Salmeron, Betty Jo; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. [Devous, Michael D., Sr.] Avid Radiopharmaceut, Philadelphia, PA USA. [Adinoff, Bryon] VA North Texas Hlth Care Syst, Dallas, TX USA. [Adinoff, Bryon] Univ Texas Southwestern Med Ctr Dallas, Dept Psychiat, Dallas, TX USA. RP McHugh, MJ (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM meredith.mchugh@nih.gov; estein@intra.nida.nih.gov RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 FU Intramural Research Program of the National Institute on Drug Abuse, NIDA [DA023203, ULT1R000451] FX The authors gratefully acknowledge the assistance of the Substance Abuse Team at the VA North Texas Health Care System, Homeward Bound, Inc., and Nexus Recovery Center for their support in the screening and recruitment of study subjects. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIDA grant DA023203 (BA, MDD) and ULT1R000451 (National Institutes of Health CTSA/UT-STAR). NR 102 TC 20 Z9 20 U1 0 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD FEB 27 PY 2014 VL 5 AR 16 DI 10.3389/fpsyt.2014.00016 PG 13 WC Psychiatry SC Psychiatry GA V46RD UT WOS:000209900400001 PM 24578695 ER PT J AU Barbey, AK Colom, R Paul, E Forbes, C Krueger, F Goldman, D Grafman, J AF Barbey, Aron K. Colom, Roberto Paul, Erick Forbes, Chad Krueger, Frank Goldman, David Grafman, Jordan TI Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor SO PLOS ONE LA English DT Article ID BDNF VAL66MET POLYMORPHISM; ACTIVITY-DEPENDENT SECRETION; FAMILY-BASED ASSOCIATION; CARD SORTING TEST; ALZHEIMERS-DISEASE; NEURONAL DEVELOPMENT; RECEPTOR SORTILIN; BIPOLAR DISORDER; EPISODIC MEMORY; WORKING-MEMORY AB Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (approximate to half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI. C1 [Barbey, Aron K.; Paul, Erick] Univ Illinois, Decis Neurosci Lab, Urbana, IL 61801 USA. [Barbey, Aron K.; Paul, Erick] Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA. [Barbey, Aron K.] Univ Illinois, Dept Internal Med, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. [Barbey, Aron K.] Univ Illinois, Neurosci Program, Champaign, IL 61820 USA. [Colom, Roberto] Univ Autonoma Madrid, Fdn CIEN, Fdn Reina Sofia, Madrid, Spain. [Forbes, Chad] Univ Delaware, Dept Psychol, Delaware, MD USA. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA USA. [Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Grafman, Jordan] Rehabil Inst Chicago, Traumat Brain Injury Res Lab, Chicago, IL 60611 USA. RP Barbey, AK (reprint author), Univ Illinois, Decis Neurosci Lab, Urbana, IL 61801 USA. EM barbey@illinois.edu; jgrafman@ric.edu RI COLOM, ROBERTO/F-8779-2010; Barbey, Aron/L-7312-2015; Goldman, David/F-9772-2010 OI COLOM, ROBERTO/0000-0001-5865-163X; Barbey, Aron/0000-0002-6092-0912; Goldman, David/0000-0002-1724-5405 FU U.S. National Institute of Neurological Disorders and Stroke; United States Army Medical Research and Material Command [DAMD17-01-1-0675]; Ministerio de Ciencia e Innovacion [Ministry of Science and Innovation, Spain] [PSI2010-20364]; Universidad Autonoma de Madrid [CEMU-2012-004] FX This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, grant number DAMD17-01-1-0675). R. Colom was supported by grant PSI2010-20364 from Ministerio de Ciencia e Innovacion [Ministry of Science and Innovation, Spain] and and CEMU-2012-004 [Universidad Autonoma de Madrid]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 9 Z9 9 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 26 PY 2014 VL 9 IS 2 AR e88733 DI 10.1371/journal.pone.0088733 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BC UT WOS:000332389000017 PM 24586380 ER PT J AU Poncet, N Mitchell, FE Ibrahim, AFM McGuire, VA English, G Arthur, JSC Shi, YB Taylor, PM AF Poncet, Nadege Mitchell, Fiona E. Ibrahim, Adel F. M. McGuire, Victoria A. English, Grant Arthur, J. Simon C. Shi, Yun-Bo Taylor, Peter M. TI The Catalytic Subunit of the System L1 Amino Acid Transporter (Slc7a5) Facilitates Nutrient Signalling in Mouse Skeletal Muscle SO PLOS ONE LA English DT Article ID PROTEIN; MICE; LEUCINE; GENE; ACTIVATION; IMPROVES; DISEASE; GLUCOSE; MTORC1; AVAILABILITY AB The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5(+/-)) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Musclespecific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by similar to 40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e. g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e. g. SLC7A8 (LAT2)) for maintenance of normal muscle mass. C1 [Poncet, Nadege; Mitchell, Fiona E.; McGuire, Victoria A.; Arthur, J. Simon C.; Taylor, Peter M.] Univ Dundee, Coll Life Sci, Div Cell Signalling & Immunol, Dundee, Scotland. [Ibrahim, Adel F. M.] Univ Dundee, Coll Life Sci, Med Res Council, Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland. [English, Grant] Univ Dundee, Coll Life Sci, Div Mol Microbiol, Dundee, Scotland. [Mitchell, Fiona E.; Shi, Yun-Bo] NICHD, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20814 USA. RP Shi, YB (reprint author), NICHD, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20814 USA. EM shiyu@mail.nih.gov; p.m.taylor@dundee.ac.uk RI Ibrahim, Adel/E-5273-2012; OI McGuire, Victoria/0000-0002-7808-3278 FU Wellcome Trust [WT094226]; Intramural Research Program of NICHD/National Institutes of Health (NIH); Diabetes UK [10/0004089]; UK Biotechnology and Biological Sciences Research Council; Physiological Society; Nuffield Foundation; Carnegie Trust FX This work was supported by The Wellcome Trust (WT094226) (http://www.wellcome.ac.uk); The Intramural Research Program of NICHD/National Institutes of Health (NIH) (http://www.nichd.nih.gov); Diabetes UK (10/0004089) (http://www.diabetes.org.uk); UK Biotechnology and Biological Sciences Research Council (http://bbsrc.ac.uk); The Physiological Society (http://www.physoc.org); the Nuffield Foundation (http://www.nuffieldfoundation.org/); and Carnegie Trust (http://www.carnegie-trust.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 14 Z9 14 U1 2 U2 13 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 FEB 26 PY 2014 VL 9 IS 2 AR e89547 DI 10.1371/journal.pone.0089547 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BC UT WOS:000332389000057 PM 24586861 ER PT J AU Mo, AXY Augustine, AD AF Mo, Annie X. Y. Augustine, Alison Deckhut TI NIAID meeting report: Improving malaria vaccine strategies through the application of immunological principles SO VACCINE LA English DT Article DE Malaria vaccine; Adaptive immunity; Innate immunity; Conference report ID TRANSMISSION-BLOCKING IMMUNITY; PAPUA-NEW-GUINEA; T-CELLS; PLASMODIUM-FALCIPARUM; SPOROZOITE INOCULATION; PHASE-3 TRIAL; NAIVE ADULTS; PROTECTION; CHILDREN; IMMUNOGENICITY AB A highly efficacious vaccine to prevent malaria infection or clinical disease is still far from reality despite several decades of intensive effort and a growing global commitment in malaria vaccine development. Further understanding of the mechanisms required for induction of effective host immune responses and maintenance of long-term protective immunity is needed to facilitate rational approaches for vaccine design and evaluation. The National Institute of Allergy and Infectious Diseases (NIAID) conducted a workshop on June 18-19, 2012 with experts in the fields of malaria vaccine development, malaria immunology, and basic immunology to address issues associated with improving our current understanding of malaria vaccine immunity. This report summarizes the discussion and major recommendations generated by the workshop participants regarding the application of recent advances in basic immunology and state-of-the-art immunological tools to improve progress and help address current challenges and knowledge gaps in malaria vaccine development. C1 [Mo, Annie X. Y.; Augustine, Alison Deckhut] NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Augustine, AD (reprint author), NIAID, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Augustine@niaid.nih.gov FU NIH FX Both authors are employees of NIH and are supported by NIH operating funds rather than grants or other awards. NR 42 TC 3 Z9 3 U1 0 U2 4 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 FEB 26 PY 2014 VL 32 IS 10 BP 1132 EP 1138 DI 10.1016/j.vaccine.2013.09.011 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AC3SW UT WOS:000332442500002 PM 24060568 ER PT J AU Alter, BP Giri, N Pan, YJ Savage, SA Pinto, LA AF Alter, Blanche P. Giri, Neelam Pan, Yuanji Savage, Sharon A. Pinto, Ligia A. TI Antibody response to human papillomavirus vaccine in subjects with inherited bone marrow failure syndromes SO VACCINE LA English DT Article DE Human papillomavirus; Vaccine; Fanconi anemia; dyskeratosis congenita; Inherited bone marrow failure syndromes ID CERVICAL-CANCER; FANCONI-ANEMIA; HEAD AB Patients with Fanconi anemia (FA) and other inherited bone marrow failure syndromes (IBMFS) have extremely high risks of squamous cell head and neck, and gynecologic carcinomas. In the general population, these sites are often associated with infection with human papillomaviruses (HPV), particularly HPV16 and HPV18. Our objectives were to measure the levels of HPV antibodies in unvaccinated patients, and to determine whether these patients developed and maintained similar levels of antibodies as those observed in healthy women, following vaccination with the currently licensed HPV L1 virus-like particles (VLP) vaccines. We measured anti-HPV IgG antibody levels in sera from patients using an HPV16 or HPV18 L1 VLP enzyme-linked immunoabsorbent assay. Most unvaccinated patients did not have detectable antibody levels, except for a few women above age 25. Both FA and other IBMFS patients developed antibody levels following vaccination that were similar to those previously described in healthy women, and those levels appeared to be sustained out to 5 years after immunization. Thus, antibody responses to the HPV L1 VLP vaccine in patients with FA and other IBMFS appeared to be similar to the responses reported in the general population, implying potential efficacy against future infections with the HPV types contained in the vaccine. Published by Elsevier Ltd. C1 [Alter, Blanche P.; Giri, Neelam; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Pan, Yuanji; Pinto, Ligia A.] Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD 21702 USA. RP Alter, BP (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, 9609 Med Ctr Dr,Room 6E452, Rockville, MD 20850 USA. EM alterb@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU National Institutes of Health; National Cancer Institute; Westat, Incorporated [N02-CP-91026, N02-CP-11019, HHSN261200655001C]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute (B.P.A., N.G., and S.A.S.), and by contracts N02-CP-91026, N02-CP-11019 and HHSN261200655001C with Westat, Incorporated. The project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (L.A.P. and Y.P.) The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 18 TC 6 Z9 6 U1 0 U2 4 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 FEB 26 PY 2014 VL 32 IS 10 BP 1169 EP 1173 DI 10.1016/j.vaccine.2013.11.048 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AC3SW UT WOS:000332442500007 PM 24295807 ER PT J AU Rosta, E Yang, W Hummer, G AF Rosta, Edina Yang, Wei Hummer, Gerhard TI Calcium Inhibition of Ribonuclease H1 Two-Metal Ion Catalysis SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DIVALENT METAL-IONS; DNA-POLYMERASE-I; 3'-5' EXONUCLEASE ACTIVITY; FREE-ENERGY CALCULATIONS; ENZYME ENDONUCLEASE-IV; ESCHERICHIA-COLI; RNASE-H; RESTRICTION-ENDONUCLEASE; RNA/DNA HYBRID; MAGNESIUM-IONS AB Most phosphate-processing enzymes require Mg2+ as a cofactor to catalyze nucleotide cleavage and transfer reactions. Ca2+ ions inhibit many of these enzymatic activities, despite Ca2+ and Mg2+ having comparable binding affinities and overall biological abundances. Here we study the molecular details of the calcium inhibition mechanism for phosphodiester cleavage, an essential reaction in the metabolism of nucleic acids and nucleotides, by comparing Ca2+- and Mg2+ catalyzed reactions. We study the functional roles of the specific metal ion sites A and B in enabling the catalytic cleavage of an RNA/DNA hybrid substrate by B. halodurans ribonuclease (RNase) HI using hybrid quantum-mechanics/molecular mechanics (QM/MM) free energy calculations. We find that Ca2+ substitution of either of the two active-site Mg2+ ions substantially increases the height of the reaction barrier and thereby abolishes the catalytic activity. Remarkably, Ca2+ at the A. site is inactive also in Mg2+-optimized active-site structures along the reaction path, whereas Mg2+ substitution recovers activity in Ca2+-optimized structures. Geometric changes resulting from Ca2+ substitution at metal ion site A may thus be a secondary factor in the loss of catalytic activity. By contrast, at metal ion site B geometry plays a more important role, with only a partial recovery of activity after Mg2+ substitution in Ca2+-optimized structures. Ca2+-substitution also leads to a change in mechanism, with deprotonation of the water nucleophile requiring a closer approach to the scissile phosphate, which in turn increases the barrier. As a result, Ca2+ is less efficient in activating the water. As a likely cause for the different reactivities of Mg2+ and Ca2+ ions in site A, we identify differences in charge transfer to the ions and the associated decrease in the pK(a) of the oxygen nucleophile attacking the phosphate group. C1 [Rosta, Edina; Hummer, Gerhard] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Rosta, Edina] Kings Coll London, Dept Chem, London SE1 1DB, England. [Yang, Wei] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. RP Rosta, E (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Edina.Rosta@kcl.ac.uk; Gerhard.Hummer@biophys.mpg.de RI Yang, Wei/D-4926-2011; Hummer, Gerhard/A-2546-2013; OI Yang, Wei/0000-0002-3591-2195; Hummer, Gerhard/0000-0001-7768-746X; Rosta, Edina/0000-0002-9823-4766 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Max Planck Society FX We thank Drs. Bernard Brooks, Yihan Shao, and Nicolae-Viorel Buchete for their valuable help. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and by the Max Planck Society (G.H.), and used the computational resources of the NIH Biowulf Cluster (http://biowulf.nih.gov). NR 93 TC 12 Z9 12 U1 6 U2 50 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 26 PY 2014 VL 136 IS 8 BP 3137 EP 3144 DI 10.1021/ja411408x PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AB9VR UT WOS:000332144300037 PM 24499076 ER PT J AU Yoo, DJ Agodoa, L Yuan, CM Abbott, KC Nee, R AF Yoo, David J. Agodoa, Lawrence Yuan, Christina M. Abbott, Kevin C. Nee, Robert TI Risk of intracranial hemorrhage associated with autosomal dominant polycystic kidney disease in patients with end stage renal disease SO BMC NEPHROLOGY LA English DT Article DE Intracranial hemorrhage; Intracranial aneurysm; Autosomal dominant polycystic kidney disease; Stroke; Dialysis; USRDS; Competing risk ID LOBAR INTRACEREBRAL HEMORRHAGE; SUBARACHNOID HEMORRHAGE; MEDICAL PROGRESS; ANEURYSMS; POPULATION; STROKE; ANGIOGRAPHY; PREVALENCE; BLACKS; WHITES AB Background: An analysis of intracranial hemorrhage (ICH) in a national sample of autosomal dominant polycystic kidney disease (ADPKD) patients receiving long-term dialysis has not been reported. It is often assumed that patients with ADPKD are not at increased risk of ICH after starting dialysis. We hypothesized that patients with ADPKD would have a higher subsequent risk of ICH even after the start of chronic dialysis. Methods: Retrospective cohort study of Medicare primary patients with and without ADPKD in the United States Renal Data System (USRDS), initiated on chronic dialysis or transplanted between 1 January 1999 and 3 July 2009, and followed until 31 December 2009. Covariates included age, gender, race, prior stroke, diabetes mellitus, dialysis modality, body mass index, serum albumin and other co-morbid conditions from the Medical Evidence Form. Primary outcome was ICH, based on inpatient and outpatient Medicare claims, and all-cause mortality. Kaplan-Meier analysis was used for unadjusted assessment of time to events. Cox regression was used for assessment of factors associated with ICH and mortality. We performed competing risk regression using kidney transplant and death as competing risks. Kidney transplant was also modeled as a time-dependent covariate in Cox regression. Results: Competing risk regression demonstrated that ADPKD had a subhazard ratio 2.97 for ICH (95% CI 2.27-3.89). Adjusted Cox analysis showed that ADPKD patients had an AHR for death of 0.59 vs. non-ADPKD patients (95% CI 0.57-0.61). Conclusions: ADPKD is a significant risk factor for ICH among patients on maintenance dialysis. Our Medicare primary cohort was older than in previous studies of intracranial aneurysm rupture among ADPKD patients. There are also limitations inherent to using the USRDS database. C1 [Yoo, David J.; Yuan, Christina M.; Abbott, Kevin C.; Nee, Robert] Nephrol Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD USA. RP Abbott, KC (reprint author), Nephrol Walter Reed Natl Mil Med Ctr, 8901 Wisconsin Ave, Bethesda, MD USA. EM kevin.c.abbott.mil@health.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 41 TC 5 Z9 5 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD FEB 26 PY 2014 VL 15 AR 39 DI 10.1186/1471-2369-15-39 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AB9QH UT WOS:000332129900001 PM 24571546 ER PT J AU Adrover, MF Shin, JH Alvarez, VA AF Adrover, Martin F. Shin, Jung Hoon Alvarez, Veronica A. TI Glutamate and Dopamine Transmission from Midbrain Dopamine Neurons Share Similar Release Properties But Are Differentially Affected by Cocaine SO JOURNAL OF NEUROSCIENCE LA English DT Article DE co-release; cocaine; D2 receptors; dopamine; feedback inhibition; glutamate ID LONG-TERM DEPRESSION; RAT CAUDATE-PUTAMEN; NUCLEUS-ACCUMBENS; SUBSTANTIA-NIGRA; CHOLINERGIC INTERNEURONS; UPTAKE INHIBITORS; BASAL GANGLIA; IN-VITRO; STRIATUM; MICE AB Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals. C1 [Adrover, Martin F.; Shin, Jung Hoon; Alvarez, Veronica A.] NIAAA, Sect Neuronal Struct, NIH, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015 OI Alvarez, Veronica /0000-0003-2611-8675 FU Intramural Programs of National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute of Neurological Disorders and Stroke [ZIA-AA000421] FX This study was funded by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute of Neurological Disorders and Stroke Grant ZIA-AA000421. We are grateful to Roland Bock [NIAAA/National Institutes of Health (NIH)] for developing the analysis software, Dr. Fumihito Ono (NIAAA/NIH) for sharing their confocal microscope, and Drs. Karl Deisseroth (Stanford University, Stanford, CA) and Nicole Calakos (Duke University, Durham, NC) for providing the channelrhodopsin-2 constructs and Drd1-tdTomato mice, respectively. We also thank the members of the Alvarez laboratory for their valuable comments on this manuscript. NR 49 TC 24 Z9 27 U1 0 U2 18 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 26 PY 2014 VL 34 IS 9 BP 3183 EP 3192 DI 10.1523/JNEUROSCI.4958-13.2014 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AB8IX UT WOS:000332034700007 PM 24573277 ER PT J AU Douglas, AD Baldeviano, GC Miura, K Wright, GJ Draper, SJ AF Douglas, Alexander D. Baldeviano, G. Christian Miura, Kazutoyo Wright, Gavin J. Draper, Simon J. TI PfRH5 vaccine efficacy against heterologous strain blood-stage Plasmodium falciparum SO LANCET LA English DT Meeting Abstract C1 [Douglas, Alexander D.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford, England. [Baldeviano, G. Christian] US Naval Med Res Unit 6, Lima, Peru. [Miura, Kazutoyo] NIAID, Malaria Immunol Sect, NIH, Bethesda, MD 20892 USA. [Wright, Gavin J.] Wellcome Trust Sanger Inst, Cell Signalling Lab, Cambridge, England. EM sandy.douglas@ndm.ox.ac.uk RI Douglas, Alexander/E-7040-2012 OI Douglas, Alexander/0000-0002-5410-7562 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 26 PY 2014 VL 383 SU 1 BP 43 EP 43 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CQ4EZ UT WOS:000360558400042 ER PT J AU Goddings, AL Mills, K Clasen, L Giedd, J Viner, R Blakemore, SJ AF Goddings, Anne-Lise Mills, Kathryn Clasen, Liv Giedd, Jay Viner, Russell Blakemore, Sarah-Jayne TI Longitudinal MRI to assess effect of puberty on subcortical brain development: an observational study SO LANCET LA English DT Meeting Abstract C1 [Goddings, Anne-Lise; Viner, Russell] UCL, Inst Child Hlth, London WC1N 1EH, England. [Goddings, Anne-Lise; Mills, Kathryn; Blakemore, Sarah-Jayne] UCL, Inst Cognit Neurosci, London WC1N 1EH, England. [Mills, Kathryn; Clasen, Liv; Giedd, Jay] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. EM algoddings@gmail.com RI Giedd, Jay/J-9644-2015; Viner, Russell/A-1441-2009 OI Giedd, Jay/0000-0003-2002-8978; Viner, Russell/0000-0003-3047-2247 NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 26 PY 2014 VL 383 SU 1 BP 52 EP 52 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CQ4EZ UT WOS:000360558400051 ER PT J AU Chugh, SS Havmoeller, R Narayanan, K Singh, D Rienstra, M Benjamin, EJ Gillum, RF Kim, YH McAnulty, JH Zheng, ZJ Forouzanfar, MH Naghavi, M Mensah, GA Ezzati, M Murray, CJL AF Chugh, Sumeet S. Havmoeller, Rasmus Narayanan, Kumar Singh, David Rienstra, Michiel Benjamin, Emelia J. Gillum, Richard F. Kim, Young-Hoon McAnulty, John H. Zheng, Zhi-Jie Forouzanfar, Mohammad H. Naghavi, Mohsen Mensah, George A. Ezzati, Majid Murray, Christopher J. L. TI Worldwide Epidemiology of Atrial Fibrillation A Global Burden of Disease 2010 Study SO CIRCULATION LA English DT Article DE atrial fibrillation; epidemiology; incidence; prevalence; risk factors; prevention ID CHRONIC HEART-FAILURE; SYSTEMATIC ANALYSIS; RISK-FACTORS; SECULAR TRENDS; LIFETIME RISK; 21 REGIONS; PREVALENCE; MORTALITY; DISABILITY; HEALTH AB Background The global burden of atrial fibrillation (AF) is unknown. Methods and Results We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5-22.2 million] and 12.6 million women [95% UI, 12.0-13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8-19.3) in men and 18.9% (95% UI, 15.8-23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8-612.7) and 359.9 in women (95% UI, 334.7-392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2-78.5) and 43.8 in women (95% UI, 35.9-55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2-95.4) in men and 59.5 (95% UI, 49.9-74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0-2.2) and 1.9-fold (95% UI, 1.8-2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. Conclusions These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies. C1 [Chugh, Sumeet S.; Havmoeller, Rasmus; Narayanan, Kumar; Singh, David] Cedars Sinai Heart Inst, Los Angeles, CA USA. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Benjamin, Emelia J.] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med & Publ Hlth, Boston, MA 02215 USA. [Gillum, Richard F.] Howard Univ, Coll Med, Dept Med, Washington, DC USA. [Kim, Young-Hoon] Korea Univ, Coll Med, Seoul 136705, South Korea. [McAnulty, John H.] Legacy Good Samaritan Med Ctr, Portland, OR USA. [Zheng, Zhi-Jie; Mensah, George A.] NHLBI, Bethesda, MD 20892 USA. [Forouzanfar, Mohammad H.; Naghavi, Mohsen; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Ezzati, Majid] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Chugh, SS (reprint author), Cedars Sinai Med Ctr, Inst Heart, AHSP Ste A3300,127 S San Vicente Blvd, Los Angeles, CA 90048 USA. EM sumeet.chugh@cshs.org OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU Bill & Melinda Gates Foundation; Swedish Research Council [2011-1071]; Netherlands Organization for Scientific Research [016.136.055]; [1R01HL092577]; [1R01HL102214]; [1RC1HL101056]; [1R01AG028321] FX This research was supported by core funding from the Bill & Melinda Gates Foundation. Dr Chugh holds the Pauline and Harold Price Endowed Chair of Cardiac Electrophysiology at the Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. Dr Havmoeller is supported by a grant from the Swedish Research Council (grant 2011-1071). Dr Benjamin is supported by 1R01HL092577, 1R01HL102214, 1RC1HL101056, and 1R01AG028321. Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). The funding sources had no influence over the study or the interpretation of the results. NR 37 TC 380 Z9 398 U1 15 U2 43 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD FEB 25 PY 2014 VL 129 IS 8 BP 837 EP 847 DI 10.1161/CIRCULATIONAHA.113.005119 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB4RF UT WOS:000331776900008 PM 24345399 ER PT J AU Yamano, K Fogel, AI Wang, CX van der Bliek, AM Youle, RJ AF Yamano, Koji Fogel, Adam I. Wang, Chunxin van der Bliek, Alexander M. Youle, Richard J. TI Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy SO ELIFE LA English DT Article ID GTPASE-ACTIVATING PROTEINS; PEROXISOMAL FISSION; MAMMALIAN-CELLS; SELECTIVE AUTOPHAGY; PARKIN; FIS1; MEMBRANE; DEGRADATION; RECRUITMENT; P62/SQSTM1 AB Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson's disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/ GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. C1 [Yamano, Koji; Fogel, Adam I.; Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [van der Bliek, Alexander M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM youle@helix.nih.gov RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU NIGMS NIH HHS [GM051866] NR 70 TC 47 Z9 47 U1 3 U2 12 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 25 PY 2014 VL 3 AR e01612 DI 10.7554/eLife.01612 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AC6HW UT WOS:000332623500004 PM 24569479 ER PT J AU Brown, VL Drake, JM Barton, HD Stallknecht, DE Brown, JD Rohani, P AF Brown, Vicki L. Drake, John M. Barton, Heather D. Stallknecht, David E. Brown, Justin D. Rohani, Pejman TI Neutrality, Cross-Immunity and Subtype Dominance in Avian Influenza Viruses SO PLOS ONE LA English DT Article ID A VIRUSES; ENVIRONMENTAL TRANSMISSION; EVOLUTION; PATHOGENS; DYNAMICS; PATTERNS; H5N1; DETERMINANTS; COEXISTENCE; PERSISTENCE AB Avian influenza viruses (AIVs) are considered a threat for their potential to seed human influenza pandemics. Despite their acknowledged importance, there are significant unknowns regarding AIV transmission dynamics in their natural hosts, wild birds. Of particular interest is the difference in subtype dynamics between human and bird populations-in human populations, typically only two or three subtypes cocirculate, while avian populations are capable of simultaneously hosting a multitude of subtypes. One species in particular-ruddy turnstones (Arenaria interpres)-has been found to harbour a very wide range of AIV subtypes, which could make them a key player in the spread of new subtypes in wild bird populations. Very little is known about the mechanisms that drive subtype dynamics in this species, and here we address this gap in our knowledge. Taking advantage of two independent sources of data collected from ruddy turnstones in Delaware Bay, USA, we examine patterns of subtype diversity and dominance at this site. We compare these patterns to those produced by a stochastic, multi-strain transmission model to investigate possible mechanisms that are parsimonious with the observed subtype dynamics. We find, in agreement with earlier experimental work, that subtype differences are unnecessary to replicate the observed dynamics, and that neutrality alone is sufficient. We also evaluate the role of subtype cross-immunity and find that it is not necessary to generate patterns consistent with observations. This work offers new insights into the mechanisms behind subtype diversity and dominance in a species that has the potential to be a key player in AIV dynamics in wild bird populations. C1 [Brown, Vicki L.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Brown, Vicki L.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Drake, John M.; Barton, Heather D.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Stallknecht, David E.; Brown, Justin D.] Univ Georgia, Southeastern Cooperat Wildlife Dis Study, Athens, GA 30602 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rohani, P (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM rohani@umich.edu OI Drake, John/0000-0003-4646-1235 FU James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Department of Health and Human Services [HHSN266200700007C] FX This work was supported by the James S. McDonnell Foundation and the National Science Foundation (DEB-0917853). PR was also supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. DES and JDB were also supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Department of Health and Human Services, under Contract HHSN266200700007C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 1 Z9 1 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 25 PY 2014 VL 9 IS 2 AR e88817 DI 10.1371/journal.pone.0088817 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC2ZX UT WOS:000332385900013 PM 24586401 ER PT J AU Yamada, S Nakamura, J Asada, M Takase, M Matsusaka, T Iguchi, T Yamada, R Tanaka, M Higashi, AY Okuda, T Asada, N Fukatsu, A Kawachi, H Graf, D Muso, E Kita, T Kimura, T Pastan, I Economides, AN Yanagita, M AF Yamada, Sachiko Nakamura, Jin Asada, Misako Takase, Masayuki Matsusaka, Taiji Iguchi, Taku Yamada, Ryo Tanaka, Mari Higashi, Atsuko Y. Okuda, Tomohiko Asada, Nariaki Fukatsu, Atsushi Kawachi, Hiroshi Graf, Daniel Muso, Eri Kita, Toru Kimura, Takeshi Pastan, Ira Economides, Aris N. Yanagita, Motoko TI Twisted Gastrulation, a BMP Antagonist, Exacerbates Podocyte Injury SO PLOS ONE LA English DT Article ID BONE MORPHOGENETIC PROTEIN-7; DIABETIC-NEPHROPATHY; EPITHELIAL-CELL; RENAL FIBROSIS; MOUSE MODELS; KIDNEY; GLOMERULOSCLEROSIS; PROGRESSION; DISEASES; USAG-1 AB Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury. C1 [Yamada, Sachiko; Nakamura, Jin; Asada, Misako; Takase, Masayuki; Yamada, Ryo; Tanaka, Mari; Okuda, Tomohiko; Asada, Nariaki; Yanagita, Motoko] Kyoto Univ, Dept Nephrol, Grad Sch Med, Kyoto, Japan. [Matsusaka, Taiji] Tokai Univ, Sch Med, Dept Internal Med, Isehara, Kanagawa 25911, Japan. [Iguchi, Taku] Kyoto Univ, TMK Project, Grad Sch Med, Kyoto, Japan. [Higashi, Atsuko Y.; Kimura, Takeshi] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto, Japan. [Fukatsu, Atsushi] Yachiyo Hosp, Anjo, Aichi, Japan. [Kawachi, Hiroshi] Niigata Univ, Grad Sch Med & Dent Sci, Dept Cell Biol, Inst Nephrol, Niigata, Japan. [Graf, Daniel] Univ Zurich, Inst Oral Biol, Fac Med, Zurich, Switzerland. [Muso, Eri] Tazuke Kofukai Med Res Inst, Dept Nephrol & Dialysis, Kitano Hosp, Osaka, Japan. [Kita, Toru] Kobe City Med Ctr Gen Hosp, Kobe, Hyogo, Japan. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Economides, Aris N.] Regeneron Pharmaceut Inc, Tarrytown, NY USA. RP Yanagita, M (reprint author), Kyoto Univ, Dept Nephrol, Grad Sch Med, Kyoto, Japan. EM motoy@kuhp.kyoto-u.ac.jp OI Economides, Aris/0000-0002-6508-8942 FU Japan Society of the Promotion of Science (JSPS) through the Funding Program for Next-Generation World-Leading Researchers (NEXT program); Ministry of Education, Culture, Sports, Science and Technology of Japan [Shin-gakujyutsu 21200080]; Astellas Foundation for Research on Metabolic Disorders FX This study was supported by the Japan Society of the Promotion of Science (JSPS) through the Funding Program for Next-Generation World-Leading Researchers (NEXT program), Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Shin-gakujyutsu 21200080), and grants from the Astellas Foundation for Research on Metabolic Disorders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 25 PY 2014 VL 9 IS 2 AR e89135 DI 10.1371/journal.pone.0089135 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC2ZX UT WOS:000332385900028 PM 24586548 ER PT J AU Lee, YS Gregory, MT Yang, W AF Lee, Young-Sam Gregory, Mark T. Yang, Wei TI Human Pol zeta purified with accessory subunits is active in translesion DNA synthesis and complements Pol. in cisplatin bypass SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TLS; REV3L; MAD2L2; processivity; two-polymerase lesion bypass ID FRAGILE SITE STABILITY; POLYMERASE-ZETA; SACCHAROMYCES-CEREVISIAE; CATALYTIC SUBUNIT; STRUCTURAL BASIS; REPLICATION FORK; REV1 PROTEIN; ZINC-FINGER; DELTA; YEAST AB DNA polymerase zeta (Pol zeta) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis and is essential for normal embryogenesis. At a minimum, Pol zeta consists of a catalytic subunit Rev3 and an accessory subunit Rev7. Mammalian Rev3 contains >3,000 residues and is twice as large as the yeast homolog. To date, no vertebrate Pol zeta has been purified for biochemical characterization. Here we report purification of a series of human Rev3 deletion constructs expressed in HEK293 cells and identification of a minimally catalytically active human Pol zeta variant. With a tagged form of an active Pol zeta variant, we isolated two additional accessory subunits of human Pol zeta, PolD2 and PolD3. The purified four-subunit Pol zeta 4 (Rev3-Rev7-PolD2-PolD3) is much more efficient and more processive at bypassing a 1,2-intrastrand d(GpG)-cisplatin cross-link than the two-subunit Pol zeta 2 (Rev3-Rev7). We show that complete bypass of cisplatin lesions requires Pol eta to insert dCTP opposite the 3' guanine and Pol zeta 4 to extend the primers. C1 [Lee, Young-Sam; Gregory, Mark T.; Yang, Wei] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM l.youngsam@gmail.com; weiy@mail.nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Institutes of Health Intramural Research Grant [DK036146-07] FX We thank Dr. Christopher W. Lawrence for human REV3L and MAD2L2 cDNAs and Drs. R. Craigie and D. J. Leahy for editing this manuscript. This work is supported by National Institutes of Health Intramural Research Grant DK036146-07. NR 47 TC 42 Z9 42 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 25 PY 2014 VL 111 IS 8 BP 2954 EP 2959 DI 10.1073/pnas.1324001111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900026 PM 24449906 ER PT J AU Cimbro, R Gallant, TR Dolan, MA Guzzo, C Zhang, P Lin, Y Miao, HY Van Ryk, D Arthos, J Gorshkova, I Brown, PH Hurt, DE Lusso, P AF Cimbro, Raffaello Gallant, Thomas R. Dolan, Michael A. Guzzo, Christina Zhang, Peng Lin, Yin Miao, Huiyi Van Ryk, Donald Arthos, James Gorshkova, Inna Brown, Patrick H. Hurt, Darrell E. Lusso, Paolo TI Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2-V3 interaction and modulates neutralization sensitivity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN TRIMER; STRUCTURAL BASIS; POTENT NEUTRALIZATION; CRYSTAL-STRUCTURE; ANTIBODY PG16; V1/V2 DOMAIN; N-TERMINUS; VACCINE; RECOGNITION AB Elicitation of broadly neutralizing antibodies is essential for the development of a protective vaccine against HIV-1. However, the native HIV-1 envelope adopts a protected conformation that conceals highly conserved sites of vulnerability from antibody recognition. Although high-definition structures of the monomeric core of the envelope glycoprotein subunit gp120 and, more recently, of a stabilized soluble gp140 trimer have been solved, fundamental aspects related to the conformation and function of the native envelope remain unresolved. Here, we show that the conserved central region of the second variable loop (V2) of gp120 contains sulfated tyrosines (Tys173 and Tys177) that in the CD4-unbound prefusion state mediate intramolecular interaction between V2 and the conserved base of the third variable loop (V3), functionally mimicking sulfated tyrosines in CCR5 and anti-coreceptor-binding-site antibodies such as 412d. Recombinant gp120 expressed in continuous cell lines displays low constitutive levels of V2 tyrosine sulfation, which can be enhanced markedly by overexpression of the tyrosyl sulfotransferase TPST2. In contrast, virion-associated gp120 produced by primary CD4(+) T cells is inherently highly sulfated. Consistent with a functional role of the V2 sulfotyrosines, enhancement of tyrosine sulfation decreased binding and neutralization of HIV-1 BaL by monomeric soluble CD4, 412d, and anti-V3 antibodies and increased recognition by the trimer-preferring antibodies PG9, PG16, CH01, and PGT145. Conversely, inhibition of tyrosine sulfation increased sensitivity to soluble CD4, 412d, and anti-V3 antibodies and diminished recognition by trimer-preferring antibodies. These results identify the sulfotyrosine-mediated V2-V3 interaction as a critical constraint that stabilizes the native HIV-1 envelope trimer and modulates its sensitivity to neutralization. C1 [Cimbro, Raffaello; Gallant, Thomas R.; Guzzo, Christina; Zhang, Peng; Lin, Yin; Miao, Huiyi; Van Ryk, Donald; Arthos, James; Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Dolan, Michael A.; Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Gorshkova, Inna; Brown, Patrick H.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Lusso, P (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM plusso@niaid.nih.gov OI Cimbro, Raffaello/0000-0002-6251-5160 FU National Institute for Allergy and Infectious Diseases, NIH, Intramural Research Program FX We thank Edward A. Berger and Anthony S. Fauci for helpful suggestions and critical reading of the manuscript; John R. Mascola, George K. Lewis, and James E. Robinson for anti-gp120 mAbs; Michael Farzan for the TPST2-expressing vector; Jocelyn Ray for help in producing recombinant gp120; the IAVI consortium for mAbs PG9, PG16, CH01, and PGT145; and the National Institutes of Health (NIH) AIDS Reagent Program for cell lines and reagents. This work was supported by the National Institute for Allergy and Infectious Diseases, NIH, Intramural Research Program. NR 48 TC 12 Z9 12 U1 0 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 25 PY 2014 VL 111 IS 8 BP 3152 EP 3157 DI 10.1073/pnas.1314718111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900059 PM 24569807 ER PT J AU Ben-Shlomo, Y Spears, M Boustred, C May, M Anderson, SG Benjamin, EJ Boutouyrie, P Cameron, J Chen, CH Cruickshank, JK Hwang, SJ Lakatta, EG Laurent, S Maldonado, J Mitchell, GF Najjar, SS Newman, AB Ohishi, M Pannier, B Pereira, T Vasan, RS Shokawa, T Sutton-Tyrell, K Verbeke, F Wang, KL Webb, DJ Hansen, TW Zoungas, S McEniery, CM Cockcroft, JR Wilkinson, IB AF Ben-Shlomo, Yoav Spears, Melissa Boustred, Chris May, Margaret Anderson, Simon G. Benjamin, Emelia J. Boutouyrie, Pierre Cameron, James Chen, Chen-Huan Cruickshank, J. Kennedy Hwang, Shih-Jen Lakatta, Edward G. Laurent, Stephane Maldonado, Joao Mitchell, Gary F. Najjar, Samer S. Newman, Anne B. Ohishi, Mitsuru Pannier, Bruno Pereira, Telmo Vasan, Ramachandran S. Shokawa, Tomoki Sutton-Tyrell, Kim Verbeke, Francis Wang, Kang-Ling Webb, David J. Hansen, Tine Willum Zoungas, Sophia McEniery, Carmel M. Cockcroft, John R. Wilkinson, Ian B. TI Aortic Pulse Wave Velocity Improves Cardiovascular Event Prediction An Individual Participant Meta-Analysis of Prospective Observational Data From 17,635 Subjects SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; meta-analysis; prognostic factor; pulse wave velocity ID CORONARY-HEART-DISEASE; STAGE RENAL-DISEASE; ISOLATED SYSTOLIC HYPERTENSION; INTIMA-MEDIA THICKNESS; ARTERIAL STIFFNESS; INDEPENDENT PREDICTOR; BLOOD-PRESSURE; RISK-FACTORS; TASK-FORCE; ALL-CAUSE AB Objectives The goal of this study was to determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors. Background Several studies have shown that aPWV may be a useful risk factor for predicting CVD, but they have been underpowered to examine whether this is true for different subgroups. Methods We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with CVD outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects. Results Of 17,635 participants, a total of 1,785 (10%) had a CVD event. The pooled age-and sex-adjusted hazard ratios (HRs) per 1-SD change in loge aPWV were 1.35 (95% confidence interval [CI]: 1.22 to 1.50; p < 0.001) for coronary heart disease, 1.54 (95% CI: 1.34 to 1.78; p < 0.001) for stroke, and 1.45 (95% CI: 1.30 to 1.61; p < 0.001) for CVD. Associations stratified according to sex, diabetes, and hypertension were similar but decreased with age (1.89, 1.77, 1.36, and 1.23 for age <= 50, 51 to 60, 61 to 70, and > 70 years, respectively; pinteraction < 0.001). After adjusting for conventional risk factors, aPWV remained a predictor of coronary heart disease (HR: 1.23 [95% CI: 1.11 to 1.35]; p < 0.001), stroke (HR: 1.28 [95% CI: 1.16 to 1.42]; p < 0.001), and CVD events (HR: 1.30 [95% CI: 1.18 to 1.43]; p < 0.001). Reclassification indices showed that the addition of aPWV improved risk prediction (13% for 10-year CVD risk for intermediate risk) for some subgroups. Conclusions Consideration of aPWV improves model fit and reclassifies risk for future CVD events in models that include standard risk factors. aPWV may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management. (C) 2014 by the American College of Cardiology Foundation C1 [Ben-Shlomo, Yoav; Spears, Melissa; Boustred, Chris; May, Margaret] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Anderson, Simon G.] Univ Manchester, Inst Cardiovasc Sci, Manchester M13 9PL, Lancs, England. [Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Framingham Heart Study,Cardiol Sect, Boston, MA 02118 USA. [Boutouyrie, Pierre; Laurent, Stephane] Paris Descartes Univ, Hop Europeen Georges Pompidou, AP HP, INSERM U970, Paris, France. [Cameron, James] MonashHEART, Monash Cardiovasc Res Ctr, Melbourne, Vic, Australia. [Cameron, James] Monash Univ, Dept Med MMC, Melbourne, Vic 3004, Australia. [Chen, Chen-Huan; Wang, Kang-Ling] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Cruickshank, J. Kennedy] Kings Coll London, London WC2R 2LS, England. [Cruickshank, J. Kennedy] St Thomas & Guys Hosp, Kings Hlth Partners, London, England. [Hwang, Shih-Jen] NHLBI, Branch Populat Sci, Div Intramural Res, Bethesda, MD 20892 USA. [Lakatta, Edward G.; Najjar, Samer S.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Maldonado, Joao] Inst Invest & Formacao Cardiovasc, Penacova, Portugal. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Najjar, Samer S.] MedStar Heart Res Inst, Washington, DC USA. [Newman, Anne B.; Sutton-Tyrell, Kim] Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Ohishi, Mitsuru] Osaka Univ, Dept Geriatr Med, Osaka, Japan. [Pannier, Bruno] Ctr Invest Prevent & Clin, Paris, France. [Pereira, Telmo] Escola Super Tecnol Saude Coimbra, Coimbra, Portugal. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Framingham Heart Study, Boston, MA USA. [Shokawa, Tomoki] Hiroshima Univ, Grad Sch Biomed Sci, Dept Mol & Internal Med, Hiroshima, Japan. [Verbeke, Francis] Ghent Univ Hosp, Dept Nephrol, Ghent, Belgium. [Webb, David J.] Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Hansen, Tine Willum] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Hansen, Tine Willum] Steno Diabet Ctr, Glostrup, Denmark. [Zoungas, Sophia] Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia. [McEniery, Carmel M.; Wilkinson, Ian B.] Univ Cambridge, Clin Pharmacol Unit, Cambridge, England. [Cockcroft, John R.] Wales Heart Res Inst, Cardiff, S Glam, Wales. RP Ben-Shlomo, Y (reprint author), Sch Social & Community Med, 39 Whatley Rd, Bristol BS8 2PS, Avon, England. EM y.ben-shlomo@bristol.ac.uk RI Boutouyrie, Pierre/J-8592-2015; Laurent, Stephane/J-8624-2015; Newman, Anne/C-6408-2013; Pereira, Telmo/M-4626-2013; OI Boutouyrie, Pierre/0000-0002-4375-3569; Newman, Anne/0000-0002-0106-1150; Pereira, Telmo/0000-0001-9119-7774; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Anderson, Simon/0000-0002-8896-073X FU National Institutes of Health Research Methods Training Fellowship; National Institutes of Health; HeartWare Inc.; British Heart Foundation and Cambridge Biomedical Research Centre FX There was no funding supplied for the meta-analysis, but Online Appendix 1 presents details for the individual study funding. Ms. Spears was funded by a National Institutes of Health Research Methods Training Fellowship. Dr. Anderson is a National Institutes of Health Research Clinical Lecturer in Cardiology. Dr. Boutouyrie has received research grants from AtCor and Esaote. Dr. Mitchell is owner of Cardiovascular Engineering, Inc., a company that develops and manufactures devices to measure vascular stiffness; is a consultant for Novartis and Merck; and has received grants from the National Institutes of Health. Dr. Najjar has received research support from HeartWare Inc. Drs. McEniery and Wilkinson are supported by the British Heart Foundation and Cambridge Biomedical Research Centre. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Sutton-Tyrell is deceased. NR 54 TC 250 Z9 256 U1 5 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 25 PY 2014 VL 63 IS 7 BP 636 EP 646 DI 10.1016/j.jacc.2013.09.063 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WB UT WOS:000331719800005 PM 24239664 ER PT J AU Whitman, IR Patel, VV Soliman, EZ Bluemke, DA Praestgaard, A Jain, A Herrington, D Lima, JAC Kawut, SM AF Whitman, Isaac R. Patel, Vickas V. Soliman, Elsayed Z. Bluemke, David A. Praestgaard, Amy Jain, Aditya Herrington, David Lima, Joao A. C. Kawut, Steven M. TI Validity of the Surface Electrocardiogram Criteria for Right Ventricular Hypertrophy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE electrocardiogram; magnetic resonance imaging; right ventricular hypertrophy ID TIME 3-DIMENSIONAL ECHOCARDIOGRAPHY; CORONARY-HEART-DISEASE; PULMONARY ARTERIAL-HYPERTENSION; CARDIOVASCULAR MAGNETIC-RESONANCE; IMPROVED ECG MODELS; EJECTION FRACTION; PROGNOSTIC VALUE; FOLLOW-UP; MYOCARDIAL-INFARCTION; SYSTOLIC FUNCTION AB Objectives The study aimed to assess the diagnostic properties of electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) measured by cardiac magnetic resonance imaging (cMRI) in adults without clinical cardiovascular disease. Background Current ECG criteria for RVH were based on cadaveric dissection in small studies. Methods MESA (Multi-Ethnic Study of Atherosclerosis) performed cMRIs with complete right ventricle (RV) interpretation on 4,062 participants without clinical cardiovascular disease. Endocardial margins of the RV were manually contoured on diastolic and systolic images. The ECG screening criteria for RVH from the 2009 American Heart Association Recommendations for Standardization and Interpretation of the ECG were examined in participants with and without left ventricular (LV) hypertrophy or reduced ejection fraction. RVH was defined using sex-specific normative equations based on age, height, and weight. Results The study sample with normal LV morphology and function (n = 3,719) was age 61.3 +/- 10.0 years, 53.5% female, 39.6% Caucasian, 25.5% African American, 21.9% Hispanic, and 13.0% Asian. The mean body mass index was 27.9 +/- 5.0 kg/m(2). A total of 6% had RVH, which was generally mild. Traditional ECG criteria were specific (many > 95%) but had low sensitivity for RVH by cMRI. The positive predictive values were not sufficiently high as to be clinically useful (maximum 12%). The results did not differ based on age, sex, race, or smoking status, or with the inclusion of participants with abnormal LV mass or function. Classification and regression tree analysis revealed that no combination of ECG variables was better than the criteria used singly. Conclusions The recommended ECG screening criteria for RVH are not sufficiently sensitive or specific for screening for mild RVH in adults without clinical cardiovascular disease. (C) 2014 by the American College of Cardiology Foundation C1 [Whitman, Isaac R.] Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA. [Patel, Vickas V.; Kawut, Steven M.] Univ Penn, Dept Med, Penn Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Soliman, Elsayed Z.] Wake Forest Univ Hlth Sci, Dept Epidemiol & Prevent, Cardiol Sect, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Soliman, Elsayed Z.] Wake Forest Univ Hlth Sci, Dept Internal Med, Cardiol Sect, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. [Praestgaard, Amy; Kawut, Steven M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Jain, Aditya; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Herrington, David] Wake Forest Univ Hlth Sci, Div Cardiol, Dept Internal Med, Winston Salem, NC USA. RP Kawut, SM (reprint author), Hosp Univ Penn, Dept Med, 718 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@upenn.edu FU National Institutes of Health [R01-HL086719, N01-HC95159, HC95165, N01-HC95169, K24 HL103844] FX National Institutes of Health funding was obtained via R01-HL086719, N01-HC95159 through HC95165, N01-HC95169, and K24 HL103844. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Francois Haddad, MD, served as Guest Editor for this paper. NR 77 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 25 PY 2014 VL 63 IS 7 BP 672 EP 681 DI 10.1016/j.jacc.2013.08.1633 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WB UT WOS:000331719800010 PM 24080107 ER PT J AU Iben, JR Maraia, RJ AF Iben, James R. Maraia, Richard J. TI tRNA gene copy number variation in humans SO GENE LA English DT Article DE Codon; Anti-codon; Translation; Next-generation; Sequencing; Genome-wide ID NONOPTIMAL CODON USAGE; DNA-DAMAGE RESPONSE; EXPRESSED GENES; GENOMIC SEQUENCE; YEAST; CONSEQUENCES; TRANSLATION; ELONGATOR; MECHANISM; ABUNDANCE AB The human tRNAome consists of more than 500 interspersed tRNA genes comprising 51 anticodon families of largely unequal copy number. We examined tRNA gene copy number variation (tgCNV) in six individuals; two kindreds of two parents and a child, using high coverage whole genome sequence data. Such differences may be important because translation of some mRNAs is sensitive to the relative amounts of tRNAs and because tRNA competition determines translational efficiency vs. fidelity and production of native vs. misfolded proteins. We identified several tRNA gene clusters with CNV, which in some cases were part of larger iterations. In addition there was an isolated tRNALysCUU gene that was absent as a homozygous deletion in one of the parents. When assessed by semiquantitative PCR in 98 DNA samples representing a wide variety of ethnicities, this allele was found deleted in hetero- or homozygosity in all groups at -50% frequency. This is the first report of copy number variation of human tRNA genes. We conclude that tgCNV exists at significant levels among individual humans and discuss the results in terms of genetic diversity and prior genome wide association studies (GWAS) that suggest the importance of the ratio of tRNALys isoacceptors in Type-2 diabetes. Published by Elsevier B.V. C1 [Iben, James R.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), 31 Ctr Dr,Bld 31,Rm 2A25, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH. NR 49 TC 5 Z9 5 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD FEB 25 PY 2014 VL 536 IS 2 BP 376 EP 384 DI 10.1016/j.gene.2013.11.049 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AA3VC UT WOS:000331021800022 PM 24342656 ER PT J AU Wang, C Chao, ZM Wu, XY Sun, W Ito, Y AF Wang, Chun Chao, Zhimao Wu, Xiaoyi Sun, Wen Ito, Yoichiro TI ENRICHMENT AND PURIFICATION OF PEDUNCULOSIDE AND SYRINGIN FROM THE BARKS OF ILEX ROTUNDA WITH MACROPOROUS RESINS SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE adsorption; desorption; Ilex rotunda; macroporous resin; pedunculoside; syringin ID ADSORPTION; EXTRACTS AB Pedunculoside and syringin are two bioactive compounds in herbal tea and Chinese drug Jiubiying, the dried barks of Ilex rotunda Thunb. In the present study, the enrichment and purification of pedunculoside and syringin were investigated on the macroporous resins. The evaluation results of performance and adsorption characteristics of eight macroporous resins indicated that SP825 was most suitable for the separation of pedunculoside and syringin. Based on the series of experiments of separation, dynamic adsorption, and desorption on the column of SP825 resin, the optimal conditions were determined as follows: processing volume: 2 BV; temperature: 25 degrees C; for desorption of syringin: ethanol-water (30:70, v/v), 4 BV as an eluent, flow rate: 1.0mL/min/cm(2); for desorption of pedunculoside:ethanol-water (60:40, v/v), 5 BV as an eluent, flow rate: 1.0mL/min/cm(2). One-step treatment of 600mL Jiubiying extract containing 4.346mg/mL pedunculoside and 1.478mg/mL syringin, yielded 7.04g (29.6% purity) crude pedunculoside powder and 2.32g (31.0% purity) crude syringin powder. Followed by repeated recrystallization in methanol, 1600mg pedunculoside with 99% purity, and 533mg syringin with 96% purity were obtained. The method provides a new approach for scale-up enrichment and purification of pedunculoside and syringin from Jiubiying extract. C1 [Wang, Chun; Chao, Zhimao; Wu, Xiaoyi; Sun, Wen] China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Chao, ZM (reprint author), China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China. EM chaozhimao@yahoo.com.cn FU General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China [201210209] FX The authors gratefully acknowledge the financial support by the public welfare research special project in General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China (No.201210209). NR 20 TC 4 Z9 4 U1 2 U2 24 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1082-6076 EI 1520-572X J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD FEB 25 PY 2014 VL 37 IS 4 BP 572 EP 587 DI 10.1080/10826076.2012.749499 PG 16 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 274IJ UT WOS:000328599700010 PM 25104900 ER PT J AU Rahma, OE Hamilton, JM Wojtowicz, M Dakheel, O Bernstein, S Liewehr, DJ Steinberg, SM Khleif, SN AF Rahma, Osama E. Hamilton, J. Michael Wojtowicz, Malgorzata Dakheel, Omar Bernstein, Sarah Liewehr, David J. Steinberg, Seth M. Khleif, Samir N. TI The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Ras; Peptide; Vaccine; IL-2; GM-CSF; Immune response ID COLONY-STIMULATING FACTOR; COOPERATIVE-ONCOLOGY-GROUP; PHASE-II TRIAL; METASTATIC MELANOMA; ONCOGENE ACTIVATION; CANCER-PATIENTS; MUTANT RAS; ADJUVANT; ADENOCARCINOMA; INTERLEUKIN-2 AB Background: Mutant Ras oncogenes produce proteins that are unique to cancer cells and represent attractive targets for vaccine therapy. We have shown previously that vaccinating cancer patients with mutant ras peptides is feasible and capable of inducing a specific immune response against the relevant mutant proteins. Here, we tested the mutant ras peptide vaccine administered in combination with low dose interleukin-2 (IL-2) or/and granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to enhance the vaccine immune response. Methods: 5000 mu g of the corresponding mutant ras peptide was given subcutaneously (SQ) along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m(2)/day starting at day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 mu g/day one day prior to each ras peptide vaccination for 4 days. Vaccines were repeated every 5 weeks on arm A and C, and every 4 weeks on arm B, for a maximum of 15 cycles or until disease progression. Results: We treated 53 advanced cancer patients (38 with colorectal, 11 with pancreatic, 1 with common bile duct and 3 with lung) on 3 different arms (16 on arm A, 18 on arm B, and 19 on arm C). The median progression free survival (PFS) and overall survival (OS) was 3.6 and 16.9 months, respectively, for all patients evaluable for clinical response (n = 48). There was no difference in PFS or OS between the three arms (P = 0.73 and 0.99, respectively). Most adverse events were grade 1-2 toxicities and resolved spontaneously. The vaccine induced an immune response to the relevant ras peptide in a total of 20 out of 37 evaluable patients (54%) by ELISPOT, proliferative assay, or both. While 92.3% of patients on arm B had a positive immune response, only 31% of patients on arm A and 36% of patients on arm C had positive immune responses (P = 0.003, Fisher's exact test). Conclusions: The reported data showed that IL-2 might have a negative effect on the specific immune response induced by the relevant mutant ras vaccine in patients with advanced cancer. This observation deserves further investigations. C1 [Rahma, Osama E.; Dakheel, Omar; Khleif, Samir N.] NCI, Canc Vaccine Branch, CCR, Bethesda, MD 20892 USA. [Hamilton, J. Michael] NCI, OD, CCR, Bethesda, MD 20892 USA. [Wojtowicz, Malgorzata] NCI, LUACR, DCP, Rockville, MD 20850 USA. [Bernstein, Sarah] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20814 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, CCR, Rockville, MD 20850 USA. [Khleif, Samir N.] Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA. [Rahma, Osama E.] Univ Virginia, Charlottesville, VA 22908 USA. RP Khleif, SN (reprint author), NCI, Canc Vaccine Branch, CCR, 10 Ctr Dr, Bethesda, MD 20892 USA. EM skhleif@gru.edu FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported 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 US Government. NR 36 TC 13 Z9 13 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 24 PY 2014 VL 12 AR 55 DI 10.1186/1479-5876-12-55 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AG6MT UT WOS:000335533400002 PM 24565030 ER PT J AU Barbeau, B Hiscott, J Bazarbachi, A Carvalho, E Jones, K Martin, F Matsuoka, M Murphy, EL Ratner, L Switzer, WM Watanabe, T AF Barbeau, Benoit Hiscott, John Bazarbachi, Ali Carvalho, Edgar Jones, Kathryn Martin, Fabiola Matsuoka, Masao Murphy, Edward L. Ratner, Lee Switzer, William M. Watanabe, Toshiki TI Conference Highlights of the 16th International Conference on Human Retrovirology: HTLV and Related Retroviruses, 26-30 June 2013, Montreal, Canada SO RETROVIROLOGY LA English DT Review DE HTLV-1; HTLV-2; BLV; Foamy virus; Adult T-cell leukemia/lymphoma; HTLV-1-associated myelopathy/tropical spastic paraparesis ID T-CELL LEUKEMIA; LYMPHOTROPIC VIRUS TYPE-1; PRIMARY BILIARY-CIRRHOSIS; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; SIMIAN FOAMY VIRUS; READING FRAME II; IN-VIVO; MOLECULAR-FEATURES; VIRAL INFECTIVITY; INTERFERON-ALPHA AB The 16th International Conference on Human Retrovirology: HTLV and Related Retroviruses was held in Montreal, Quebec from June 26th to June 30th, 2013 and was therefore hosted by a Canadian city for the first time. The major topic of the meeting was human T-lymphotropic viruses (HTLVs) and was covered through distinct oral and poster presentation sessions: clinical research, animal models, immunology, molecular and cellular biology, human endogenous and emerging exogenous retroviruses and virology. In this review, highlights of the meeting are provided by different experts for each of these research areas. C1 [Barbeau, Benoit] Univ Quebec, Dept Sci Biol, Montreal, PQ, Canada. [Barbeau, Benoit] Univ Quebec, Biomed Res Ctr, Montreal, PQ, Canada. [Hiscott, John] VGTI Florida, Lucie, FL USA. [Hiscott, John] Lady Davis Inst, Montreal, PQ, Canada. [Bazarbachi, Ali] Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon. [Carvalho, Edgar] Univ Fed Bahia UFBA, Dept Immunol, Salvador, BA, Brazil. [Jones, Kathryn] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Basic Res Program, Frederick, MD USA. [Martin, Fabiola] Univ York, Hull & York Med Sch, Dept Biol, Ctr Immunol & Infect, York YO10 5DD, N Yorkshire, England. [Matsuoka, Masao] Kyoto Univ, Inst Virus Res, Lab Virus Control, Sakyo Ku, Kyoto 606, Japan. [Murphy, Edward L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Murphy, Edward L.] Blood Syst Res Inst, San Francisco, CA USA. [Ratner, Lee] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Switzer, William M.] Ctr Dis Control & Prevent, Lab Branch, Div HIV AIDS Prevent, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA USA. [Watanabe, Toshiki] Univ Tokyo, Grad Sch Frontier Sci, Tokyo, Japan. RP Barbeau, B (reprint author), Univ Quebec, Dept Sci Biol, Room SB 3335,2080 St Urbain, Montreal, PQ, Canada. EM barbeau.benoit@uqam.ca OI Matsuoka, Masao/0000-0002-0473-754X FU Canadian Institutes of Health Research [KDE124772] FX This work was supported by a Dissemination events grant from the Canadian Institutes of Health Research (#KDE124772) (B.B. and J.H.). We are thankful toward the conference staff (especially Gabriella Di Pancrazio) and the sponsors for having helped in organizing this meeting. We also thank Luc Willems, Graham P. Taylor and Charles R. M. Bangham for their helpful suggestions. NR 197 TC 2 Z9 2 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 24 PY 2014 VL 11 AR 19 DI 10.1186/1742-4690-11-19 PG 21 WC Virology SC Virology GA AD5ZS UT WOS:000333332900001 PM 24558960 ER PT J AU Rao, M Gottesfeld, JM AF Rao, Mahendra Gottesfeld, Joel M. TI Introduction to Thematic Minireview Series: Development of Human Therapeutics Based on Induced Pluripotent Stem Cell (iPSC) Technology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review DE Genomic Instability; Induced Pluripotent Stem Cells; Regenerative Medicine; Stem Cells; Toxicology; Gene Correction; Immunogenicity AB With the advent of human induced pluripotent stem cell (hiPSC) technology, it is now possible to derive patient-specific cell lines that are of great potential in both basic research and the development of new therapeutics for human diseases. Not only do hiPSCs offer unprecedented opportunities to study cellular differentiation and model human diseases, but the differentiated cell types obtained from iPSCs may become therapeutics themselves. These cells can also be used in the screening of therapeutics and in toxicology assays for potential liabilities of therapeutic agents. The remarkable achievement of transcription factor reprogramming to generate iPSCs was recognized by the award of the Nobel Prize in Medicine to Shinya Yamanaka in 2012, just 6 years after the first publication of reprogramming methods to generate hiPSCs (Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Cell 131, 861-872). This minireview series highlights both the promises and challenges of using iPSC technology for disease modeling, drug screening, and the development of stem cell therapeutics. C1 [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Gottesfeld, Joel M.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Gottesfeld, JM (reprint author), Scripps Res Inst, La Jolla, CA 92037 USA. EM joelg@scripps.edu OI Gottesfeld, Joel/0000-0002-4643-5777 NR 6 TC 4 Z9 4 U1 0 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 21 PY 2014 VL 289 IS 8 BP 4553 EP 4554 DI 10.1074/jbc.R113.543652 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB2FF UT WOS:000331607900002 PM 24362035 ER PT J AU Harding, J Mirochnitchenko, O AF Harding, John Mirochnitchenko, Oleg TI Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review DE Animal Models; Differentiation; Induced Pluripotent Stem Cell (iPSC); Regenerative Medicine; Stem Cells ID HUMAN IPS CELLS; HEPATOCYTE-LIKE CELLS; SOMATIC-CELLS; MYOCARDIAL-INFARCTION; FUNCTIONAL RECOVERY; DNA METHYLATION; SUICIDE GENE; BETA-CELLS; DIFFERENTIATION; GENERATION AB Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions. C1 [Harding, John; Mirochnitchenko, Oleg] NIH, Div Comparat Med, Off Res Infrastruct Programs,Off Director, Div Program Coordinat Planning & Strateg Initiat, Bethesda, MD 20892 USA. RP Mirochnitchenko, O (reprint author), NIH, Div Comparat Med, Off Res Infrastruct Programs,Off Director, Div Program Coordinat Planning & Strateg Initiat, Bethesda, MD 20892 USA. EM oleg.mirochnitchenko@nih.gov NR 99 TC 17 Z9 17 U1 3 U2 29 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 21 PY 2014 VL 289 IS 8 BP 4585 EP 4593 DI 10.1074/jbc.R113.463737 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB2FF UT WOS:000331607900007 PM 24362021 ER PT J AU Qi, SQ O'Hayre, M Gutkind, JS Hurley, JH AF Qi, Shiqian O'Hayre, Morgan Gutkind, J. Silvio Hurley, James H. TI Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 ( ARRDC3)* SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Arrestin; Isothermal Titration Calorimetry; Protein Crystallization; Ubiquitin; Ubiquitin Ligase ID EPITHELIAL NA+ CHANNEL; WW DOMAIN; RECEPTOR TRAFFICKING; COUPLED RECEPTORS; PY MOTIF; NEDD4; COMPLEX; ENDOCYTOSIS; ENAC; REFINEMENT AB Background: ARRDC proteins bind ubiquitin ligases and are involved in receptor down-regulation. Results: ARRDC3 recruitment of Nedd4 is explained. Conclusion: The first PPXY motif of ARRDC3 binds to the third WW domain of Nedd4 with high affinity, whereas other domains also contribute. Significance: The structure explains aspects of high affinity recognition. After protracted stimulation, the 2-adrenergic receptor and many other G-protein-coupled receptors are ubiquitinated and down-regulated. Arrestin-related domain-containing protein-3 (ARRDC3) has been proposed to recruit the ubiquitin ligase Nedd4 to the 2-adrenergic receptor. ARRDC3 contains two PPXY motifs that could potentially interact with any of the four WW domains of Nedd4. Here we dissect the interaction determinants. ARRDC3 PPXY-Nedd4 WW dissociation constants vary from unmeasurable to K-d = 3 m for the third WW domain of Nedd4 binding to the first PPXY motif of ARRDC3. Structures of the uncomplexed and PPXY1-bound WW3 domain were determined at 1.1 and 1.7 resolution. The structures revealed conformational changes upon binding and the hydrogen bonding network in exquisite detail. Tight packing of ARRDC3 Val-352, part of a 3(10) helix at the C terminus of PPXY1, is important for high affinity binding to WW3. Although no single WW domain is strictly essential for the binding of Nedd4 and ARRDC3 expressed in HEK293 cells, high affinity binding of full-length ARRDC3 and Nedd4 is driven by the avid interaction of both PPXY motifs with either the WW2-WW3 or WW3-WW4 combinations, with K-d values as low as 300 nm. C1 [Qi, Shiqian; Hurley, James H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Qi, Shiqian; Hurley, James H.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [O'Hayre, Morgan; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM jimhurley@berkeley.edu RI Qi, Shiqian/P-9177-2014 FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; United States Department of Energy [DE-AC02-06CH11357] FX We thank J. Martin-Serrano and F. Bouamr for DNA constructs. We thank M. Ragusa for experimental advice. Crystallographic data were collected at the SE Regional Collaborative Access Team 22-ID and 22-BM beamlines at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract W-31-109-Eng-38 and was supported by the United States Department of Energy Contract DE-AC02-06CH11357. NR 36 TC 15 Z9 16 U1 2 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 21 PY 2014 VL 289 IS 8 BP 4743 EP 4752 DI 10.1074/jbc.M113.527473 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB2FF UT WOS:000331607900021 PM 24379409 ER PT J AU Wang, YZ Xu, WP Zhou, DJ Neckers, L Chen, SA AF Wang, Yuanzhong Xu, Wanping Zhou, Dujin Neckers, Len Chen, Shiuan TI Coordinated Regulation of Serum-andGlucocorticoid- inducible Kinase 3 by a C- terminal Hydrophobic Motif and Hsp90-Cdc37 Chaperone Complex* SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Hsp90; Molecular Chaperone; PI 3-Kinase (PI3K); Protein Stability; Ubiquitination; CHIP; Cdc37; SGK3; Hydrophobic Motif ID GLUCOCORTICOID-INDUCED KINASE-1; BREAST-CANCER; LIGASE CHIP; DEGRADATION; HSP90; AKT; PATHWAY; CISK; PHOSPHORYLATION; IDENTIFICATION AB Background: Serum- and glucocorticoid-inducible kinase 3 (SGK3) plays a pivotal role in Akt-independent oncogenic signaling. Results: Hsp90-Cdc37 chaperone complex acts in concert with the hydrophobic motif of SGK3 to regulate SGK3 stability and activation. Conclusion: Hsp90-Cdc37 complex is essential for SGK3 stability and activation. Significance: The involvement of Hsp90-Cdc37 in SGK3 regulation provides a rationale for Hsp90 inhibition in treating SGK3-dependent cancers. Serum- and glucocorticoid-inducible kinase 3 (SGK3) mediates a variety of cellular processes including membrane transport, cell proliferation, and survival, and it has been implicated in Akt-independent signaling downstream of oncogenic PIK3CA mutations (activating mutations in the catalytic subunit of PI3K) in human cancers. However, the regulation of SGK3 is poorly understood. Here we report that SGK3 stability and kinase activation are regulated by the Hsp90-Cdc37 chaperone complex. Hsp90-Cdc37 associates with the kinase domain of SGK3 and acts in concert with a C-terminal hydrophobic motif of SGK3 to prevent Hsp70 association and ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein)-mediated degradation. Phosphorylation of hydrophobic motif triggers release of Cdc37 and concomitant association of 3-phosphoinositide dependent kinase 1 (PDK1) to activate SGK3. Our study provides new insights into regulation of SGK3 stability and activation and the rationale for application of Hsp90 inhibitors in treating SGK3-dependent cancers. C1 [Wang, Yuanzhong; Zhou, Dujin; Chen, Shiuan] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Biol, Duarte, CA 91010 USA. [Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, SA (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Biol, Duarte, CA 91010 USA. EM schen@coh.org FU National Institutes of Health Grant [CA44735]; Carr Baird grant; Hope Idol; ThinkCure grant FX This work was supported, in whole or in part, by National Institutes of Health Grant CA44735 (to S. C.). This work was also supported by a Carr Baird grant (to Y. W.) and by Hope Idol 2012 (to S. C.) and a ThinkCure grant (to S. C.). NR 34 TC 7 Z9 8 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 21 PY 2014 VL 289 IS 8 BP 4815 EP 4826 DI 10.1074/jbc.M113.518480 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB2FF UT WOS:000331607900029 PM 24379398 ER PT J AU Zanusso, G Fiorini, M Ferrari, S Meade-White, K Barbieri, I Brocchi, E Ghetti, B Monaco, S AF Zanusso, Gianluigi Fiorini, Michele Ferrari, Sergio Meade-White, Kimberly Barbieri, Ilaria Brocchi, Emiliana Ghetti, Bernardino Monaco, Salvatore TI Gerstmann-Str ussler-Scheinker Disease and "Anchorless Prion Protein" Mice Share Prion Conformational Properties Diverging from Sporadic Creutzfeldt-Jakob Disease* SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Amyloid; Glycosyl Phosphatidylinositol Anchors; Neurodegenerative Diseases; Prions; Transgenic Mice ID TRUNCATED FORMS; PHOSPHOLIPASE-C; HUMAN URINE; SCRAPIE; PHENOTYPE; IDENTIFICATION; AMYLOIDOSIS; ANTIBODIES; ISOFORMS; VARIANT AB Background: Prion strains exhibit distinct physical and biochemical repertoires, aggregation propensity, and biological properties. Results: A biochemical approach is developed for defining the conformational features of prions with or without glycosylphosphatidylinositol (GPI)-anchor. Conclusion: GPI anchorless prions are detected in human genetic prion diseases, but not in sporadic forms. Significance: Unveiling the structure of GPI anchorless prions to predict pathological properties. The role of the GPI-anchor in prion disease pathogenesis is still a challenging issue. In vitro studies have shown that anchorless cellular prion protein (PrPC) undergoes aberrant post-translational processing and metabolism. Moreover, transgenic (Tg) mice overexpressing anchorless PrPC develop a spontaneous neurological disease accompanied with widespread brain PrP amyloid deposition, in the absence of spongiform changes. Generation of PrP forms lacking the GPI and PrP amyloidosis are striking features of human stop codon mutations in the PrP gene (PRNP), associated with PrP cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Straussler-Scheinker (GSS) syndrome. More recently, the presence of anchorless PrP species has been also claimed in sporadic Creutzfeldt-Jakob disease (sCJD). Using a highly sensitive protein separation technique and taking advantage of reference maps of synthetic PrP peptides, we investigated brain tissues from scrapie-infected anchorless PrP Tg mice and wild type mice to determine the contribution of the GPI-anchor to the molecular mass and isoelectric point of PrP quasispecies under two-dimensional electrophoresis. We also assessed the conformational properties of anchorless and anchored prions under standard and inactivating conditions. These studies were extended to sCJD and GSS. At variance with GSS, characterization of PrP quasispecies in different sCJD subtypes ruled out the presence of anchorless prions. Moreover, under inactivating conditions, mice anchorless prions, but not sCJD prions, generated internal PrP fragments, cleaved at both N and C termini, similar to those found in PrP-CAA and GSS brain tissues. These findings show that anchorless PrPSc generates GSS-like PrP fragments, and suggest a major role for unanchored PrP in amyloidogenesis. C1 [Zanusso, Gianluigi; Fiorini, Michele; Ferrari, Sergio; Monaco, Salvatore] Univ Verona, Dept Neurol & Movement Sci, I-37134 Verona, Italy. [Meade-White, Kimberly] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Barbieri, Ilaria; Brocchi, Emiliana] Ist Zooprofilatt Sperimentale Lombardia & Emilia, I-25124 Brescia, Italy. [Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. RP Zanusso, G (reprint author), Univ Verona, Dept Neurol & Movement Sci, I-37134 Verona, Italy. EM gianluigi.zanusso@univr.it; salvatore.monaco@univr.it OI ZANUSSO, Gianluigi/0000-0001-5199-6264 FU "Disabilita cognitiva e comportamentale nelle demenze e nelle psicosi" from Fondazione Cariverona; [RF2009-1474758] FX This work was supported in part by RF2009-1474758 (to G. Z.) and by "Disabilita cognitiva e comportamentale nelle demenze e nelle psicosi" from Fondazione Cariverona (to S. M.). NR 30 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 21 PY 2014 VL 289 IS 8 BP 4870 EP 4881 DI 10.1074/jbc.M113.531335 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB2FF UT WOS:000331607900034 PM 24398683 ER PT J AU Lee, M Chang, J Chang, S Lee, KS Rhee, K AF Lee, Miseon Chang, Jaerak Chang, Sunghoe Lee, Kyung S. Rhee, Kunsoo TI Asymmetric spindle pole formation in CPAP-depleted mitotic cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Spindle pole; CPAP; Centriole maturation; Asymmetric cell division ID PERICENTRIOLAR MATERIAL PROTEINS; CENTROSOME DUPLICATION; C-ELEGANS; PROCENTRIOLE FORMATION; CENTRIOLE DUPLICATION; CYCLE; SAS-4; RECRUITMENT; STIL; SIZE AB CPAP is an essential component for centriole formation. Here, we report that CPAP is also critical for symmetric spindle pole formation during mitosis. We observed that pericentriolar material between the mitotic spindle poles were asymmetrically distributed in CPAP-depleted cells even with intact numbers of centrioles. The length of procentrioles was slightly reduced by CPAP depletion, but the length of mother centrioles was not affected. Surprisingly, the young mother centrioles of the CPAP-depleted cells are not fully matured, as evidenced by the absence of distal and subdistal appendage proteins. We propose that the selective absence of centriolar appendages at the young mother centrioles may be responsible for asymmetric spindle pole formation in CPAP-depleted cells. Our results suggest that the neural stem cells with CPAP mutations might form asymmetric spindle poles, which results in premature initiation of differentiation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lee, Miseon; Chang, Jaerak; Rhee, Kunsoo] Seoul Natl Univ, Dept Biol Sci, Seoul 151747, South Korea. [Chang, Sunghoe] Seoul Natl Univ, Dept Physiol & Biomed Sci, Seoul 151747, South Korea. [Lee, Kyung S.] NCI, NIH, Bethesda, MD 20892 USA. RP Rhee, K (reprint author), Seoul Natl Univ, Dept Biol Sci, Seoul 151747, South Korea. EM rheek@snu.ac.kr FU BioImaging Research Center at GIST; Basic Research Program [2012R1A2 A201003512]; Science Research Center Program of the Ministry of Education, Science and Technology [2011-0006425]; BK-Plus Project FX This study was supported by grants from the BioImaging Research Center at GIST; the Basic Research Program (2012R1A2 A201003512); the Science Research Center Program (Grant No. 2011-0006425) of the Ministry of Education, Science and Technology. M. Lee is supported by the BK-Plus Project. NR 30 TC 1 Z9 1 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 21 PY 2014 VL 444 IS 4 BP 644 EP 650 DI 10.1016/j.bbrc.2014.01.129 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AC3PG UT WOS:000332433100034 PM 24491538 ER PT J AU Islami, F Nasseri-Moghaddam, S Pourshams, A Poustchi, H Semnani, S Kamangar, F Etemadi, A Merat, S Khoshnia, M Dawsey, SM Pharoah, PD Brennan, P Abnet, CC Boffetta, P Malekzadeh, R AF Islami, Farhad Nasseri-Moghaddam, Siavosh Pourshams, Akram Poustchi, Hossein Semnani, Shahryar Kamangar, Farin Etemadi, Arash Merat, Shahin Khoshnia, Masoud Dawsey, Sanford M. Pharoah, Paul D. Brennan, Paul Abnet, Christian C. Boffetta, Paolo Malekzadeh, Reza TI Determinants of Gastroesophageal Reflux Disease, Including Hookah Smoking and Opium Use- A Cross-Sectional Analysis of 50,000 Individuals SO PLOS ONE LA English DT Article ID LIFE-STYLE FACTORS; BODY-MASS INDEX; GENERAL-POPULATION; RISK-FACTORS; BARRETTS-ESOPHAGUS; WATERPIPE TOBACCO; GASTROINTESTINAL SYMPTOMS; SOCIOECONOMIC-STATUS; EROSIVE ESOPHAGITIS; CARCINOGEN EXPOSURE AB Background:Gastroesophageal reflux disease (GERD) is a common cause of discomfort and morbidity worldwide. However, information on determinants of GERD from large-scale studies in low- to medium-income countries is limited. We investigated the factors associated with different measures of GERD symptoms, including frequency, patient-perceived severity, and onset time. Methods: We performed a cross-sectional analysis of the baseline data from a population-based cohort study of,50,000 individuals in in Golestan Province, Iran. GERD symptoms in this study included regurgitation and/or heartburn. Results: Approximately 20% of participants reported at least weekly symptoms. Daily symptoms were less commonly reported by men, those of Turkmen ethnicity, and nass chewers. On the other hand, age, body mass index, alcohol drinking, cigarette smoking, opium use, lower socioeconomic status, and lower physical activity were associated with daily symptoms. Most of these factors showed similar associations with severe symptoms. Women with higher BMI and waist to hip ratio were more likely to report frequent and severe GERD symptoms. Hookah smoking (OR 1.34, 95% CI 1.02-1.75) and opium use (OR 1.70, 95% CI 1.55-1.87) were associated with severe symptoms, whereas nass chewing had an inverse association (OR 0.87, 95% CI 0.76-0.99). After exclusion of cigarette smokers, hookah smoking was still positively associated and nass chewing was inversely associated with GERD symptoms (all frequencies combined). Conclusion: GERD is common in this population. The associations of hookah and opium use and inverse association of nass use with GERD symptoms are reported for the first time. Further studies are required to investigate the nature of these associations. Other determinants of GERD were mostly comparable to those reported elsewhere. C1 [Islami, Farhad; Nasseri-Moghaddam, Siavosh; Pourshams, Akram; Poustchi, Hossein; Kamangar, Farin; Etemadi, Arash; Merat, Shahin; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY USA. [Semnani, Shahryar; Khoshnia, Masoud] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Etemadi, Arash; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Islami, F (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Digest Oncol Res Ctr, Tehran, Iran. EM farhad.islami@mssm.edu; sianasseri@yahoo.com RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Semnani, Shahryar/N-2270-2016; Khoshnia, Masoud/P-5665-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Semnani, Shahryar/0000-0002-8768-6142; Khoshnia, Masoud/0000-0001-7352-8058; Malekzadeh, Reza/0000-0003-1043-3814 FU Tehran University of Medical Sciences [81/15]; Cancer Research UK [C20/A5860]; Intramural Research Program of the US National Cancer Institute; International Agency for Research on Cancer FX The Golestan Cohort Study was supported by Tehran University of Medical Sciences (grant No: 81/15), Cancer Research UK (grant No: C20/A5860), the Intramural Research Program of the US National Cancer Institute, and various collaborative research agreements with the International Agency for Research on Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 4 Z9 5 U1 0 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 FEB 21 PY 2014 VL 9 IS 2 AR e89256 DI 10.1371/journal.pone.0089256 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3VI UT WOS:000331717900072 PM 24586635 ER PT J AU Trachtenberg, S Schuck, P Phillips, TM Andrews, SB Leapman, RD AF Trachtenberg, Shlomo Schuck, Peter Phillips, Terry M. Andrews, S. Brian Leapman, Richard D. TI A Structural Framework for a Near-Minimal Form of Life: Mass and Compositional Analysis of the Helical Mollicute Spiroplasma melliferum BC3 SO PLOS ONE LA English DT Article ID BACTERIAL LINEAR MOTOR; VECTOR CIRCULIFER-HAEMATOCEPS; CORN STUNT DISEASE; CRYOELECTRON TOMOGRAPHY; ELECTRON-MICROSCOPY; SYNTHETIC BIOLOGY; MYCOPLASMA-PNEUMONIAE; PHYLOGENETIC ANALYSIS; LEAFHOPPER VECTOR; IMAGE-ANALYSIS AB Spiroplasma melliferum is a wall-less bacterium with dynamic helical geometry. This organism is geometrically well defined and internally well ordered, and has an exceedingly small genome. Individual cells are chemotactic, polar, and swim actively. Their dynamic helicity can be traced at the molecular level to a highly ordered linear motor (composed essentially of the proteins fib and MreB) that is positioned on a defined helical line along the internal face of the cell's membrane. Using an array of complementary, informationally overlapping approaches, we have taken advantage of this uniquely simple, near-minimal life-form and its helical geometry to analyze the copy numbers of Spiroplasma's essential parts, as well as to elucidate how these components are spatially organized to subserve the whole living cell. Scanning transmission electron microscopy (STEM) was used to measure the mass-per-length and mass-per-area of whole cells, membrane fractions, intact cytoskeletons and cytoskeletal components. These local data were fit into whole-cell geometric parameters determined by a variety of light microscopy modalities. Hydrodynamic data obtained by analytical ultracentrifugation allowed computation of the hydration state of whole living cells, for which the relative amounts of protein, lipid, carbohydrate, DNA, and RNA were also estimated analytically. Finally, ribosome and RNA content, genome size and gene expression were also estimated (using stereology, spectroscopy and 2D-gel analysis, respectively). Taken together, the results provide a general framework for a minimal inventory and arrangement of the major cellular components needed to support life. C1 [Trachtenberg, Shlomo] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Microbiol & Mol Genet, IL-91010 Jerusalem, Israel. [Andrews, S. Brian] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Schuck, Peter; Phillips, Terry M.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Trachtenberg, S (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Microbiol & Mol Genet, IL-91010 Jerusalem, Israel. EM shlomot@ekmd.huji.ac.il OI Schuck, Peter/0000-0002-8859-6966 FU Israel Science Foundation (ISF); US-Israel Science Foundation (BSF); Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH), USA FX This research was supported by funds from the Israel Science Foundation (ISF) and US-Israel Science Foundation (BSF) and in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 3 Z9 3 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 21 PY 2014 VL 9 IS 2 AR e87921 DI 10.1371/journal.pone.0087921 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3VI UT WOS:000331717900015 PM 24586297 ER PT J AU van der Straten, A Stadler, J Montgomery, E Hartmann, M Magazi, B Mathebula, F Schwartz, K Laborde, N Soto-Torres, L AF van der Straten, Ariane Stadler, Jonathan Montgomery, Elizabeth Hartmann, Miriam Magazi, Busiswe Mathebula, Florence Schwartz, Katie Laborde, Nicole Soto-Torres, Lydia TI Women's Experiences with Oral and Vaginal Pre-Exposure Prophylaxis: The VOICE-C Qualitative Study in Johannesburg, South Africa SO PLOS ONE LA English DT Article ID HIV PREVENTION; MICROBICIDE ACCEPTABILITY; TREATMENT ADHERENCE; CLINICAL-TRIAL; GEL; INTERVENTION; MOTIVATION; ZIMBABWE; SUPPORT; BARRIER AB Background: In VOICE, a multisite HIV pre-exposure prophylaxis (PrEP) trial, plasma drug levels pointed to widespread product nonuse, despite high adherence estimated by self-reports and clinic product counts. Using a socio-ecological framework (SEF), we explored socio-cultural and contextual factors that influenced participants' experience of daily vaginal gel and oral tablet regimens in VOICE. Methods: In Johannesburg, a qualitative ancillary study was concurrently conducted among randomly selected VOICE participants assigned to in-depth interviews (n = 41), serial ethnographic interviews (n = 21), or focus group discussions (n = 40). Audiotaped interviews were transcribed, translated, and coded thematically for analysis. Results: Of the 102 participants, the mean age was 27 years, and 96% had a primary sex partner with whom 43% cohabitated. Few women reported lasting nonuse, which they typically attributed to missed visits, lack of product replenishments, and family-related travel or work. Women acknowledged occasionally skipping or mistiming doses because they forgot, were busy, felt lazy or bored, feared or experienced side effects. However, nearly all knew or heard of other study participants who did not use products daily. Three overarching themes emerged from further analyses: ambivalence toward research, preserving a healthy status, and managing social relationships. These themes highlighted the profound and complex meanings associated with participating in a blinded HIV PrEP trial and taking antiretroviral-based products. The unknown efficacy of products, their connection with HIV infection, challenges with daily regimen given social risks, lack of support-from partners and significant others-and the relationship tradeoffs entailed by using the products appear to discourage adequate product use. Conclusions: Personal acknowledgment of product nonuse was challenging. This qualitative inquiry highlighted key influences at all SEF levels that shaped women's perceptions of trial participation and experiences with investigational products. Whether these impacted women's behaviors and may have contributed to ineffective trial results warrants further investigation. C1 [van der Straten, Ariane; Montgomery, Elizabeth; Hartmann, Miriam; Laborde, Nicole] RTI Int, Womens Global Hlth Imperat, San Francisco, CA 94104 USA. [van der Straten, Ariane] UCSF, Dept Med, Ctr AIDS Prevent Studies, San Francisco, CA USA. [Stadler, Jonathan; Magazi, Busiswe; Mathebula, Florence] Univ Witwatersrand, Sch Clin Med, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Soto-Torres, Lydia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP van der Straten, A (reprint author), RTI Int, Womens Global Hlth Imperat, San Francisco, CA 94104 USA. EM ariane@rti.org FU Microbicide Trials Network (MTN) grant; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; U.S. National Institutes of Health (NIH) [5UM1AI068633] FX This study was funded by the Microbicide Trials Network (MTN) grant, an HIV/AIDS clinical trials network funded by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH) (5UM1AI068633). This cooperative agreement involved the active collaboration of the sponsor, NIH, with the grant recipients within the MTN. One NIH employee is co-author on this paper. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 49 Z9 49 U1 2 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 21 PY 2014 VL 9 IS 2 AR e89118 DI 10.1371/journal.pone.0089118 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3VI UT WOS:000331717900054 PM 24586534 ER PT J AU Mueller, CM Korde, LA McMaster, ML Peters, JA Bratslavsky, G Watkins, RJ Ling, A Kratz, CP Wulfsberg, EA Rosenberg, PS Greene, MH AF Mueller, Christine M. Korde, Larissa A. McMaster, Mary L. Peters, June A. Bratslavsky, Gennady Watkins, Rissah J. Ling, Alex Kratz, Christian P. Wulfsberg, Eric A. Rosenberg, Philip S. Greene, Mark H. TI Familial testicular germ cell tumor: no associated syndromic pattern identified SO HEREDITARY CANCER IN CLINICAL PRACTICE LA English DT Article DE Familial testicular cancer; Dysmorphology; Developmental anomalies ID MORPHOLOGICAL ABNORMALITIES; SUSCEPTIBILITY LOCI; DYSGENESIS SYNDROME; CANCER; MEN; PREVALENCE; VARIANTS; DMRT1; CRYPTORCHIDISM; EPIDEMIOLOGY AB Background: Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT. Methods: We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies. Results: The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected. Conclusions: Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility. C1 [Mueller, Christine M.; Peters, June A.; Kratz, Christian P.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Korde, Larissa A.] Univ Washington, Seattle Canc Care Alliance, Div Med Oncol, Seattle, WA 98195 USA. [McMaster, Mary L.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] NCI, Urol Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Watkins, Rissah J.] Westat Corp, Rockville, MD USA. [Ling, Alex] NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Wulfsberg, Eric A.] Univ Maryland, Sch Med, Dept Pediat, Div Human Genet, Baltimore, MD 21201 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Greene, MH (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM greenem@mail.nih.gov FU National Cancer Institute Intramural Research Program; Westat Inc., Rockville MD [NO2-CP-11019-50, NO2-CP-65504-50] FX We acknowledge the contributions and support of Dr Marston Linehan, Dr Ahalya Premkumar, Susan Pfeiffer, and Jennifer Loud to the CGB Familial Testicular Cancer study. We also offer special thanks to our study participants, whose personal commitment has made this research possible. This work was supported by funding from the National Cancer Institute Intramural Research Program and by support services contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat Inc., Rockville MD. NR 43 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1731-2302 EI 1897-4287 J9 HERED CANCER CLIN PR JI Hered. Cancer Clin. Pract. PD FEB 21 PY 2014 VL 12 AR 3 DI 10.1186/1897-4287-12-3 PG 7 WC Oncology SC Oncology GA AB8AK UT WOS:000332012300002 PM 24559313 ER PT J AU Hyman, DM Eaton, AA Gounder, MM Smith, GL Pamer, EG Hensley, ML Spriggs, DR Ivy, P Iasonos, A AF Hyman, David M. Eaton, Anne A. Gounder, Mrinal M. Smith, Gary L. Pamer, Erika G. Hensley, Martee L. Spriggs, David R. Ivy, Percy Iasonos, Alexia TI Nomogram to Predict Cycle-One Serious Drug-Related Toxicity in Phase I Oncology Trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NATIONAL-CANCER-INSTITUTE; CLINICAL-TRIALS; PROGNOSTIC MODELS; CENTER EXPERIENCE; VALIDATION; PROGRAM; AGENTS; SCORE; RISK AB Purpose All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials. Patients and Methods The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program-sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade 4 hematologic or grade 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set. Results Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64). Conclusion This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials. (C) 2014 by American Society of Clinical Oncology C1 [Hyman, David M.; Eaton, Anne A.; Gounder, Mrinal M.; Pamer, Erika G.; Hensley, Martee L.; Spriggs, David R.; Iasonos, Alexia] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Hyman, David M.; Gounder, Mrinal M.; Hensley, Martee L.; Spriggs, David R.; Iasonos, Alexia] Weill Cornell Med Coll, New York, NY USA. [Hyman, David M.; Gounder, Mrinal M.; Hensley, Martee L.; Spriggs, David R.; Iasonos, Alexia] Weill Cornell Med Coll, New York, NY USA. [Smith, Gary L.; Ivy, Percy] NCI, Bethesda, MD 20892 USA. RP Hyman, DM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM hymand@mskcc.org FU NCI NIH HHS [P30 CA008748] NR 20 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2014 VL 32 IS 6 BP 519 EP + DI 10.1200/JCO.2013.49.8808 PG 12 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900010 PM 24419130 ER PT J AU Palumbo, A Rajkumar, SV San Miguel, JF Larocca, A Niesvizky, R Morgan, G Landgren, O Hajek, R Einsele, H Anderson, KC Dimopoulos, MA Richardson, PG Cavo, M Spencer, A Stewart, AK Shimizu, K Lonial, S Sonneveld, P Durie, BGM Moreau, P Orlowski, RZ AF Palumbo, Antonio Rajkumar, S. Vincent San Miguel, Jesus F. Larocca, Alessandra Niesvizky, Ruben Morgan, Gareth Landgren, Ola Hajek, Roman Einsele, Hermann Anderson, Kenneth C. Dimopoulos, Meletios A. Richardson, Paul G. Cavo, Michele Spencer, Andrew Stewart, A. Keith Shimizu, Kazuyuki Lonial, Sagar Sonneveld, Pieter Durie, Brian G. M. Moreau, Philippe Orlowski, Robert Z. TI International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; RANDOMIZED CONTROLLED-TRIAL; LENALIDOMIDE PLUS DEXAMETHASONE; IMPAIRED RENAL-FUNCTION; BORTEZOMIB-MELPHALAN-PREDNISONE; NEUROPATHIC CANCER PAIN; ELDERLY-PATIENTS; PERIPHERAL NEUROPATHY; ZOLEDRONIC ACID; BONE-DISEASE AB Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice. (C) 2014 by American Society of Clinical Oncology C1 [Palumbo, Antonio; Larocca, Alessandra] Univ Turin, I-10126 Turin, Italy. [Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Rajkumar, S. Vincent] Mayo Clin, Rochester, MN USA. [San Miguel, Jesus F.] Univ Hosp Salamanca, Salamanca, Spain. [Niesvizky, Ruben] Weill Cornell Med Coll, New York, NY USA. [Morgan, Gareth] Royal Marsden Hosp, London SW3 6JJ, England. [Landgren, Ola] NCI, Bethesda, MD 20892 USA. [Hajek, Roman] Univ Ostrava, Sch Med, CZ-70103 Ostrava, Czech Republic. [Hajek, Roman] Univ Hosp Ostrava, Ostrava, Czech Republic. [Einsele, Hermann] Univ Wurzburg, D-97070 Wurzburg, Germany. [Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Spencer, Andrew] Alfred Hosp, Melbourne, Vic, Australia. [Stewart, A. Keith] Mayo Clin, Scottsdale, AZ USA. [Shimizu, Kazuyuki] Aichi Gakuin Hosp, Nagoya, Aichi, Japan. [Lonial, Sagar] Emory Univ, Atlanta, GA 30322 USA. [Sonneveld, Pieter] Erasmus MC, Rotterdam, Netherlands. [Durie, Brian G. M.] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. [Moreau, Philippe] Univ Hosp, Nantes, France. [Orlowski, Robert Z.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Palumbo, A (reprint author), Univ Turin, Dept Hematol, Via Genova 3, I-10126 Turin, Italy. EM appalumbo@yahoo.com RI richard, chrystelle/K-8595-2015; OI SAN MIGUEL, JESUS/0000-0002-9183-4857; CAVO, MICHELE/0000-0003-4514-3227 FU Onyx Pharmaceuticals; Millennium Pharmaceuticals; Celgene; Janssen-Cilag; Daiichi Sankyo; Bristol-Myers Squibb FX Research Funding: Ruben Niesvizky, Onyx Pharmaceuticals, Millennium Pharmaceuticals, Celgene; Hermann Einsele, Celgene, Janssen-Cilag; Meletios A. Dimopoulos, Celgene; Kazuyuki Shimizu, Daiichi Sankyo; Pieter Sonneveld, Celgene, Janssen-Cilag, Onyx Pharmaceuticals; Robert Z. Orlowski, Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Bristol-Myers Squibb NR 122 TC 84 Z9 88 U1 1 U2 11 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 FEB 20 PY 2014 VL 32 IS 6 BP 587 EP + DI 10.1200/JCO.2013.48.7934 PG 17 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900019 PM 24419113 ER PT J AU Swain, SM Tang, G Geyer, CE AF Swain, Sandra M. Tang, Gong Geyer, Charles E., Jr. TI Reply to EJ Moylan et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID POSITIVE BREAST-CANCER; CHEMOTHERAPY; WOMEN C1 [Swain, Sandra M.] Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15212 USA. [Swain, Sandra M.] Medstar Washington Hosp Ctr, Washington, DC USA. [Tang, Gong] NSABP Biostatist Ctr, Pittsburgh, PA USA. [Tang, Gong] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Geyer, Charles E., Jr.] NSABP, Pittsburgh, PA USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Richmond, VA USA. RP Swain, SM (reprint author), Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA 15212 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 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 FEB 20 PY 2014 VL 32 IS 6 BP 606 EP 607 DI 10.1200/JCO.2013.53.8744 PG 2 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900025 PM 24419136 ER PT J AU Salaverria, I Martin-Guerrero, I Wagener, R Kreuz, M Kohler, CW Richter, J Pienkowska-Grela, B Adam, P Burkhardt, B Claviez, A Damm-Welk, C Drexler, HG Hummel, M Jaffe, ES Kuppers, R Lefebvre, C Lisfeld, J Loffler, M Macleod, RAF Nagel, I Oschlies, I Rosolowski, M Russell, RB Rymkiewicz, G Schindler, D Schlesner, M Scholtysik, R Schwaenen, C Spang, R Szczepanowski, M Trumper, L Vater, I Wessendorf, S Klapper, W Siebert, R AF Salaverria, Itziar Martin-Guerrero, Idoia Wagener, Rabea Kreuz, Markus Kohler, Christian W. Richter, Julia Pienkowska-Grela, Barbara Adam, Patrick Burkhardt, Birgit Claviez, Alexander Damm-Welk, Christine Drexler, Hans G. Hummel, Michael Jaffe, Elaine S. Kueppers, Ralf Lefebvre, Christine Lisfeld, Jasmin Loeffler, Markus Macleod, Roderick A. F. Nagel, Inga Oschlies, Ilske Rosolowski, Maciej Russell, Robert B. Rymkiewicz, Grzegorz Schindler, Detlev Schlesner, Matthias Scholtysik, Rene Schwaenen, Carsten Spang, Rainer Szczepanowski, Monika Truemper, Lorenz Vater, Inga Wessendorf, Swen Klapper, Wolfram Siebert, Reiner CA Non-Hodgkin Lymphoma Grp Molecular Mech Malignant Lymphoma Berlin-Frankfurt-Munster TI A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; FOLLICULAR LYMPHOMAS; TUMOR-SUPPRESSOR; GENE; MUTATIONS; GENOME; HYBRIDIZATION; ABNORMALITIES; DEREGULATION; PATHOGENESIS AB The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q. C1 [Salaverria, Itziar; Martin-Guerrero, Idoia; Wagener, Rabea; Richter, Julia; Nagel, Inga; Vater, Inga; Siebert, Reiner] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein, Kiel, Germany. [Salaverria, Itziar] Univ Barcelona, Dept Pathol, Hematopathol Unit, Hosp Clin,Inst Invest Biomed Augus Pi & Sunyer, Barcelona, Spain. [Martin-Guerrero, Idoia] Univ Basque Country, Univ Pais Vasco, Euskal Herriko Univ, Dept Genet Phys Anthropol & Anim Physiol, Leioa, Spain. [Kreuz, Markus; Loeffler, Markus; Rosolowski, Maciej] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Kohler, Christian W.; Spang, Rainer] Univ Regensburg, Inst Funct Genom, D-93053 Regensburg, Germany. [Pienkowska-Grela, Barbara] Maria Sklodowska Curie Mem Inst & Oncol Ctr, Dept Pathol, Cytogenet Lab, Warsaw, Poland. [Adam, Patrick] Univ Tubingen, Inst Pathol, Tubingen, Germany. [Burkhardt, Birgit] Univ Childrens Hosp, Non Hodgkin Lymphoma Berlin Frankfurt Munster Stu, Munster, Germany. [Burkhardt, Birgit] Univ Childrens Hosp, Dept Pediat Hematol & Oncol, Munster, Germany. [Claviez, Alexander] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Pediat, Kiel, Germany. [Damm-Welk, Christine; Lisfeld, Jasmin] Univ Giessen, Non Hodgkin Lymphoma Berlin Frankfurt Munster Stu, D-35390 Giessen, Germany. [Damm-Welk, Christine; Lisfeld, Jasmin] Univ Giessen, Dept Pediat Hematol & Oncol, D-35390 Giessen, Germany. [Drexler, Hans G.; Macleod, Roderick A. F.] Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany. [Hummel, Michael] Charite, Inst Pathol, Campus Benjamin Franklin, D-13353 Berlin, Germany. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kueppers, Ralf; Scholtysik, Rene] Univ Duisburg Essen, Sch Med, Inst Cell Biol Canc Res, Essen, Germany. [Lefebvre, Christine] Inst Biol & Pathol, Dept Hematol Oncogenet & Immunol, Grenoble, France. [Oschlies, Ilske] Univ Kiel, Dept Pathol, Hematopathol Sect, Univ Hosp Schleswig Holstein, Kiel, Germany. [Oschlies, Ilske; Szczepanowski, Monika] Univ Kiel, Lymph Node Registry, Univ Hosp Schleswig Holstein, Kiel, Germany. [Russell, Robert B.] Heidelberg Univ, CellNetworks Cluster Excellence, Heidelberg, Germany. [Rymkiewicz, Grzegorz] Maria Sklodowska Curie Mem Inst & Oncol Ctr, Flow Cytometry Lab, Dept Pathol, Warsaw, Poland. [Schindler, Detlev] Univ Wurzburg, Dept Human Genet, Bioctr, Wurzburg, Germany. [Schlesner, Matthias] Deutsch Krebsforschungszentrum Heidelberg DKFZ, Div Theoret Bioinformat, Heidelberg, Germany. [Schwaenen, Carsten; Wessendorf, Swen] Klinikum Esslingen, Esslingen, Germany. [Truemper, Lorenz] Univ Gottingen, Dept Hematol & Oncol, Gottingen, Germany. RP Salaverria, I (reprint author), Univ Hosp Schleswig Holstein, Inst Human Genet, Campus Kiel,Schwanenweg 24, D-24105 Kiel, Germany. EM isalaverria@medgen.uni-kiel.de; rsiebert@medgen.uni-kiel.de RI Schlesner, Matthias/I-4030-2013; SALAVERRIA, ITZIAR/L-2246-2015; Siebert, Reiner/A-8049-2010; Klapper, Wolfram/S-6314-2016; OI Schlesner, Matthias/0000-0002-5896-4086; SALAVERRIA, ITZIAR/0000-0002-2427-9822; Jaffe, Elaine/0000-0003-4632-0301; Claviez, Alexander/0000-0002-1561-5185; Kuppers, Ralf/0000-0002-6691-7191 FU Deutsche Krebshilfe through the Network project "Molecular Mechanisms in Malignant Lymphomas" [70-3173-Tr3]; KinderKrebsInitiative Buchholz/Holm-Seppensen; International Cancer Genome Consortium MMML-Seq Project - Federal Ministry of Education and Research in Germany within the Program for Medical Genome Research [01KU1002A, 01KU1002B, 01KU1002C, 01KU1002D, 01KU1002E, 01KU1002F, 01KU1002G, 01KU1002H, 01KU1002I, 01KU1002J]; Alexander von Humboldt Foundation; Subprograma Juan de la Cierva "Ministerio de Ciencia e Innovacion" [JCI-2011-10232]; Basque Government; Christoph-Schubert-Award of the KinderKrebsInitiative Buchholz/Holm-Seppensen; Dr Werner Jackstadt Stiftung through a Junior Excellence Research Group FX This study was supported by the Deutsche Krebshilfe (70-3173-Tr3) through the Network project "Molecular Mechanisms in Malignant Lymphomas" (from 2003 to 2011); the KinderKrebsInitiative Buchholz/Holm-Seppensen (W. K., R. S.); the International Cancer Genome Consortium MMML-Seq Project funded by the Federal Ministry of Education and Research in Germany within the Program for Medical Genome Research (01KU1002A to 01KU1002J); a fellowship from the Alexander von Humboldt Foundation and the Subprograma Juan de la Cierva "Ministerio de Ciencia e Innovacion" (JCI-2011-10232) (I. S.); a grant from the Basque Government ("Ayuda del programa de perfeccionamiento postdoctoral en el extranjero del Departamento de Educacion, Universidades e Investigacion") (I.M.-G.); a Christoph-Schubert-Award of the KinderKrebsInitiative Buchholz/Holm-Seppensen (R.W.); and Dr Werner Jackstadt Stiftung through a Junior Excellence Research Group (J.R.). NR 46 TC 24 Z9 25 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 20 PY 2014 VL 123 IS 8 BP 1187 EP 1198 DI 10.1182/blood-2013-06-507996 PG 12 WC Hematology SC Hematology GA AH0VG UT WOS:000335838100018 PM 24398325 ER PT J AU Scott, DW Wright, GW Williams, PM Lih, CJ Walsh, W Jaffe, ES Rosenwald, A Campo, E Chan, WC Connors, JM Smeland, EB Mottok, A Braziel, RM Ott, G Delabie, J Tubbs, RR Cook, JR Weisenburger, DD Greiner, TC Glinsmann-Gibson, BJ Fu, K Staudt, LM Gascoyne, RD Rimsza, LM AF Scott, David W. Wright, George W. Williams, P. Mickey Lih, Chih-Jian Walsh, William Jaffe, Elaine S. Rosenwald, Andreas Campo, Elias Chan, Wing C. Connors, Joseph M. Smeland, Erlend B. Mottok, Anja Braziel, Rita M. Ott, German Delabie, Jan Tubbs, Raymond R. Cook, James R. Weisenburger, Dennis D. Greiner, Timothy C. Glinsmann-Gibson, Betty J. Fu, Kai Staudt, Louis M. Gascoyne, Randy D. Rimsza, Lisa M. TI Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue SO BLOOD LA English DT Article ID MOLECULAR CLASSIFICATION; SURVIVAL; PREDICTS; CHEMOTHERAPY; MICROARRAY; MODEL AB The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell-like or activated B cell-like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)-based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management. C1 [Scott, David W.; Connors, Joseph M.; Mottok, Anja; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Wright, George W.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Williams, P. Mickey; Lih, Chih-Jian; Walsh, William] Leidos Med Res Inc, Mol Characterizat Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Campo, Elias] Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain. [Chan, Wing C.; Greiner, Timothy C.; Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Smeland, Erlend B.] Univ Oslo, Dept Immunol, Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Ctr Canc Biomed, Oslo, Norway. [Smeland, Erlend B.; Delabie, Jan] Oslo Univ Hosp, Oslo, Norway. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Tubbs, Raymond R.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Cook, James R.] Cleveland Clin, Dept Mol Pathol & Lab Med, Cleveland, OH 44106 USA. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA USA. [Glinsmann-Gibson, Betty J.; Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. RP Rimsza, LM (reprint author), 1501 N Campbell Ave,POB 245043, Tucson, AZ 85724 USA. EM lrimsza@email.arizona.edu RI Campo, elias/O-7192-2016; OI Campo, elias/0000-0001-9850-9793; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301 FU National Cancer Institute grant [1U01CA157581-01]; Canadian Institutes of Health Research Post-Doctoral Fellowship; Mildred Scheel Cancer Foundation FX The project was funded by National Cancer Institute grant 1U01CA157581-01. D.W.S. is supported by a Canadian Institutes of Health Research Post-Doctoral Fellowship. A.M. is supported by a fellowship award by the Mildred Scheel Cancer Foundation. NR 22 TC 95 Z9 98 U1 2 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 20 PY 2014 VL 123 IS 8 BP 1214 EP 1217 DI 10.1182/blood-2013-11-536433 PG 4 WC Hematology SC Hematology GA AH0VG UT WOS:000335838100021 PM 24398326 ER PT J AU Fernandez-Vina, MA Wang, T Lee, SJ Haagenson, M Aljurf, M Askar, M Battiwalla, M Baxter-Lowe, LA Gajewski, J Jakubowski, AA Marino, S Oudshoorn, M Marsh, SGE Petersdorf, EW Schultz, K Turner, EV Waller, EK Woolfrey, A Umejiego, J Spellman, SR Setterholm, M AF Fernandez-Vina, Marcelo A. Wang, Tao Lee, Stephanie J. Haagenson, Michael Aljurf, Mahmoud Askar, Medhat Battiwalla, Minoo Baxter-Lowe, Lee-Ann Gajewski, James Jakubowski, Ann A. Marino, Susana Oudshoorn, Machteld Marsh, Steven G. E. Petersdorf, Effie W. Schultz, Kirk Turner, E. Victoria Waller, Edmund K. Woolfrey, Ann Umejiego, John Spellman, Stephen R. Setterholm, Michelle TI Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANT; VERSUS-HOST-DISEASE; UNRELATED DONOR; CLASS-I; HISTOCOMPATIBILITY ANTIGEN; UNITED-STATES; FAILURE PROBABILITIES; ACUTE GVHD; C ALLELES; GRAFT AB In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P<.0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches. C1 [Fernandez-Vina, Marcelo A.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Wang, Tao] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Lee, Stephanie J.; Petersdorf, Effie W.; Woolfrey, Ann] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Haagenson, Michael; Umejiego, John; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Aljurf, Mahmoud] King Faisal Canc Ctr, Riyadh, Saudi Arabia. [Askar, Medhat] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Battiwalla, Minoo] NHLBI, NIH, Bethesda, MD 20892 USA. [Baxter-Lowe, Lee-Ann] San Francisco Med Ctr, San Francisco, CA USA. [Gajewski, James] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Jakubowski, Ann A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Marino, Susana] Univ Chicago Med, Chicago, IL USA. [Oudshoorn, Machteld] Leiden Univ, Med Ctr, Europdonor Fdn, Leiden, Netherlands. [Marsh, Steven G. E.] Anthony Nolan Res Inst, London, England. [Marsh, Steven G. E.] UCL, London, England. [Schultz, Kirk] Univ British Columbia, British Columbia Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Turner, E. Victoria] St Jude Childrens Res Hosp, HLA Lab, Memphis, TN 38105 USA. [Waller, Edmund K.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Setterholm, Michelle] Natl Marrow Donor Program, Minneapolis, MN USA. RP Fernandez-Vina, MA (reprint author), Stanford Univ, Sch Med, Dept Pathol, 3373 Hillview Ave, Palo Alto, CA 94304 USA. EM marcelof@stanford.edu FU National Cancer Institute [U24-CA76518]; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute [5U01HL069294]; National Cancer Institute; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-10058]; Allos Inc.; Amgen Inc.; Angioblast; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America Inc.; Gamida Cell Teva Joint Venture Ltd; Genentech Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics Inc.; Kiadis Pharma The Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co. Inc.; Millennium: The Takeda Oncology Co.; Milliman USA Inc.; Miltenyi Biotec Inc.; National Marrow Donor Program; Optum Healthcare Solutions Inc.; Osiris Therapeutics Inc.; Otsuka America Pharmaceutical Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tao Pharmaceuticals; Soligenix Inc.; Stem-Cyte; A Global Cord Blood Therapeutics Co.; Stemsoft Software Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience Inc.; THERAKOS Inc.; Wellpoint Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases, Grant/Cooperative Agreement 5U01HL069294 from National Heart, Lung, and Blood Institute and National Cancer Institute, contract HHSH234200637015C with the Health Resources and Services Administration, grants N00014-06-1-0704 and N00014-08-10058 from the Office of Naval Research, and grants from Allos Inc., Amgen Inc., Angioblast, an anonymous donation to the Medical College of Wisconsin, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Buchanan Family Foundation, CaridianBCT Celgene Corporation, CellGenix GmbH, Children's Leukemia Research Association, Fresenius-Biotech North America Inc., Gamida Cell Teva Joint Venture Ltd, Genentech Inc., Genzyme Corporation, GlaxoSmithKline, HistoGenetics Inc., Kiadis Pharma The Leukemia & Lymphoma Society, The Medical College of Wisconsin, Merck & Co. Inc., Millennium: The Takeda Oncology Co., Milliman USA Inc., Miltenyi Biotec Inc., National Marrow Donor Program, Optum Healthcare Solutions Inc., Osiris Therapeutics Inc., Otsuka America Pharmaceutical Inc., RemedyMD, Sanofi, Seattle Genetics, Sigma-Tao Pharmaceuticals, Soligenix Inc., Stem-Cyte, A Global Cord Blood Therapeutics Co., Stemsoft Software Inc., Swedish Orphan Biovitrum, Tarix Pharmaceuticals, Teva Neuroscience Inc., THERAKOS Inc., and Wellpoint Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US government. NR 43 TC 34 Z9 34 U1 1 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 20 PY 2014 VL 123 IS 8 BP 1270 EP 1278 DI 10.1182/blood-2013-10-532671 PG 9 WC Hematology SC Hematology GA AH0VG UT WOS:000335838100027 PM 24408320 ER PT J AU Kim, SYH Miller, FG AF Kim, Scott Y. H. Miller, Franklin G. TI Informed Consent for Pragmatic Trials - The Integrated Consent Model SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 [Kim, Scott Y. H.; Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 33 Z9 33 U1 2 U2 4 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 FEB 20 PY 2014 VL 370 IS 8 BP 769 EP 772 DI 10.1056/NEJMhle1312508 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900014 PM 24552326 ER PT J AU Izumi, Y Kawahara, K Nonoguchi, H AF Izumi, Yuichiro Kawahara, Katsumasa Nonoguchi, Hiroshi TI Combined Angiotensin Inhibition in Diabetic Nephropathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Izumi, Yuichiro] NHLBI, Bethesda, MD 20892 USA. [Kawahara, Katsumasa] Kitasato Univ, Sch Med, Sagamihara, Kanagawa 228, Japan. [Nonoguchi, Hiroshi] Kitasato Univ, Med Ctr, Kitamoto, Japan. RP Izumi, Y (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM nono@insti.kitasato-u.ac.jp NR 3 TC 1 Z9 1 U1 1 U2 1 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 FEB 20 PY 2014 VL 370 IS 8 BP 777 EP 778 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900017 PM 24552330 ER PT J AU Gordon, DJ Lauer, MS AF Gordon, David J. Lauer, Michael S. TI Publication of Trials Funded by the National Heart, Lung, and Blood Institute REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB To the Editor: Leaning and Guha-Sapir (Nov. 7 issue)(1) do not mention one important challenge in the delivery of health care during disasters. For example, during the 2011-2012 drought in Somalia, $1.3 billion was used to provide services during a disaster that threatened approximately 3.7 million people.(2) In contrast, in Malawi, health care is provided in a continuous emergency situation. Our hospital serves 680,000 persons in inpatient and outpatient settings per year, providing therapy in a wide variety of specialties (e.g., 12,000 surgical operations) with a budget of $5.5 million. On a per capita basis, my colleagues and I could ... C1 [Gordon, David J.; Lauer, Michael S.] NHLBI, Bethesda, MD 20892 USA. RP Gordon, DJ (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov NR 0 TC 3 Z9 3 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 FEB 20 PY 2014 VL 370 IS 8 BP 782 EP 782 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900026 PM 24552337 ER PT J AU Sobral, LM Sousa, LO Coletta, RD Cabral, H Greene, LJ Tajara, EH Gutkind, JS Curti, C Leopoldino, AM AF Sobral, Lays M. Sousa, Lucas O. Coletta, Ricardo D. Cabral, Hamilton Greene, Lewis J. Tajara, Eloiza H. Gutkind, J. Silvio Curti, Carlos Leopoldino, Andreia M. TI Stable SET knockdown in head and neck squamous cell carcinoma promotes cell invasion and the mesenchymal-like phenotype in vitro, as well as necrosis, cisplatin sensitivity and lymph node metastasis in xenograft tumor models SO MOLECULAR CANCER LA English DT Article DE SET; Head and neck cancer; MMP; ERK; EMT; p53; Invasion; Cisplatin; Metastasis ID PROTEIN PHOSPHATASE 2A; BREAST-CANCER; P53; PHOSPHORYLATION; GROWTH; TRANSITION; MIGRATION; APOPTOSIS; LEUKEMIA; SURVIVAL AB Background: SET/I2PP2A is a multifunctional protein that is up-regulated in head and neck squamous cell carcinoma (HNSCC). The action of SET in HNSCC tumorigenicity is unknown. Methods: Stable SET knockdown by shRNA (shSET) was established in three HNSCC cell lines: HN12, HN13, and Cal27. Protein expression and phosphorylated protein levels were determined by Western blotting and immunofluorescence, cell migration and invasion were measured by functional analysis, and PP2A activity was determined using a serine/threonine phosphatase assay. A real-time PCR array was used to quantify 84 genes associated with cell motility. Metalloproteinase (MMP) activity was assessed by zymographic and fluorometric assays. HN12shSET xenograft tumors (flank and tongue models) were established in Balb/c nude mice; the xenograft characteristics and cisplatin sensitivity were demonstrated by macroscopic, immunohistochemical, and histological analyses, as well as lymph node metastasis by histology. Results: The HN12shSET cells displayed reduced ERK1/2 and p53 phosphorylation compared with control. ShSET reduced HN12 cell proliferation and increased the sub-G1 population of HN12 and Cal27 cells. Increased PP2A activity was also associated with shSET. The PCR array indicated up-regulation of three mRNAs in HN12 cells: vimentin, matrix metalloproteinase-9 (MMP9) and non-muscle myosin heavy chain IIB. Reduced E-cadherin and pan-cytokeratin, as well as increased vimentin, were also demonstrated as the result of SET knockdown. These changes were accompanied by an increase in MMP-9 and MMP-2 activities, migration and invasion. The HN12shSET subcutaneous xenograft tumors presented a poorly differentiated phenotype, reduced cell proliferation, and cisplatin sensitivity. An orthotopic xenograft tumor model using the HN12shSET cells displayed increased metastatic potential. Conclusions: SET accumulation has important actions in HNSCC. As an oncogene, SET promotes cell proliferation, survival, and resistance to cell death by cisplatin in vivo. As a metastasis suppressor, SET regulates invasion, the epithelial mesenchymal transition, and metastasis. C1 [Sobral, Lays M.; Leopoldino, Andreia M.] Univ Sao Paulo, Sch Pharmaceut Sci Riberiao Preto, Dept Clin Anal Toxicol & Food Sci, BR-14040903 Ribeirao Preto, SP, Brazil. [Sousa, Lucas O.; Greene, Lewis J.] Univ Sao Paulo, Sch Med, Dept Cellular & Mol Biol, BR-14040903 Ribeirao Preto, SP, Brazil. [Sousa, Lucas O.; Greene, Lewis J.] Univ Sao Paulo, Sch Med Ribeirao Preto, INCT, Ctr Cell Therapy & Hemotherapy Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil. [Coletta, Ricardo D.] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Oral Diag, Piracicaba, SP, Brazil. [Cabral, Hamilton] Univ Sao Paulo, Sch Pharmaceut Sci Riberiao Preto, Dept Pharmaceut Sci, BR-14040903 Ribeirao Preto, SP, Brazil. [Tajara, Eloiza H.] Sch Med Sao Jose do Rio Preto, Dept Mol Biol, Ribeirao Preto, SP, Brazil. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Curti, Carlos] Univ Sao Paulo, Sch Pharmaceut Sci Riberiao Preto, Dept Chem & Phys, BR-14040903 Ribeirao Preto, SP, Brazil. RP Leopoldino, AM (reprint author), Univ Sao Paulo, Sch Pharmaceut Sci Riberiao Preto, Dept Clin Anal Toxicol & Food Sci, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP, Brazil. EM andreiaml@usp.br RI Coletta, Ricardo/B-4909-2015; Sobral, Lays/G-4831-2012; Curti, Carlos/H-6982-2016 OI Coletta, Ricardo/0000-0001-5285-3046; Sobral, Lays/0000-0002-8731-850X; Curti, Carlos/0000-0001-8154-5595 FU FAPESP [2010/20384-0, 2013/10898-4, 2009/52228-0, CEPID 2013/08135-2]; CNPq, Brazil; [2010/18544-9] FX This work was supported by grants from FAPESP (research projects: 2010/20384-0, 2013/10898-4, 2009/52228-0; CEPID 2013/08135-2); fellowship 2010/18544-9 to LMS) and CNPq, Brazil. The authors thank Cristiana B. Garcia for technical assistance and Elettra Greene for English revisions. The real-time PCR equipment for our experiments was provided by Dr. Sergio A. Uyemura's laboratory. NR 46 TC 12 Z9 14 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD FEB 20 PY 2014 VL 13 AR 32 DI 10.1186/1476-4598-13-32 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AF2ID UT WOS:000334534900003 PM 24555657 ER PT J AU Lyoo, CH Zanotti-Fregonara, P Zoghbi, SS Liow, JS Xu, R Pike, VW Zarate, CA Fujita, M Innis, RB AF Lyoo, Chul Hyoung Zanotti-Fregonara, Paolo Zoghbi, Sami S. Liow, Jeih-San Xu, Rong Pike, Victor W. Zarate, Carlos A., Jr. Fujita, Masahiro Innis, Robert B. TI Image- Derived Input Function Derived from a Supervised Clustering Algorithm: Methodology and Validation in a Clinical Protocol Using [C-11](R)-Rolipram SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; DYNAMIC PET IMAGES; BRAIN PET; MICROGLIAL ACTIVATION; PHOSPHODIESTERASE-4; QUANTIFICATION; SEGMENTATION; RADIOLIGAND; DISEASE AB Image-derived input function (IDIF) obtained by manually drawing carotid arteries (manual-IDIF) can be reliably used in [C-11](R)-rolipram positron emission tomography (PET) scans. However, manual-IDIF is time consuming and subject to interand intra-operator variability. To overcome this limitation, we developed a fully automated technique for deriving IDIF with a supervised clustering algorithm (SVCA). To validate this technique, 25 healthy controls and 26 patients with moderate to severe major depressive disorder (MDD) underwent T1-weighted brain magnetic resonance imaging (MRI) and a 90-minute [C-11](R)-rolipram PET scan. For each subject, metabolite-corrected input function was measured from the radial artery. SVCA templates were obtained from 10 additional healthy subjects who underwent the same MRI and PET procedures. ClusterIDIF was obtained as follows: 1) template mask images were created for carotid and surrounding tissue; 2) parametric image of weights for blood were created using SVCA; 3) mask images to the individual PET image were inversely normalized; 4) carotid and surrounding tissue time activity curves (TACs) were obtained from weighted and unweighted averages of each voxel activity in each mask, respectively; 5) partial volume effects and radiometabolites were corrected using individual arterial data at four points. Logan-distribution volume (VT/fP) values obtained by cluster-IDIF were similar to reference results obtained using arterial data, as well as those obtained using manual-IDIF; 39 of 51 subjects had a VT/fP error of,5%, and only one had error.10%. With automatic voxel selection, cluster-IDIF curves were less noisy than manual-IDIF and free of operator-related variability. Cluster-IDIF showed widespread decrease of about 20% [C-11](R)-rolipram binding in the MDD group. Taken together, the results suggest that cluster-IDIF is a good alternative to full arterial input function for estimating Logan-VT/fP in [C-11](R)-rolipram PET clinical scans. This technique enables fully automated extraction of IDIF and can be applied to other radiotracers with similar kinetics. C1 [Lyoo, Chul Hyoung] Yonsei Univ, Coll Med, Dept Neurol, Gangnam Severance Hosp, Seoul, South Korea. [Zanotti-Fregonara, Paolo; Zoghbi, Sami S.; Liow, Jeih-San; Xu, Rong; Pike, Victor W.; Fujita, Masahiro; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Zanotti-Fregonara, Paolo] Univ Bordeaux, CNRS, INCIA, UMR 5287, Talence, France. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM robert.innis@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This work was supported by Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2014 VL 9 IS 2 AR e89101 DI 10.1371/journal.pone.0089101 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3UC UT WOS:000331714700060 PM 24586526 ER PT J AU Qu, TT Feng, Y Jiang, Y Zhu, PQ Wei, ZQ Chen, Y Otto, M Yu, YS AF Qu, Tingting Feng, Ye Jiang, Yan Zhu, Peiqiong Wei, Zeqing Chen, Yan Otto, Michael Yu, Yunsong TI Whole Genome Analysis of a Community-Associated Methicillin-Resistant Staphylococcus aureus ST59 Isolate from a Case of Human Sepsis and Severe Pneumonia in China SO PLOS ONE LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; VIRULENCE DETERMINANTS; MOLECULAR EPIDEMIOLOGY; SEQUENCE; TOXIN; INFECTIONS; EXPRESSION; ALIGNMENT; TAIWAN; GENES AB We report a case of necrotizing pneumonia in a young patient caused by community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) in a teaching hospital in the People's Republic of China. The patient had a typical clinical presentation and was successfully treated with antibiotics and intravenous immunoglobulin. A CA-MRSA strain, named SA268, was isolated from the blood of the patient. The isolate was susceptible to most antimicrobial agents, except cephalosporins, penicillins, and b-lactamase inhibitor combinations. Multi-locus sequence typing (MLST) assigned SA268 to ST59, a clone widely spread in eastern Asia. The strain was positive for Panton Valentine Leukocidin (PVL)-encoding genes and SCCmec type V. We sequenced the complete genome of the SA268 isolate. The genome of SA268 was almost identical to that of the Taiwanese ST59 CA-MRSA strains M013 and SA957. However, we observed several differences in gene composition, which included differences in the SCCmec element and several lipoprotein genes that were present in the Taiwanese strains but absent from SA268. C1 [Qu, Tingting; Wei, Zeqing] Zhejiang Univ, Coll Med, Affiliated Hosp 1, State Key Lab Diag & Treatment Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China. [Feng, Ye; Jiang, Yan; Chen, Yan; Yu, Yunsong] Zhejiang Univ, Coll Med, Sir Run Run Shaw Hosp, Dept Infect Dis, Hangzhou, Zhejiang, Peoples R China. [Zhu, Peiqiong] Zhejiang Med Coll, Dept Clin Med, Hangzhou, Zhejiang, Peoples R China. [Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM MOtto@niaid.nih.gov; yvys119@163.com OI Otto, Michael/0000-0002-2222-4115 FU National Science and Technology Major Project [2012ZX10004215]; Medicine and Health Research fund of Zhejiang Province [2009A009]; Ministry of Health of the People's Republic of China [201002021]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This work was supported by research grants from the National Science and Technology Major Project (2012ZX10004215), the Medicine and Health Research fund of Zhejiang Province (No. 2009A009), the Ministry of Health of the People's Republic of China (no. 201002021), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 4 Z9 6 U1 4 U2 14 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 FEB 20 PY 2014 VL 9 IS 2 AR e89235 DI 10.1371/journal.pone.0089235 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3UC UT WOS:000331714700079 PM 24586619 ER PT J AU Yoshida, Y Yoshimi, R Yoshii, H Kim, D Dey, A Xiong, HB Munasinghe, J Yazawa, I O'Donovan, MJ Maximova, OA Sharma, S Zhu, JF Wang, HS Morse, HC Ozato, K AF Yoshida, Yuko Yoshimi, Ryusuke Yoshii, Hiroaki Kim, Daniel Dey, Anup Xiong, Huabao Munasinghe, Jeeva Yazawa, Itaru O'Donovan, Michael J. Maximova, Olga A. Sharma, Suveena Zhu, Jinfang Wang, Hongsheng Morse, Herbert C., III Ozato, Keiko TI The Transcription Factor IRF8 Activates Integrin-Mediated TGF-beta Signaling and Promotes Neuroinflammation SO IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; INTERFERON REGULATORY FACTOR-8; CELL SUBSET DEVELOPMENT; T-HELPER-CELLS; MULTIPLE-SCLEROSIS; DENDRITIC CELLS; CHRONIC INFLAMMATION; FAMILY CYTOKINES; ROR-GAMMA AB Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8(-/-) mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced alpha v beta 8 integrin expression in APCs and activated TGF-beta signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 production, but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS. C1 [Yoshida, Yuko; Yoshimi, Ryusuke; Yoshii, Hiroaki; Kim, Daniel; Dey, Anup; Ozato, Keiko] NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Xiong, Huabao] Mt Sinai Sch Med, Inst Immunol, Dept Med, New York, NY 10029 USA. [Munasinghe, Jeeva] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Yazawa, Itaru; O'Donovan, Michael J.] NINDS, Lab Neural Control, NIH, Bethesda, MD 20892 USA. [Maximova, Olga A.] NIAID, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. [Sharma, Suveena; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20892 USA. RP Ozato, K (reprint author), NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI o'donovan, michael/A-2357-2015; Zhu, Jinfang/B-7574-2012; OI o'donovan, michael/0000-0003-2487-7547; Yoshimi, Ryusuke/0000-0002-3945-307X; Morse, Herbert/0000-0002-9331-3705 FU NICHD; NIAID; NINDS, National Institutes of Health FX We thank Alan Koretsky (NINDS) for his support and critical reading of the manuscript, Takayuki Ito and Makoto Horiuchi (UC, Davis), Ulrich Siebenlist (NIAID) for useful advice on experiments and reagents, and Mehrnoosh Abshari for assistance in cell sorting and in vitro experiments. This work was supported by the Intramural Program of NICHD, NIAID, and NINDS, National Institutes of Health. NR 49 TC 32 Z9 34 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 20 PY 2014 VL 40 IS 2 BP 187 EP 198 DI 10.1016/j.immuni.2013.11.022 PG 12 WC Immunology SC Immunology GA AB2QQ UT WOS:000331637600007 PM 24485804 ER PT J AU Honda, T Egen, JG Lammermann, T Kastenmuller, W Torabi-Parizi, P Germain, RN AF Honda, Tetsuya Egen, Jackson G. Laemmermann, Tim Kastenmueller, Wolfgang Torabi-Parizi, Parizad Germain, Ronald N. TI Tuning of Antigen Sensitivity by T Cell Receptor-Dependent Negative Feedback Controls T Cell Effector Function in Inflamed Tissues SO IMMUNITY LA English DT Article ID LYMPH-NODES; DENDRITIC CELLS; IMMUNE-SYSTEM; STOP-SIGNAL; IN-VIVO; MYCOBACTERIAL GRANULOMAS; IMMUNOLOGICAL SYNAPSE; MOTILITY; DYNAMICS; CD4(+) AB Activated T cells must mediate effector responses sufficiently to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4(+) T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen-presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs T cell recruitment, transient activation, and rapid desensitization to allow the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host. C1 [Honda, Tetsuya; Egen, Jackson G.; Laemmermann, Tim; Kastenmueller, Wolfgang; Torabi-Parizi, Parizad; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad] NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rgermain@nih.gov OI Egen, Jackson/0000-0003-2053-0837 FU NIAID; NIH; Uehara Memorial Foundation; HFSP FX The authors wish to thank G.J. Freeman for anti-PD-L2 blocking antibody; D. L. Barber for PD-1-deficient mice; and N. Subramanian, M. Clatworthy, H. Qi, M. Bajenoff, and N. Peters for helpful discussions and/or technical advice. This work was supported by the Intramural Research Program of NIAID, NIH, the Uehara Memorial Foundation (T.H.), and an HFSP Long-term Fellowship (T.L). NR 54 TC 55 Z9 56 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 20 PY 2014 VL 40 IS 2 BP 235 EP 247 DI 10.1016/j.immuni.2013.11.017 PG 13 WC Immunology SC Immunology GA AB2QQ UT WOS:000331637600011 PM 24440150 ER PT J AU Liang, J Lacroix, L Gamot, A Cuddapah, S Queille, S Lhoumaud, P Lepetit, P Martin, PGP Vogelmann, J Court, F Hennion, M Micas, G Urbach, S Bouchez, O Nollmann, M Zhao, K Emberly, E Cuvier, O AF Liang, Jun Lacroix, Laurent Gamot, Adrien Cuddapah, Suresh Queille, Sophie Lhoumaud, Priscillia Lepetit, Pierre Martin, Pascal G. P. Vogelmann, Jutta Court, Franck Hennion, Magali Micas, Gael Urbach, Serge Bouchez, Olivier Noellmann, Marcelo Zhao, Keji Emberly, Eldon Cuvier, Olivier TI Chromatin Immunoprecipitation Indirect Peaks Highlight Long-Range Interactions of Insulator Proteins and Pol II Pausing SO MOLECULAR CELL LA English DT Article ID CHROMOSOME CONFORMATION CAPTURE; RNA-POLYMERASE-II; GENE-EXPRESSION; DROSOPHILA GENOME; TRANSCRIPTION REGULATION; BINDING-SITES; ORGANIZATION; DOMAINS; PROMOTERS; PRINCIPLES AB Eukaryotic chromosomes are partitioned into topologically associating domains (TADs) that are demarcated by distinct insulator-binding proteins (IBPs) in Drosophila. Whether IBPs regulate specific long-range contacts and how this may impact gene expression remains unclear. Here we identify "indirect peaks'' of multiple IBPs that represent their distant sites of interactions through long-range contacts. Indirect peaks depend on protein-protein interactions among multiple IBPs and their common cofactors, including CP190, as confirmed by high-resolution analyses of long-range contacts. Mutant IBPs unable to interact with CP190 impair long-range contacts as well as the expression of hundreds of distant genes that are specifically flanked by indirect peaks. Regulation of distant genes strongly correlates with RNAPII pausing, highlighting how this key transcriptional stage may trap insulator-based long-range interactions. Our data illustrate how indirect peaks may decipher gene regulatory networks through specific long-range interactions. C1 [Liang, Jun; Lacroix, Laurent; Gamot, Adrien; Queille, Sophie; Lhoumaud, Priscillia; Lepetit, Pierre; Martin, Pascal G. P.; Court, Franck; Hennion, Magali; Micas, Gael; Cuvier, Olivier] Univ Toulouse UPS, LBME, CNRS, F-31000 Toulouse, France. [Cuddapah, Suresh] NHLBI, NIH, Syst Biol Ctr, Bethesda, MD 20824 USA. [Vogelmann, Jutta; Noellmann, Marcelo] CNRS, Ctr Biochimie Struct, F-34090 Montpellier, France. [Urbach, Serge] CNRS, IGF, Platform Prote Fonctionnelle, F-34060 Montpellier, France. [Lacroix, Laurent; Bouchez, Olivier] INRA, UMR444 GeT PlaGe, Genotoul, F-31326 Toulouse, France. [Emberly, Eldon] Simon Fraser Univ, Dept Phys, Burnaby, BC V5A 1S6, Canada. RP Cuvier, O (reprint author), Univ Toulouse UPS, LBME, CNRS, F-31000 Toulouse, France. EM cuvier@ibcg.biotoul.fr RI Lacroix, Laurent/C-7024-2009; OI Lacroix, Laurent/0000-0002-6382-9057; Martin, Pascal/0000-0002-4271-658X FU Division of Intramural Research Program of the National Heart, Lung and Blood Institute, NIH; European Research Council [260787]; NSERC; Canadian Institute for Advanced Research (CIFAR); ANR; ARC; CNRS-Inserm ATIP-AVENIR program FX We thank T. Forne for help and advice regarding 3C; G. Cavalli, T. Sexton, and A. Tanay for Hi-C data and/or for suggestions; D. Gilmour for the generous gift of anti-GAF antibodies; C. Carles for help with web servers; and O. C. lab members including E. Guillou for RNAi and K. Z. lab members for performing Hi-Seq (A. Barski and K. Cui). K. Z.'s lab was supported by the Division of Intramural Research Program of the National Heart, Lung and Blood Institute, NIH. M.N.'s lab was supported by the European Research Council (Starting Grant 260787 to M.N.). E.E.'s lab was supported by NSERC and the Canadian Institute for Advanced Research (CIFAR). O.C.'s lab was supported by a grant of the ANR, the ARC cancer research funding, and the CNRS-Inserm ATIP-AVENIR program. NR 41 TC 31 Z9 32 U1 2 U2 22 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 FEB 20 PY 2014 VL 53 IS 4 BP 672 EP 681 DI 10.1016/j.molcel.2013.12.029 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AB2ZE UT WOS:000331660200015 PM 24486021 ER PT J AU Bond, SR Naus, CC AF Bond, Stephen R. Naus, Christian C. TI The pannexins: past and present SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE pannexin; Panx1; Panx2; Panx3; distribution; biochemistry; structure; gating ID GAP-JUNCTION PROTEINS; CELL-CELL COMMUNICATION; MAMMALIAN TASTE CELLS; MEDIATED ATP RELEASE; HUMAN SUBCUTANEOUS FIBROBLASTS; P2X RECEPTOR ACTIVATION; MAXI-ANION CHANNEL; C6 GLIOMA-CELLS; EXTRACELLULAR ATP; CALCIUM WAVES AB The pannexins (Panxs) are a family of chordate proteins homologous to the invertebrate gap junction forming proteins named innexins. Three distinct Panx paralogs (Panx1, Panx2, and Panx3) are shared among the major vertebrate phyla, but they appear to have suppressed (or even lost) their ability to directly couple adjacent cells. Connecting the intracellular and extracellular compartments is now widely accepted as Panx's primary function, facilitating the passive movement of ions and small molecules along electrochemical gradients. The tissue distribution of the Panxs ranges from pervasive to very restricted, depending on the paralog, and are often cell type-specific and/or developmentally regulated within any given tissue. In recent years, Panxs have been implicated in an assortment of physiological and pathophysiological processes, particularly with respect to ATP signaling and inflammation, and they are now considered to be a major player in extracellular purinergic communication. The following is a comprehensive review of the Panx literature, exploring the historical events leading up to their discovery, outlining our current understanding of their biochemistry, and describing the importance of these proteins in health and disease. C1 [Bond, Stephen R.] NHGRI, Genome Technol Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Bond, Stephen R.; Naus, Christian C.] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada. RP Bond, SR (reprint author), NHGRI, Genome Technol Branch, Div Intramural Res, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM steve.bond@nih.gov OI Bond, Stephen/0000-0001-5825-591X FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Canadian Institute of Health Research FX We would like to thank Dr. Moises Freitas-Andrade, Mr. Maxence Le Vasseur, Dr. Silvia Penuela, and Dr. Andy Baxevanis for their constructive and insightful feedback during the writing of this review. Preparation of this manuscript was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (Stephen R. Bond) and the Canadian Institute of Health Research (Christian C. Naus). NR 264 TC 32 Z9 32 U1 3 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD FEB 19 PY 2014 VL 5 AR 58 DI 10.3389/fphys.2014.00058 PG 24 WC Physiology SC Physiology GA AX3FT UT WOS:000346826400003 PM 24600404 ER PT J AU Graybeal, C Bachu, M Mozhui, K Saksida, LM Bussey, TJ Sagalyn, E Williams, RW Holmes, A AF Graybeal, Carolyn Bachu, Munisa Mozhui, Khyobeni Saksida, Lisa M. Bussey, Timothy J. Sagalyn, Erica Williams, Robert W. Holmes, Andrew TI Strains and Stressors: An Analysis of Touchscreen Learning in Genetically Diverse Mouse Strains SO PLOS ONE LA English DT Article ID REPEATED MATERNAL SEPARATION; REACTION-TIME-TASK; INBRED STRAINS; BEHAVIORAL PROFILES; COGNITIVE SYMPTOMS; MAZE PERFORMANCE; OPERANT PLATFORM; DBA/2J MICE; GO/NO-GO; MEMORY AB Touchscreen-based systems are growing in popularity as a tractable, translational approach for studying learning and cognition in rodents. However, while mouse strains are well known to differ in learning across various settings, performance variation between strains in touchscreen learning has not been well described. The selection of appropriate genetic strains and backgrounds is critical to the design of touchscreen-based studies and provides a basis for elucidating genetic factors moderating behavior. Here we provide a quantitative foundation for visual discrimination and reversal learning using touchscreen assays across a total of 35 genotypes. We found significant differences in operant performance and learning, including faster reversal learning in DBA/2J compared to C57BL/6J mice. We then assessed DBA/2J and C57BL/6J for differential sensitivity to an environmental insult by testing for alterations in reversal learning following exposure to repeated swim stress. Stress facilitated reversal learning (selectively during the late stage of reversal) in C57BL/6J, but did not affect learning in DBA/2J. To dissect genetic factors underlying these differences, we phenotyped a family of 27 BXD strains generated by crossing C57BL/6J and DBA/2J. There was marked variation in discrimination, reversal and extinction learning across the BXD strains, suggesting this task may be useful for identifying underlying genetic differences. Moreover, different measures of touchscreen learning were only modestly correlated in the BXD strains, indicating that these processes are comparatively independent at both genetic and phenotypic levels. Finally, we examined the behavioral structure of learning via principal component analysis of the current data, plus an archival dataset, totaling 765 mice. This revealed 5 independent factors suggestive of "reversal learning,'' "motivation-related late reversal learning,'' "discrimination learning,'' "speed to respond,'' and "motivation during discrimination.'' Together, these findings provide a valuable reference to inform the choice of strains and genetic backgrounds in future studies using touchscreen-based tasks. C1 [Graybeal, Carolyn; Bachu, Munisa; Sagalyn, Erica; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. [Mozhui, Khyobeni; Williams, Robert W.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Williams, Robert W.] Univ Tennessee, Ctr Hlth Sci, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. [Saksida, Lisa M.; Bussey, Timothy J.] Med Res Council & Wellcome Trust, Behav & Clin Neurosci Inst, Cambridge, England. RP Graybeal, C (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. EM carolyn_graybeal@alumni.brown.edu RI Bussey, Timothy/M-2758-2016; Saksida, Lisa/M-2753-2016; OI Bussey, Timothy/0000-0001-7518-4041; Saksida, Lisa/0000-0002-8416-8171; Williams, Robert/0000-0001-8924-4447 FU NIAAA Intramural Research Program; NIAAA INIA [U01 11016662, U01 AA013499] FX Research supported by the NIAAA Intramural Research Program and NIAAA INIA grants U01 11016662 and U01 AA013499. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 12 Z9 12 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 19 PY 2014 VL 9 IS 2 AR e87745 DI 10.1371/journal.pone.0087745 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3TA UT WOS:000331711900016 PM 24586288 ER PT J AU Rees, MG Davis, MI Shen, M Titus, S Raimondo, A Barrett, A Gloyn, AL Collins, FS Simeonov, A AF Rees, Matthew G. Davis, Mindy I. Shen, Min Titus, Steve Raimondo, Anne Barrett, Amy Gloyn, Anna L. Collins, Francis S. Simeonov, Anton TI A Panel of Diverse Assays to Interrogate the Interaction between Glucokinase and Glucokinase Regulatory Protein, Two Vital Proteins in Human Disease SO PLOS ONE LA English DT Article ID TYPE-2 DIABETES-MELLITUS; GENOME-WIDE ASSOCIATION; RAT PRIMARY HEPATOCYTES; LIVER GLUCOKINASE; PLASMA-GLUCOSE; FRUCTOSE 1-PHOSPHATE; TRIGLYCERIDE LEVELS; STRUCTURAL BASIS; IMAGE-ANALYSIS; P446L VARIANT AB Recent genetic and clinical evidence has implicated glucokinase regulatory protein (GKRP) in the pathogenesis of type 2 diabetes and related traits. The primary role of GKRP is to bind and inhibit hepatic glucokinase (GCK), a critically important protein in human health and disease that exerts a significant degree of control over glucose metabolism. As activation of GCK has been associated with improved glucose tolerance, perturbation of the GCK-GKRP interaction represents a potential therapeutic target for pharmacological modulation. Recent structural and kinetic advances are beginning to provide insight into the interaction of these two proteins. However, tools to comprehensively assess the GCK-GKRP interaction, particularly in the context of small molecules, would be a valuable resource. We therefore developed three robust and miniaturized assays for assessing the interaction between recombinant human GCK and GKRP: an HTRF assay, a diaphorase-coupled assay, and a luciferase-coupled assay. The assays are complementary, featuring distinct mechanisms of detection (luminescence, fluorescence, FRET). Two assays rely on GCK enzyme activity modulation by GKRP while the FRET-based assay measures the GCK-GKRP protein-protein interaction independent of GCK enzymatic substrates and activity. All three assays are scalable to low volumes in 1536-well plate format, with robust Z' factors (> 0.7). Finally, as GKRP sequesters GCK in the hepatocyte nucleus at low glucose concentrations, we explored cellular models of GCK localization and translocation. Previous findings from freshly isolated rat hepatocytes were confirmed in cryopreserved rat hepatocytes, and we further extended this study to cryopreserved human hepatocytes. Consistent with previous reports, there were several key differences between the rat and human systems, with our results suggesting that human hepatocytes can be used to interrogate GCK translocation in response to small molecules. The assay panel developed here should help direct future investigation of the GCK-GKRP interaction in these or other physiologically relevant human systems. C1 [Rees, Matthew G.; Davis, Mindy I.; Shen, Min; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA. [Rees, Matthew G.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rees, Matthew G.; Raimondo, Anne; Barrett, Amy; Gloyn, Anna L.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Titus, Steve] GE Healthcare, Life Sci, Piscataway, NJ USA. [Gloyn, Anna L.] Churchill Hosp, OCDEM, ORH Trust, NIHR Oxford Biomed Res Ctr, Oxford OX3 7LJ, England. RP Simeonov, A (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20852 USA. EM asimeono@mail.nih.gov FU NIH; NHGRI [Z01- HG000024]; Wellcome Trust [095101/Z/10/Z] FX This work was funded at NIH by the Molecular Libraries Common Fund Program of the NIH and NHGRI project number Z01- HG000024 (to FSC) and in Oxford by the Wellcome Trust (095101/Z/10/Z). ALG is a Wellcome Trust Senior Fellow in Basic Biomedical Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 19 PY 2014 VL 9 IS 2 AR e89335 DI 10.1371/journal.pone.0089335 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3TA UT WOS:000331711900126 PM 24586696 ER PT J AU Biesso, A Xu, JH Muino, PL Callis, PR Knutson, JR AF Biesso, Arianna Xu, Jianhua Muino, Pedro L. Callis, Patrik R. Knutson, Jay R. TI Charge Invariant Protein-Water Relaxation in GB1 via Ultrafast Tryptophan Fluorescence SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN SERUM-ALBUMIN; HYDRATION DYNAMICS; SOLVATION DYNAMICS; B1 DOMAIN; MOLECULAR-DYNAMICS; BIOLOGICAL WATER; SURFACE; SHIFT; PROBE; DECAY AB The protein water interface is a critical determinant of protein structure and function, yet the precise nature of dynamics in this complex system remains elusive. Tryptophan fluorescence has become the probe of choice for such dynamics on the picosecond time scale (especially via fluorescence "upconversion"). In the absence of ultrafast ("quasi-static") quenching from nearby groups, the TDFSS (time-dependent fluorescence Stokes shift) for exposed Trp directly reports on dipolar relaxation near the interface (both water and polypeptide). The small protein GB1 contains a single Trp (W43) of this type, and its structure is refractory to pH above 3. Thus, it can be used to examine the dependence of dipolar relaxation upon charge reconfiguration with titration. Somewhat surprisingly, the dipolar dynamics in the 100 fs to 100 ps range were unchanged with pH, although nanosecond yield, rates, and access all changed. These results were rationalized with the help of molecular dynamics (including QM-MM) simulations that reveal a balancing, sometimes even countervailing influence of protein and water dipoles. Interestingly, these simulations also showed the dominant influence of water molecules which are associated with the protein interface for up to 30 ps yet free to rotate at approximately "bulk" water rates. C1 [Biesso, Arianna; Xu, Jianhua; Knutson, Jay R.] NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Muino, Pedro L.] St Francis Xavier Univ, Dept Chem, Loretto, PA 15940 USA. [Callis, Patrik R.] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jaysan@helix.nih.gov FU National Hearth Lung and Blood Institute; National Science Foundation [OCI-1053575, MCB090176] FX This work was supported by the intramural program of the National Hearth Lung and Blood Institute. The authors would like to thank Dr. Marie-Paule Strub for crucial assistance with protein purification and expression. We thank Ludwig Brand and Dmitri Toptygin for stimulating discussions. We also thank Dr. John Louis and Prof. Angela Gronenborn for fueling all our prior studies with their GB1 stock and then generously providing the GB1 plasmid used herein. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant No. OCI-1053575 through Project No. MCB090176. NR 59 TC 6 Z9 6 U1 4 U2 51 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 19 PY 2014 VL 136 IS 7 BP 2739 EP 2747 DI 10.1021/ja406126a PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA AB4SI UT WOS:000331779800013 PM 24456037 ER PT J AU Ting, CY McQueen, PG Pandya, N Lin, TY Yang, M Reddy, OV O'Connor, MB McAuliffe, M Lee, CH AF Ting, Chun-Yuan McQueen, Philip G. Pandya, Nishith Lin, Tzu-Yang Yang, Meiluen Reddy, O. Venkateswara O'Connor, Michael B. McAuliffe, Matthew Lee, Chi-Hon TI Photoreceptor-Derived Activin Promotes Dendritic Termination and Restricts the Receptive Fields of First-Order Interneurons in Drosophila SO NEURON LA English DT Article ID SELF-AVOIDANCE; VISUAL-SYSTEM; OPTIC LOBE; AXON; EXPRESSION; CIRCUIT; RETINA; BRAIN; GENE; MORPHOGENESIS AB How neurons form appropriately sized dendritic fields to encounter their presynaptic partners is poorly understood. The Drosophila medulla is organized in layers and columns and innervated by medulla neuron dendrites and photoreceptor axons. Here, we show that three types of medulla projection (Tm) neurons extend their dendrites in stereotyped directions and to distinct layers within a single column for processing retinotopic information. In contrast, the Dm8 amacrine neurons form a wide dendritic field to receive similar to 16 R7 photoreceptor inputs. R7- and R8-derived Activin selectively restricts the dendritic fields of their respective postsynaptic partners, Dm8 and Tm20, to the size appropriate for their functions. Canonical Activin signaling promotes dendritic termination without affecting dendritic routing direction or layer. Tm20 neurons lacking Activin signaling expanded their dendritic fields and aberrantly synapsed with neighboring photoreceptors. We suggest that afferent-derived Activin regulates the dendritic field size of their postsynaptic partners to ensure appropriate synaptic partnership. C1 [Ting, Chun-Yuan; Lin, Tzu-Yang; Yang, Meiluen; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [McQueen, Philip G.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Pandya, Nishith; McAuliffe, Matthew] NIH, Biomed Imaging Res Serv Sect, Ctr Informat Technol, Bethesda, MD 20892 USA. [Reddy, O. Venkateswara] Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. [O'Connor, Michael B.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD008913]; Center for Information Technology; [R01 GM095746] FX We thank Xin Li, Claude Desplan, Shinya Takemura, and Dimitri Chklovskii for communicating results prior to publication; Tzumin Lee, Takashi Suzuki, and Claude Desplan for providing critical reagents; and Edward Giniger, Hari Shroff, Alexander Borst, and Alan Hinnebusch for helpful discussion. 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 (grant HD008913 to C.-H. L.), the Center for Information Technology (P. G. M., N.P., and M. M), and R01 GM095746 to M.B.O. NR 44 TC 18 Z9 18 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD FEB 19 PY 2014 VL 81 IS 4 BP 830 EP 846 DI 10.1016/j.neuron.2013.12.012 PG 17 WC Neurosciences SC Neurosciences & Neurology GA AB0EK UT WOS:000331464400013 PM 24462039 ER PT J AU Agarwal, D Pineda, S Michailidou, K Herranz, J Pita, G Moreno, LT Alonso, MR Dennis, J Wang, Q Bolla, MK Meyer, KB Menendez-Rodriguez, P Hardisson, D Mendiola, M Gonzalez-Neira, A Lindblom, A Margolin, S Swerdlow, A Ashworth, A Orr, N Jones, M Matsuo, K Ito, H Iwata, H Kondo, N Hartman, M Hui, M Lim, WY Iau, PTC Sawyer, E Tomlinson, I Kerin, M Miller, N Kang, D Choi, JY Park, SK Noh, DY Hopper, JL Schmidt, DF Makalic, E Southey, MC Teo, SH Yip, CH Sivanandan, K Tay, WT Brauch, H Bruning, T Hamann, U Dunning, AM Shah, M Andrulis, IL Knight, JA Glendon, G Tchatchou, S Schmidt, MK Broeks, A Rosenberg, EH van't Veer, LJ Fasching, PA Renner, SP Ekici, AB Beckmann, MW Shen, CY Hsiung, CN Yu, JC Hou, MF Blot, W Cai, Q Wu, AH Tseng, CC Van Den Berg, D Stram, DO Cox, A Brock, IW Reed, MWR Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Zheng, W Deming-Halverson, S Shrubsole, MJ Long, J Shu, XO Lu, W Gao, YT Zhang, B Radice, P Peterlongo, P Manoukian, S Mariette, F Sangrajrang, S Mckay, J Couch, FJ Toland, AE Yannoukakos, D Fletcher, O Johnson, N Silva, ID Peto, J Marme, F Burwinkel, B Guenel, P Truong, T Sanchez, M Mulot, C Bojesen, SE Nordestgaard, BG Flyer, H Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Lambrechts, D Yesilyurt, BT Floris, G Leunen, K Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Wang, X Olson, JE Vachon, C Purrington, K Giles, GG Severi, G Baglietto, L Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Simard, J Dumont, M Goldberg, MS Labreche, F Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Devilee, P Tollenaar, RAEM Seynaeve, C Garcia-Closas, M Chanock, SJ Lissowska, J Figueroa, JD Czene, K Eriksson, M Humphreys, K Darabi, H Hooning, MJ Kriege, M Collee, JM Tilanus-Linthorst, M Li, J Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Bogdanova, N Dork, T Hall, P Chenevix-Trench, G Easton, DF Pharoah, PDP Arias-Perez, JI Zamora, P Benitez, J Milne, RL AF Agarwal, D. Pineda, S. Michailidou, K. Herranz, J. Pita, G. Moreno, L. T. Alonso, M. R. Dennis, J. Wang, Q. Bolla, M. K. Meyer, K. B. Menendez-Rodriguez, P. Hardisson, D. Mendiola, M. Gonzalez-Neira, A. Lindblom, A. Margolin, S. Swerdlow, A. Ashworth, A. Orr, N. Jones, M. Matsuo, K. Ito, H. Iwata, H. Kondo, N. Hartman, M. Hui, M. Lim, W. Y. Iau, P. T-C Sawyer, E. Tomlinson, I. Kerin, M. Miller, N. Kang, D. Choi, J-Y Park, S. K. Noh, D-Y Hopper, J. L. Schmidt, D. F. Makalic, E. Southey, M. C. Teo, S. H. Yip, C. H. Sivanandan, K. Tay, W-T Brauch, H. Bruening, T. Hamann, U. Dunning, A. M. Shah, M. Andrulis, I. L. Knight, J. A. Glendon, G. Tchatchou, S. Schmidt, M. K. Broeks, A. Rosenberg, E. H. van't Veer, L. J. Fasching, P. A. Renner, S. P. Ekici, A. B. Beckmann, M. W. Shen, C-Y Hsiung, C-N Yu, J-C Hou, M-F Blot, W. Cai, Q. Wu, A. H. Tseng, C-C Van Den Berg, D. Stram, D. O. Cox, A. Brock, I. W. Reed, M. W. R. Muir, K. Lophatananon, A. Stewart-Brown, S. Siriwanarangsan, P. Zheng, W. Deming-Halverson, S. Shrubsole, M. J. Long, J. Shu, X-O Lu, W. Gao, Y-T Zhang, B. Radice, P. Peterlongo, P. Manoukian, S. Mariette, F. Sangrajrang, S. Mckay, J. Couch, F. J. Toland, A. E. Yannoukakos, D. Fletcher, O. Johnson, N. dos Santos Silva, I. Peto, J. Marme, F. Burwinkel, B. Guenel, P. Truong, T. Sanchez, M. Mulot, C. Bojesen, S. E. Nordestgaard, B. G. Flyer, H. Brenner, H. Dieffenbach, A. K. Arndt, V. Stegmaier, C. Mannermaa, A. Kataja, V. Kosma, V-M Hartikainen, J. M. Lambrechts, D. Yesilyurt, B. T. Floris, G. Leunen, K. Chang-Claude, J. Rudolph, A. Seibold, P. Flesch-Janys, D. Wang, X. Olson, J. E. Vachon, C. Purrington, K. Giles, G. G. Severi, G. Baglietto, L. Haiman, C. A. Henderson, B. E. Schumacher, F. Le Marchand, L. Simard, J. Dumont, M. Goldberg, M. S. Labreche, F. Winqvist, R. Pylkaes, K. Jukkola-Vuorinen, A. Grip, M. Devilee, P. Tollenaar, R. A. E. M. Seynaeve, C. Garcia-Closas, M. Chanock, S. J. Lissowska, J. Figueroa, J. D. Czene, K. Eriksson, M. Humphreys, K. Darabi, H. Hooning, M. J. Kriege, M. Collee, J. M. Tilanus-Linthorst, M. Li, J. Jakubowska, A. Lubinski, J. Jaworska-Bieniek, K. Durda, K. Nevanlinna, H. Muranen, T. A. Aittomaeki, K. Blomqvist, C. Bogdanova, N. Doerk, T. Hall, P. Chenevix-Trench, G. Easton, D. F. Pharoah, P. D. P. Arias-Perez, J. I. Zamora, P. Benitez, J. Milne, R. L. CA KConFab Investigators Australian Ovarian Cancer Study Gr GENICA Network TNBCC TI FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; SNP; FGF receptors; susceptibility; disease subtypes ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; CONFER SUSCEPTIBILITY; BRCA2 MUTATIONS; COMMON VARIANTS; OVARIAN-CANCER; IDENTIFIES 2; RISK; LOCI; ALLELES AB Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval 1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. C1 [Agarwal, D.; Pineda, S.; Herranz, J.; Benitez, J.; Milne, R. L.] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain. [Agarwal, D.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Michailidou, K.; Dennis, J.; Wang, Q.; Bolla, M. K.; Easton, D. F.; Pharoah, P. D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Herranz, J.] IMDEA Food Inst, Biostat Unit, Madrid, Spain. [Pita, G.; Moreno, L. T.; Alonso, M. R.; Gonzalez-Neira, A.; Benitez, J.] Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Madrid, Spain. 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EM roger.milne@cancervic.org.au RI Malats, Nuria/H-7041-2015; Shrubsole, Martha/K-5052-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Dork, Thilo/J-8620-2012; Hardisson, David/E-2832-2010; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Osorio, Ana/I-4324-2014; Herranz Valera, Jesus/M-8657-2014; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Hein, Alexander/F-6999-2010; Knight, Julia/A-6843-2012; Jakubowska, Anna/O-8050-2014; Li, Jingmei/I-2904-2012; Yip, Cheng-Har/B-1909-2010; Andrulis, Irene/E-7267-2013; Gonzalez-Neira, Anna/C-5791-2015; Hartikainen, Jaana/E-6256-2015; Garcia-Closas, Montserrat /F-3871-2015; Renner, Stefan/F-1158-2014; Brinton, Louise/G-7486-2015 OI Malats, Nuria/0000-0003-2538-3784; Shrubsole, Martha/0000-0002-5591-7575; Hardisson, David/0000-0002-2183-3699; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Osorio, Ana/0000-0001-8124-3984; Rosenberg, Efraim/0000-0002-3859-6941; Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Nevanlinna, Heli/0000-0002-0916-2976; Czene, Kamila/0000-0002-3233-5695; Eeles, Rosalind/0000-0002-3698-6241; Herranz Valera, Jesus/0000-0002-7385-1311; Dunning, Alison Margaret/0000-0001-6651-7166; Cox, Angela/0000-0002-5138-1099; Yannoukakos, Drakoulis/0000-0001-7509-3510; Giles, Graham/0000-0003-4946-9099; Hein, Alexander/0000-0003-2601-3398; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Renner, Stefan/0000-0003-2057-1268; Brinton, Louise/0000-0003-3853-8562 FU Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A10710, C490/A10124, C491/A10122, C492/A10123]; European Community [223175 (HEALTH-F2-2009-223175)]; European Union COST programme [BM0606]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' programme; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Canadian Institutes of Health Research; Dutch Cancer Society [NKI2007-3839, NKI2009-4363, RUL 1997-1505, DDHK 2004-3124, DDHK 20094318]; Breast Cancer Research Trust, UK; ELAN-Programme of the University Hospital of Erlangen; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; French National Institute of Cancer (INCa); National League against Cancer; National Agency for Environmental and Occupational Health and Food Safety (ANSES); National Agency for Research (ANR); Association for Research against Cancer (ARC); Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; Michael Manzella Foundation (MMF); CNIO Summer Training Program; California Breast Cancer; California Breast Cancer Research Fund [97-10500]; California Department of Public Health; California Health and Safety [103885]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; VERDI study; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/ 5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation; Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum; Department of Internal Medicine, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Takeda Science Foundation; National Cancer Center Research and Development Fund; German Academic Exchange Program; Friends of Hannover Medical SchoolStockholm County Council; Karolinska Institutet; Stockholm Cancer Foundation; Swedish Cancer Society [5128-B07-01PAF]; Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; strategic funding of the University of Eastern Finland; National Breast Cancer Foundation; NHMRC [145684, 288704, 454508, 199600]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania; South Australia and the Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania and Cancer Foundation of Western Australia; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance [N01CN25403]; 'Stichting tegen Kanker' [232-2008, 196-2010]; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); NIH [CA128978, CA122340, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/ 1/35/19= 18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1: 1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. Findings Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4.10, exceeding the prespecified stopping boundary value of 2.87). At this point, outcome data were available for 223 patients (mean follow-up 33.3 months [SD 19.7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10.1%) patients in the medical management group compared with 35 (30.7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0.27, 95% CI 0.14-0.54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0.0001) and neurological deficits unrelated to stroke (14 vs 1, p=0.0008) in patients allocated to interventional therapy compared with medical management. Interpretation The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. C1 [Mohr, J. P.; Stapf, Christian] Columbia Univ, Neurol Inst, Med Ctr, New York, NY USA. [Parides, Michael K.; Moquete, Ellen; Overbey, Jessica R.; Moskowitz, Alan J.] Icahn Sch Med Mt Sinai, Dept Hlth Evidence & Policy, Int Ctr Hlth Outcomes & Innovat Res, New York, NY USA. [Stapf, Christian] Univ Paris Diderot Sorbonne Paris Cite, Hop Lariboisiere, AP HP, Dept Neurol, Paris, France. [Stapf, Christian] Univ Paris Diderot Sorbonne Paris Cite, Hop Lariboisiere, AP HP, DHU NeuroVasc, Paris, France. [Houdart, Emmanuel] Univ Paris Diderot Sorbonne Paris Cite, Hop Lariboisiere, AP HP, Dept Neuroradiol, Paris, France. [Vicaut, Eric] Univ Paris Diderot Sorbonne Paris Cite, Hop Lariboisiere, AP HP, Unite Rech Clin, Paris, France. [Moy, Claudia S.] NINDS, NIH, Bethesda, MD 20892 USA. [Salman, Rustam Al-Shahi] Univ Edinburgh, Ctr Clin Brain Sci, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Young, William L.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Cordonnier, Charlotte] Univ Lille Nord France, CHRU Lille, Dept Neurol, Lille, France. [Stefani, Marco A.] Hosp Clin Porto Alegre, Dept Neurol & Neurosurg, Porto Alegre, RS, Brazil. [Hartmann, Andreas] Charite, D-13353 Berlin, Germany. [Hartmann, Andreas] Klinikum Frankfurt Oder, Dept Neurol, Frankfurt, Germany. [von Kummer, Rudiger] Univ Hosp Dresden, Dept Neuroradiol, Dresden, Germany. [Biondi, Alessandra] Univ Franche Comte, Jean Minjoz Hosp, Dept Neuroradiol & Endovasc Therapy, F-25030 Besancon, France. [Berkefeld, Joachim] Univ Frankfurt Klinikum, Dept Neuroradiol, Frankfurt, Germany. [Klijn, Catharina J. M.] Univ Med Ctr, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands. [Harkness, Kirsty] Royal Hallamshire Hosp, Dept Neurol, Sheffield S10 2JF, S Yorkshire, England. [Libman, Richard] North Shore Long Isl Jewish Med Ctr, Dept Neurol, New Hyde Pk, NY USA. [Barreau, Xavier] CHU Pellegrin, Dept Diagnost & Intervent Neuroimaging, Bordeaux, France. RP Stapf, C (reprint author), Hop Lariboisiere, AP HP, Dept Neurol, Neurovasc Unit, F-75175 Paris 10, France. EM christian.stapf@lrb.aphp.fr RI van Dijk, J. Marc C./C-1078-2013; Klijn, C.J.M. (Karin)/E-1700-2016; OI van Dijk, J. Marc C./0000-0002-0814-5680; Javadpour, Mohsen/0000-0001-9836-1741; Gregson, Barbara/0000-0003-4868-9137; Moskowitz, Alan/0000-0002-4412-9450; Touze, Emmanuel/0000-0002-7254-2162; Al-Shahi Salman, Rustam/0000-0002-2108-9222 FU National Institute of Neurological Diosorders and Stroke of the US National Institutes of Health [U01NS051483, U01 NS051566]; National Institutes of Health, National Institute of Neurological Disorders and Stroke FX National Institutes of Health, National Institute of Neurological Disorders and Stroke.; This paper is dedicated in memoriam to our colleague and friend William L Young, in recognition of his contribution to brain arteriovenous malformations research and to the ARUBA trial. We thank patients who participate in this trial. This trial is funded internationally by the National Institute of Neurological Diosorders and Stroke of the US National Institutes of Health via cooperative agreements U01NS051483 (CCC; J.P. Mohr, PI) and U01 NS051566 (DCC; A.J. Moskowitz, PI). No commercial funding sources have been involved. ARUBA has been officially adopted by the UK Stroke Research Network and endorsed by the Societe Francaise Neurovasculaire (SFNV). Initial results have been presented at the European Stroke Conference; London, UK; May 28-31, 2013. NR 30 TC 209 Z9 211 U1 5 U2 30 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 15 PY 2014 VL 383 IS 9917 BP 614 EP 621 DI 10.1016/S0140-6736(13)62302-8 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AA5KP UT WOS:000331137700030 PM 24268105 ER PT J AU Andrews, C Gadsden, BJ Carr, EA Kiupel, M AF Andrews, Caroline Gadsden, Barbie J. Carr, Elizabeth A. Kiupel, Matti TI Pathology in Practice SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Editorial Material ID COMPLEX ODONTOMA C1 [Andrews, Caroline] NCI, Comparat Biomed Scientist Training Program, NIH, Bethesda, MD 20892 USA. [Andrews, Caroline; Gadsden, Barbie J.; Kiupel, Matti] Michigan State Univ, Diagnost Ctr Populat & Anim Hlth, Lansing, MI 48910 USA. [Carr, Elizabeth A.] Michigan State Univ, Coll Vet Med, Dept Large Anim Clin Sci, E Lansing, MI 48824 USA. RP Andrews, C (reprint author), NCI, Comparat Biomed Scientist Training Program, NIH, Bethesda, MD 20892 USA. EM andrewsc@dcpah.msu.edu FU NIH HHS [T35 OD010991] NR 7 TC 1 Z9 1 U1 1 U2 2 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 EI 1943-569X J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD FEB 15 PY 2014 VL 244 IS 4 BP 417 EP 419 PG 3 WC Veterinary Sciences SC Veterinary Sciences GA AA0UG UT WOS:000330812300005 PM 24479454 ER PT J AU Xie, Y Alexander, GM Schwartzman, RJ Singh, N Torjman, MC Goldberg, ME Wainer, IW Moaddel, R AF Xie, Y. Alexander, G. M. Schwartzman, R. J. Singh, N. Torjman, M. C. Goldberg, M. E. Wainer, I. W. Moaddel, R. TI Development and validation of a sensitive LC-MS/MS method for the determination of D-serine in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Enantiomeric separation; Chiral derivatization; Ketamine; Complex regional pain syndrome (CRPS) ID PERFORMANCE-LIQUID-CHROMATOGRAPHY; TANDEM MASS-SPECTROMETRY; INTRACELLULAR D-SERINE; D-AMINO ACIDS; RACEMASE; PAIN; QUANTIFICATION; SCHIZOPHRENIA; CELLS; PC-12 AB A validated LC-MS/MS method was developed for the determination of D -Serine in human plasma. The method was fully validated for use with human plasma samples and was linear from 0.19 nmol/ml to 25 nmol/ml. The coefficient of variation was <= 5% for the high QC standards and <= 8% for the low QC standards in plasma. D -Serine and L -serine were resolved by pre-column derivatization using (R)-1-Boc-2-piperidine carbonyl chloride as the derivatizating agent. The method was used to determine the concentration of D-serine in plasma samples obtained in patients receiving a continuous 5-day intravenous infusion of (R,S)-ketamine. The changes in D-Ser levels varied in the six patients, with circulating D-Ser levels increasing as much as 35% in a patient, while decreasing 20% in a patient. While only preliminary data, the results suggests the potential importance in determining the D-Ser levels in plasma and their potential role in physiological response. Published by Elsevier B.V. C1 [Xie, Y.; Singh, N.; Wainer, I. W.; Moaddel, R.] NIA, Lab Clin Invest, Div Intramural Res Programs, NIH, Baltimore, MD 21224 USA. [Xie, Y.] Shanghai Jiao Tong Univ, Inst Med Sci, Dept Pharmacol, Sch Med, Shanghai 200025, Peoples R China. [Alexander, G. M.; Schwartzman, R. J.] Drexel Univ, Dept Neurol, Coll Med, Philadelphia, PA USA. [Torjman, M. C.; Goldberg, M. E.; Wainer, I. W.] Rowan Univ, Cooper Med Sch, Camden, NJ 08103 USA. RP Moaddel, R (reprint author), NIA, Lab Clin Invest, Div Intramural Res Programs, NIH, Baltimore, MD 21224 USA. EM moaddelru@mail.nih.gov RI Singh, Nagendra/K-8966-2015 FU National Institute on Aging/NIH FX This research was supported by the Intramural Research Program of the National Institute on Aging/NIH. NR 17 TC 7 Z9 7 U1 1 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 15 PY 2014 VL 89 BP 1 EP 5 DI 10.1016/j.jpba.2013.10.028 PG 5 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 300TN UT WOS:000330487000001 PM 24247087 ER PT J AU Liu, MT Wang, JN Wu, XG Wang, E Baptista, D Scott, B Liu, P AF Liu, Mingtao Wang, Jennie Wu, Xiaogang Wang, Euphemia Baptista, Diego Scott, Brendan Liu, Paul TI HPLC method development, validation and impurity characterization for an antitumor Hsp90 inhibitor-PU-H71 (NSC 750424) SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE PU-H71; NSC 750424; Forced degradation; HPLC validation; Stability study; Impurity characterization ID CANCER; PU-H71; TARGET AB An HPLC method for the assay of the heat shock protein 90 inhibitor, PU-H71 (NSC 750424), has been developed and validated. The stress testing of PU-H71 was carried out in accordance with ICH guidelines Q1A (R2) under aqueous, acidic, alkaline, oxidative, thermolytic and photolytic conditions. The separation of PU-H71 from its impurities and degradation products was achieved within 50 min on a Mac-Mod ACE 3 C18 column (150 mm x 4.6 mm i.d., 3 mu m) with a gradient mobile phase comprising 20-95% acetonitrile in water, with 0.1% trifluroacetic acid in both phases. LC-quadrupole TOF/MS was used to obtain accurate mass data on various components as well as on their fragments for characterization of impurities and degradation products. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.1-0.3 mg/mL, r >= 0.9998), accuracy (recovery 99.7-101.1%), precision (intra-lab RSD <= 1.39%, inter-lab RSD <= 0.91%), sensitivity (LOD 0.08 mu g/mL), and ruggedness. The developed method was suitable for the assay and stability monitoring of PU-H71 drug substance. (C) 2013 Elsevier B.V. All rights reserved. C1 [Liu, Mingtao; Wang, Jennie; Wu, Xiaogang; Wang, Euphemia; Baptista, Diego] SRI Int, Menlo Pk, CA 94025 USA. [Scott, Brendan] Midwest Res Inst, Kansas City, MO 64110 USA. [Liu, Paul] NCI, Pharmaceut Resources Branch, DCTD, Bethesda, MD 20892 USA. RP Wang, JN (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM jennie.wang@sri.com FU Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S. National Institutes of Health [HHSN261200722003C, HHSN261201200028C] FX This work was funded by Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S. National Institutes of Health under Contract No. HHSN261200722003C and Contract No. HHSN261201200028C. NR 17 TC 2 Z9 2 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 15 PY 2014 VL 89 BP 34 EP 41 DI 10.1016/j.jpba.2013.10.021 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 300TN UT WOS:000330487000006 PM 24252723 ER PT J AU Shuster, LI Moore, DR Chen, G Ruscello, DM Wonderlin, WF AF Shuster, Linda I. Moore, Donna R. Chen, Gang Ruscello, Dennis M. Wonderlin, William F. TI Does experience in talking facilitate speech repetition? SO NEUROIMAGE LA English DT Article ID SUPPLEMENTARY MOTOR AREA; AGE-RELATED-CHANGES; CORPUS-CALLOSUM; WHITE-MATTER; INTERHEMISPHERIC-TRANSFER; WORD RECOGNITION; REACTION-TIME; FMRI; ACTIVATION; COMPLEXITY AB Speech is unique among highly skilled human behaviors in its ease of acquisition by virtually all individuals who have normal hearing and cognitive ability. Vocal imitation is essential for acquiring speech, and it is an important element of social communication. The extent to which age-related changes in cognitive and motor function affect the ability to imitate speech is poorly understood. We analyzed the distributions of response times (RT) for repeating real words and pseudowords during fMRI. The average RT for older and younger participants was not different In contrast detailed analysis of RT distributions revealed age-dependent differences that were associated with changes in the time course of the BOLD response and specific patterns of regional activation. RT-dependent activity was observed in the bilateral posterior cingulate, supplementary motor area, and corpus callosum. This approach provides unique insight into the mechanisms associated with changes in speech production with aging. (C) 2013 Elsevier Inc. All rights reserved. C1 [Shuster, Linda I.; Moore, Donna R.; Ruscello, Dennis M.] W Virginia Univ, Dept Speech Pathol & Audiol, Morgantown, WV 26506 USA. [Shuster, Linda I.] W Virginia Univ, Ctr Adv Imaging, Morgantown, WV 26506 USA. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Wonderlin, William F.] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA. RP Shuster, LI (reprint author), 515 Michigan St NE,Suite 200, Grand Rapids, MI USA. EM shusterl@gvsu.edu; moore.2492@buckeyemail.osu.edu; gangchen@mail.nih.gov; Dennis.Ruscello@mail.wvu.edu; wwonderlin@hsc.wvu.edu FU National Institute on Deafness and Other Communication Disorders of the National Institutes of Health [R15DC011136]; Department of Radiology at West Virginia University FX Research reported in this publication was supported by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health under grant number R15DC011136 and by the Department of Radiology at West Virginia University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 48 TC 2 Z9 2 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 80 EP 88 DI 10.1016/j.neuroimage.2013.10.064 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000008 PM 24215974 ER PT J AU Lohith, TG Zoghbi, SS Morse, CL Araneta, MDF Barth, VN Goebl, NA Tauscher, JT Pike, VW Innis, RB Fujita, M AF Lohith, Talakad G. Zoghbi, Sami S. Morse, Cheryl L. Araneta, Maria D. Ferraris Barth, Vanessa N. Goebl, Nancy A. Tauscher, Johannes T. Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Retest imaging of [C-11]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans SO NEUROIMAGE LA English DT Article DE NOP receptors; Nociceptin; Test-retest imaging; PET; retest variability; intraclass correlation coefficient ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; INPUT FUNCTION; PET; NEURORECEPTOR; RADIOLIGAND; REPRODUCIBILITY; RADIOTRACERS; C-11-NOP-1A; VALIDATION AB [C-11]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [C-11]NOP-1A binding in the brain of healthy humans. After intravenous injection of [C-11]NOP-1A, PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V-T; a measure of receptor density) was determined by compartmental (one- and two-tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of V-T were determined as measures of reproducibility and reliability respectively. Regional [C-11]NOP-1A uptake in the brain was high, with a peak radioactivity concentration of 4-7 SUV (standardized uptake value) and a rank order of putamen > cingulate cortex > cerebellum. Brain time-activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of VT was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of VT was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability >20%. The lowest retest variability and highest retest reliability of VT were achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods. Moderately good reproducibility and reliability measures of VT for [C-11]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject. (C) 2013 Published by Elsevier Inc. C1 [Lohith, Talakad G.; Zoghbi, Sami S.; Morse, Cheryl L.; Araneta, Maria D. Ferraris; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Barth, Vanessa N.; Goebl, Nancy A.; Tauscher, Johannes T.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Lohith, TG (reprint author), NIMH, Mol Imaging Branch, 10 Ctr Dr,MSC 1026,Bldg 10,Rm B1D43K5, Bethesda, MD 20892 USA. EM lohithhere@gmail.com; robert.innis@nih.gov RI Tauscher, Johannes/M-5976-2016 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); Cooperative Research and Development Agreement with Eli Lilly Co FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and by a Cooperative Research and Development Agreement with Eli Lilly & Co. We thank Denise Rallis-Frutos, Gerald L. Hodges, Kimberly Jenko, David Clark, Jeih-San Liow, Robert L Gladding, Paolo Zanotti-Fregonara, and the staff of the PET Department for assistance in completing the studies, and PMOD Technologies (Zurich, Switzerland) for providing its image analysis and modeling software. Francois Vandenhende (Eli Lilly & Co.) provided valuable statistical guidance. Ioline Henter (NIMH) provided excellent editorial assistance. NR 24 TC 8 Z9 8 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 89 EP 95 DI 10.1016/j.neuroimage.2013.10.068 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000009 PM 24225488 ER PT J AU Bright, MG Bianciardi, M de Zwart, JA Murphy, K Duyn, JH AF Bright, Molly G. Bianciardi, Marta de Zwart, Jacco A. Murphy, Kevin Duyn, Jeff H. TI Early anti-correlated BOLD signal changes of physiologic origin SO NEUROIMAGE LA English DT Article DE fMRI; Negative BOLD; Anti-correlated BOLD; Physiology; Respiratory challenge; Deactivation ID PRIMARY SOMATOSENSORY CORTEX; SENSORY STIMULATION; FMRI SIGNALS; BLOOD-FLOW; BRAIN; FLUCTUATIONS; HYPERCAPNIA; ACTIVATION; DYNAMICS; CONTRAST AB Negative BOLD signals that are synchronous with resting state fluctuations have been observed in large vessels in the cortical sulci and surrounding the ventricles. In this study, we investigated the origin of these negative BOLD signals by applying a Cued Deep Breathing (COB) task to create transient hypocapnia and a resultant global fMRI signal decrease. We hypothesized that a global stimulus would amplify the effect in large vessels and that using a global negative (vasoconstrictive) stimulus would test whether these voxels exhibit either inherently negative or simply anti-correlated BOLD responses. Significantly anti-correlated, but positive, BOLD signal changes during respiratory challenges were identified in voxels primarily located near edges of brain spaces containing CSF. These positive BOLD responses occurred earlier than the negative COB response across most of gray matter voxels. These findings confirm earlier suggestions that in some brain regions, local, fractional changes in CSF volume may overwhelm BOLD-related signal changes, leading to signal anti-correlation. We show that regions with CDB anti-correlated signals coincide with most, but not all, of the regions with negative BOLD signal changes observed during a visual and motor stimulus task. Thus, the addition of a physiological challenge to fMRI experiments can help identify which negative BOLD signals are passive physiological anti-correlations and which may have a putative neuronal origin. Published by Elsevier Inc. C1 [Bright, Molly G.; Bianciardi, Marta; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. [Bright, Molly G.; Murphy, Kevin] Cardiff Univ, Sch Psychol, CUBRIC, Cardiff CF10 3AT, S Glam, Wales. [Bianciardi, Marta] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Boston, MA USA. RP Bright, MG (reprint author), Cardiff Univ, Sch Psychol, CUBRIC, Cardiff CF10 3AT, S Glam, Wales. EM BrightMG@cardiff.ac.uk RI Murphy, Kevin/A-1581-2010; OI Murphy, Kevin/0000-0002-6516-313X; Bright, Molly/0000-0001-7257-9646 FU Intramural Research Program of NINDS/NIH; Wellcome Trust FX We thank Susan Fulton Guttman for her assistance in the data acquisition. This research was supported by the Intramural Research Program of NINDS/NIH and the Wellcome Trust. NR 35 TC 4 Z9 4 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 287 EP 296 DI 10.1016/j.neuroimage.2013.10.055 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000028 PM 24211818 ER PT J AU Danthi, N Wu, CO Shi, PB Lauer, M AF Danthi, Narasimhan Wu, Colin O. Shi, Peibei Lauer, Michael TI Percentile Ranking and Citation Impact of a Large Cohort of National Heart, Lung, and Blood Institute-Funded Cardiovascular R01 Grants SO CIRCULATION RESEARCH LA English DT Article DE bibliometrics; National Heart; Lung; and Blood Institute (U; S; ) ID SCIENTIFIC PRODUCTIVITY AB Rationale: Funding decisions for cardiovascular R01 grant applications at the National Heart, Lung, and Blood Institute (NHLBI) largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science. Objective: Our aim was to conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants. Methods and Results: We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008 and followed their progress for linked publications and citations to those publications. Our coprimary end points were citations received per million dollars of funding, citations obtained <2 years of publication, and 2-year citations for each grant's maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total National Institutes of Health awards, the portfolio yielded 16 793 publications that appeared between 2001 and 2012 (median per grant, 8; 25th and 75th percentiles, 4 and 14; range, 0-123), which received 2 224 255 citations (median per grant, 1048; 25th and 75th percentiles, 492 and 1932; range, 0-16 295). We found no association between percentile rankings and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus nonhuman focus, and institutional funding. An exploratory machine learning analysis suggested that grants with the best percentile rankings did yield more maximally cited papers. Conclusions: In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics. C1 [Danthi, Narasimhan] NHLBI, Adv Technol & Surg Branch, Bethesda, MD 20824 USA. [Wu, Colin O.; Shi, Peibei] NHLBI, Off Biostat Res, Bethesda, MD 20824 USA. [Lauer, Michael] NHLBI, Off Director, Div Cardiovasc Sci, Bethesda, MD 20824 USA. RP Lauer, M (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20824 USA. EM lauerm@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 18 TC 27 Z9 28 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD FEB 14 PY 2014 VL 114 IS 4 BP 600 EP 606 DI 10.1161/CIRCRESAHA.114.302656 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AG7GT UT WOS:000335587000010 PM 24406983 ER PT J AU Anderluh, A Klotzsch, E Reismann, AWAF Brameshuber, M Kudlacek, O Newman, AH Sitte, HH Schutz, GJ AF Anderluh, Andreas Klotzsch, Enrico Reismann, Alexander W. A. F. Brameshuber, Mario Kudlacek, Oliver Newman, Amy Hauck Sitte, Harald H. Schuetz, Gerhard J. TI Single Molecule Analysis Reveals Coexistence of Stable Serotonin Transporter Monomers and Oligomers in the Live Cell Plasma Membrane SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Membrane Proteins; Protein Dynamics; Protein-Protein Interactions; Serotonin Transporters; Single Molecule Biophysics; Oligomerization ID HUMAN DOPAMINE TRANSPORTER; ENERGY-TRANSFER MICROSCOPY; RAT GABA TRANSPORTER-1; NEUROTRANSMITTER TRANSPORTERS; LIVING CELLS; TRANSMEMBRANE SEGMENT; COCAINE ANALOGS; CROSS-LINKING; PROTEIN; TRAFFICKING AB Background: The serotonin transporter (SERT) terminates synaptic signaling by reuptake of the neurotransmitter serotonin. Results: Interaction kinetics and number of subunits are elucidated by single molecule brightness analysis of SERT complexes. Conclusion: The oligomeric state of SERT complexes is stably determined before being integrated into the plasma membrane. Significance: The results reveal the first evidence for kinetic trapping of preformed neurotransmitter transporter oligomers. The human serotonin transporter (hSERT) is responsible for the termination of synaptic serotonergic signaling. Although there is solid evidence that SERT forms oligomeric complexes, the exact stoichiometry of the complexes and the fractions of different coexisting oligomeric states still remain enigmatic. Here we used single molecule fluorescence microscopy to obtain the oligomerization state of the SERT via brightness analysis of single diffraction-limited fluorescent spots. Heterologously expressed SERT was labeled either with the fluorescent inhibitor JHC 1-64 or via fusion to monomeric GFP. We found a variety of oligomerization states of membrane-associated transporters, revealing molecular associations larger than dimers and demonstrating the coexistence of different degrees of oligomerization in a single cell; the data are in agreement with a linear aggregation model. Furthermore, oligomerization was found to be independent of SERT surface density, and oligomers remained stable over several minutes in the live cell plasma membrane. Together, the results indicate kinetic trapping of preformed SERT oligomers at the plasma membrane. C1 [Anderluh, Andreas; Klotzsch, Enrico; Reismann, Alexander W. A. F.; Brameshuber, Mario; Schuetz, Gerhard J.] Vienna Univ Technol, Inst Appl Phys, A-1060 Vienna, Austria. [Kudlacek, Oliver; Sitte, Harald H.] Med Univ Vienna, Inst Pharmacol, Ctr Physiol & Pharmacol, A-1090 Vienna, Austria. [Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Klotzsch, E (reprint author), Vienna Univ Technol, Inst Appl Phys, Getreidemarkt 9, A-1060 Vienna, Austria. EM enricoklotzsch@gmail.com; schuetz@iap.tuwien.ac.at RI Klotzsch, Enrico/J-8831-2012; Schutz, Gerhard/B-1243-2008; OI Klotzsch, Enrico/0000-0002-7577-9042; Schutz, Gerhard/0000-0003-1542-1089; Brameshuber, Mario/0000-0001-8672-2255; Sitte, Harald/0000-0002-1339-7444 FU Austrian Science Fund/FWF Projects [F3506-B20, F3519-B20]; National Institute on Drug Abuse-Intramural Research Program; Federation of European Biochemical Societies FX This work was supported by the Austrian Science Fund/FWF Projects F3506-B20 (to H. H. S.) and F3519-B20 (to G. J. S.) and by the National Institute on Drug Abuse-Intramural Research Program (to A. H. N.).; Supported by a long term fellowship from the Federation of European Biochemical Societies. To whom correspondence may be addressed. Tel.: 43-01-58801134884; E-mail: enricoklotzsch@gmail.com. NR 50 TC 20 Z9 20 U1 1 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 14 PY 2014 VL 289 IS 7 BP 4387 EP 4394 DI 10.1074/jbc.M113.531632 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA9HG UT WOS:000331403800049 PM 24394416 ER PT J AU Huang, CH Chu, YR Ye, YH Chen, X AF Huang, Chih-Hsiang Chu, Yue-Ru Ye, Yihong Chen, Xin TI Role of HERP and a HERP-related Protein in HRD1-dependent Protein Degradation at the Endoplasmic Reticulum SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cell Biology; ER Quality Control; Protein Degradation; Protein Translocation; Ubiquitin Ligase ID ER-ASSOCIATED DEGRADATION; UBIQUITIN-LIGASE; QUALITY-CONTROL; PATHWAY; COMPLEX; STRESS; HOMEOSTASIS; HRD1P AB Misfolded proteins of the endoplasmic reticulum (ER) are retrotranslocated to the cytosol and degraded by the proteasome via a process termed ER-associated degradation (ERAD). The precise mechanism of retrotranslocation is unclear. Here, we use several lumenal ERAD substrates targeted for degradation by the ubiquitin ligase HRD1 including SHH (sonic hedgehog) and NHK (null Hong Kong 1-antitrypsin) to study the geometry, organization, and regulation of the HRD1-containing ERAD machinery. We report a new HRD1-associated membrane protein named HERP2, which is homologous to the previously identified HRD1 partner HERP1. Despite sequence homology, HERP2 is constitutively expressed in cells, whereas HERP1 is highly induced by ER stress. We find that these proteins are required for efficient degradation of both glycosylated and nonglycosylated SHH proteins as well as NHK. In cells depleted of HERPs, SHH proteins are largely trapped inside the ER with a fraction of the stabilized SHH protein bound to the HRD1-SEL1L ligase complex. Ubiquitination of SHH is significantly attenuated in the absence of HERPs, suggesting a defect in retrotranslocation. Both HERP proteins interact with HRD1 through a region located in the cytosol. However, unlike its homolog in Saccharomyces cerevisiae, HERPs do not regulate HRD1 stability or oligomerization status. Instead, they help recruit DERL2 to the HRD1-SEL1L complex. Additionally, the UBL domain of HERP1 also seems to have a function independent of DERL2 recruitment in ERAD. Our studies have revealed a critical scaffolding function for mammalian HERP proteins that is required for forming an active retrotranslocation complex containing HRD1, SEL1L, and DERL2. C1 [Huang, Chih-Hsiang; Chu, Yue-Ru; Chen, Xin] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Miaoli 35053, Taiwan. [Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Xin] China Med Univ, Grad Inst Basic Med Sci, Taichung 40402, Taiwan. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@niddk.nih.gov; xchen@nhri.org.tw FU National Research Programs for Genomic Medicine (NRPGM), National Science Council; National Health Research Institutes, Taiwan, China FX This work was supported by the National Research Programs for Genomic Medicine (NRPGM), National Science Council, and National Health Research Institutes, Taiwan, China. This work was supported by the National Research Programs for Genomic Medicine (NRPGM), National Science Council and National Health Research Institutes, Taiwan, China. NR 28 TC 7 Z9 7 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 14 PY 2014 VL 289 IS 7 BP 4444 EP 4454 DI 10.1074/jbc.M113.519561 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA9HG UT WOS:000331403800054 PM 24366871 ER PT J AU Sokolowska, M Chen, LY Eberlein, M Martinez-Anton, A Liu, YQ Alsaaty, S Qi, HY Logun, C Horton, M Shelhamer, JH AF Sokolowska, Milena Chen, Li-Yuan Eberlein, Michael Martinez-Anton, Asuncion Liu, Yueqin Alsaaty, Sara Qi, Hai-Yan Logun, Carolea Horton, Maureen Shelhamer, James H. TI Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A(2)alpha and Eicosanoid Production in Monocytes and Macrophages SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cyclooxygenase (COX) Pathway; Eicosanoid; Extracellular Matrix; Inflammation; Monocytes; Toll-like Receptors (TLR); Hyaluronan; Prostaglandin; cPLA2; Macrophage Polarization ID APC(DELTA-716) KNOCKOUT MICE; HUMAN LUNG-CELLS; NF-KAPPA-B; INTESTINAL POLYPOSIS; SERUM HYALURONAN; NEGATIVE REGULATOR; MOUSE MACROPHAGES; INTERFERON-GAMMA; BINDING PROTEINS; GENE-EXPRESSION AB Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix. During inflammation, there is an increased breakdown of HA, resulting in the accumulation of low molecular weight (LMW) HA and activation of monocytes and macrophages. Eicosanoids, derived from the cytosolic phospholipase A(2) group IVA (cPLA(2)) activation, are potent lipid mediators also attributed to acute and chronic inflammation. The aim of this study was to determine the effect of LMW HA on cPLA(2) activation, arachidonic acid (AA) release, and subsequent eicosanoid production and to examine the receptors and downstream mechanisms involved in these processes in monocytes and differently polarized macrophages. LMW HA was a potent stimulant of AA release in a time- and dose-dependent manner, induced cPLA(2), ERK1/2, p38, and JNK phosphorylation, as well as activated COX2 expression and prostaglandin (PG) E-2 production in primary human monocytes, murine RAW 264.7, and wild-type bone marrow-derived macrophages. Specific cPLA(2) inhibitor blocked HA-induced AA release and PGE(2) production in all of these cells. Using CD44, TLR4, TLR2, MYD88, RHAMM or STAB2 siRNA-transfected macrophages and monocytes, we found that AA release, cPLA(2), ERK1/2, p38, and JNK phosphorylation, COX2 expression, and PGE(2) production were activated by LMW HA through a TLR4/MYD88 pathway. Likewise, PGE(2) production and COX2 expression were blocked in Tlr4(-/-) and Myd88(-/-) mice, but not in Cd44(-/-) mice, after LMW HA stimulation. Moreover, we demonstrated that LMW HA activated the M1 macrophage phenotype with the unique cPLA(2)/COX2(high) and COX1/ALOX15/ALOX5/LTA4H(low) gene and PGE(2)/PGD(2)/15-HETEhigh and LXA(4)(low) eicosanoid profile. These findings reveal a novel link between HA-mediated inflammation and lipid metabolism. C1 [Sokolowska, Milena; Chen, Li-Yuan; Eberlein, Michael; Martinez-Anton, Asuncion; Liu, Yueqin; Alsaaty, Sara; Qi, Hai-Yan; Logun, Carolea; Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Horton, Maureen] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD 21205 USA. RP Shelhamer, JH (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jshelhamer@cc.nih.gov RI Martinez Anton, Asuncion/A-5806-2017 OI Martinez Anton, Asuncion/0000-0001-9758-5911 FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health intramural program. NR 107 TC 20 Z9 20 U1 2 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 14 PY 2014 VL 289 IS 7 BP 4470 EP 4488 DI 10.1074/jbc.M113.515106 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA9HG UT WOS:000331403800056 PM 24366870 ER PT J AU Malek, NP Schmidt, S Huber, P Manns, MP Greten, TF AF Malek, Nisar P. Schmidt, Sebastian Huber, Petra Manns, Michael P. Greten, Tim F. TI The Diagnosis and Treatment of Hepatocellular Carcinoma SO DEUTSCHES ARZTEBLATT INTERNATIONAL LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CHRONIC LIVER-DISEASE; FINE-NEEDLE BIOPSY; ACID-ENHANCED MRI; RADIOFREQUENCY ABLATION; RISK-FACTORS; DIABETIC-PATIENTS; CHEMOEMBOLIZATION; CIRRHOSIS; HEPATITIS AB Background: The incidence of hepatocellular carcinoma (HCC) has continued to rise in recent years. This increase has been attributed to alcohol-induced liver diseases, metabolic syndrome, and the rising number of hepatitis B and C viral infections. Methods: Pertinent publications (2000-2011) were retrieved by a systematic Medline search. In seven different subject areas, 41 key questions were defined; 15 of them were answered on the basis of a primary search. In addition, original-source guidelines that are currently available from around the world were assessed and utilized with the aid of a systematic instrument for the evaluation of guidelines (DELBI). Results: All patients with chronic liver disease should undergo ultrasonography every six months for the early detection of HCC. Measurement of the alpha-fetoprotein (AFP) concentration is not obligatory, as this test is relatively insensitive when used for early detection. If ultrasonography reveals a mass, a tomographic imaging study with contrast should be obtained; the latter may reveal a characteristic pattern of contrast enhancement that can be accepted as definitive evidence of HCC. Fine-needle biopsy has a sensitivity and specificity of over 90% for the diagnosis of HCC. Any patient in whom HCC has been diagnosed should be referred to a center where potentially curative treatments (surgery, transplantation, local ablation) can be considered. Radiofrequency ablation (RFA) is now performed instead of percutaneous ethanol instillation. For patients with advanced tumors, sorafenib should only be offered to those in Child-Pugh stage A. This drug has been found to prolong mean overall survival from 7.9 to 10.7 months. Conclusion: HCC poses particular diagnostic and therapeutic challenges that are best met with an interdisciplinary management approach. C1 [Malek, Nisar P.] Univ Tubingen, Dept Med, Tubingen, Germany. [Schmidt, Sebastian; Huber, Petra; Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Greten, Tim F.] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Malek, NP (reprint author), Univ Klinikum Tubingen, Med Klin 1, Otfried Muller Str 10, Tubingen, Germany. EM nisar.malek@med.uni-tuebingen.de RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU German Cancer Aid through its Oncology Guideline Program FX The preparation of the guideline was funded by German Cancer Aid through its Oncology Guideline Program. NR 43 TC 25 Z9 29 U1 1 U2 11 PU DEUTSCHER AERZTE-VERLAG GMBH PI COLOGNE PA DIESELSTRABE 2, POSTFACH 400265, D-50859 COLOGNE, GERMANY SN 1866-0452 J9 DTSCH ARZTEBL INT JI Dtsch. Arztebl. Int. PD FEB 14 PY 2014 VL 111 IS 7 BP 101 EP U13 DI 10.3238/arztebl.2014.0101 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AC9KE UT WOS:000332852500001 PM 24622679 ER PT J AU Lamb, JS Chadwick, RS AF Lamb, Jessica S. Chadwick, Richard S. TI Phase of Shear Vibrations within Cochlear Partition Leads to Activation of the Cochlear Amplifier SO PLOS ONE LA English DT Article ID HAIR CELL MOTILITY; TECTORIAL MEMBRANE; BASILAR-MEMBRANE; TRAVELING-WAVES; MODEL; MECHANICS; EAR; SUBPARTITIONS; AMPLIFICATION; TRANSDUCTION AB Since Georg von Bekesy laid out the place theory of the hearing, researchers have been working to understand the remarkable properties of mammalian hearing. Because access to the cochlea is restricted in live animals, and important aspects of hearing are destroyed in dead ones, models play a key role in interpreting local measurements. Wentzel-Kramers-Brillouin (WKB) models are attractive because they are analytically tractable, appropriate to the oblong geometry of the cochlea, and can predict wave behavior over a large span of the cochlea. Interest in the role the tectorial membrane (TM) plays in cochlear tuning led us to develop models that directly interface the TM with the cochlear fluid. In this work we add an angled shear between the TM and reticular lamina (RL), which serves as an input to a nonlinear active force. This feature plus a novel combination of previous work gives us a model with TM-fluid interaction, TM-RL shear, a nonlinear active force and a second wave mode. The behavior we get leads to the conclusion the phase between the shear and basilar membrane (BM) vibration is critical for amplification. We show there is a transition in this phase that occurs at a frequency below the cutoff, which is strongly influenced by TM stiffness. We describe this mechanism of sharpened BM velocity profile, which demonstrates the importance of the TM in overall cochlear tuning and offers an explanation for the response characteristics of the Tectb mutant mouse. C1 [Lamb, Jessica S.; Chadwick, Richard S.] NIDCD, Sect Auditory Mech, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), NIDCD, Sect Auditory Mech, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov FU National Institute on Deafness and other Communication Disorders [DC00033] FX This work was supported by the intramural program project DC00033 in the National Institute on Deafness and other Communication Disorders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 6 Z9 6 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 14 PY 2014 VL 9 IS 2 AR e85969 DI 10.1371/journal.pone.0085969 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7IR UT WOS:000331271500006 PM 24551037 ER PT J AU Wang, ZW Dela Cruz, R Ji, F Guo, S Zhang, JH Wang, Y Feng, GS Birnbaumer, L Jiang, MS Chu, WM AF Wang, Zhanwei Dela Cruz, Rica Ji, Fang Guo, Sheng Zhang, Jianhua Wang, Ying Feng, Gen-Sheng Birnbaumer, Lutz Jiang, Meisheng Chu, Wen-Ming TI G(i)alpha proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells SO CELL COMMUNICATION AND SIGNALING LA English DT Article DE G(i)alpha proteins; receptor tyrosine kinase (RTK); EGFR; Gab1; Shp2; EGF; Akt; mTORC1; ERK1/2; breast cancer ID COUPLED RECEPTORS; KINASE ACTIVATION; SIGNALING PATHWAY; DRUG DISCOVERY; EGF RECEPTOR; IN-VIVO; GAB1; INSULIN; METASTASIS; LIVER AB Background: In a classic model, G(i)alpha proteins including G(i1)alpha, G(i2)alpha and G(i3)alpha are important for transducing signals from Gia protein-coupled receptors (G(i)alpha PCRs) to their downstream cascades in response to hormones and neurotransmitters. Our previous study has suggested that G(i1)alpha, G(i2)alpha and G(i3)alpha are also important for the activation of the PI3K/Akt/mTORC1 pathway by epidermal growth factor (EGF) and its family members. However, a genetic role of these Gia proteins in the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) by EGF is largely unknown. Further, it is not clear whether these Gia proteins are also engaged in the activation of both the Akt/mTORC1 and ERK1/2 pathways by other growth factor family members. Additionally, a role of these Gia proteins in breast cancer remains to be elucidated. Results: We found that Gi1/3 deficient MEFs with the low expression level of G(i2)alpha showed defective ERK1/2 activation by EGFs, IGF-1 and insulin, and Akt and mTORC1 activation by EGFs and FGFs. Gi1/2/3 knockdown breast cancer cells exhibited a similar defect in the activations and a defect in in vitro growth and invasion. The G(i)alpha proteins associated with RTKs, Gab1, FRS2 and Shp2 in breast cancer cells and their ablation impaired Gab1's interactions with Shp2 in response to EGF and IGF-1, or with FRS2 and Grb2 in response to bFGF. Conclusions: G(i)alpha proteins differentially regulate the activation of Akt, mTORC1 and ERK1/2 by different families of growth factors. G(i)alpha proteins are important for breast cancer cell growth and invasion. C1 [Wang, Zhanwei; Dela Cruz, Rica; Guo, Sheng; Zhang, Jianhua; Chu, Wen-Ming] Univ Hawaii, Ctr Canc, Canc Biol Program, Honolulu, HI 96813 USA. [Ji, Fang] Shanghai Jiao Tong Univ, Sch Med, Dept Obstet & Gynecol, Ren Ji Hosp, Shanghai 200030, Peoples R China. [Guo, Sheng; Zhang, Jianhua] Shanghai Jiao Tong Univ, Dept Pediat, Shanghai Peoples Hosp 6, Shanghai 200030, Peoples R China. [Wang, Ying; Jiang, Meisheng] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Feng, Gen-Sheng] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92037 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Jiang, MS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. EM jm@ucla.edu; wchu@cc.hawaii.edu RI wang, zhanwei/F-9958-2016 FU DOD [PR054819]; NIH [AI054128, DK069771]; Hawaii Community Foundation; Leukemia and Lymphoma Society; National Institute of Environmental Health Sciences, NIH [201-101643] FX We are grateful to Drs. Cong Cao, Xuesong Huang and John Marshall for their valuable advice and technical support. We thank Dr. David Ward for critical discussion. This work was supported in part by grants from DOD (PR054819), NIH (AI054128), Hawaii Community Foundation and Leukemia and Lymphoma Society to WMC, NIH (DK069771) to MJ, and in part from the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (project 201-101643) to LB. NR 46 TC 4 Z9 4 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-811X J9 CELL COMMUN SIGNAL JI Cell Commun. Signal. PD FEB 13 PY 2014 VL 12 AR 10 DI 10.1186/1478-811X-12-10 PG 12 WC Cell Biology SC Cell Biology GA AD5FM UT WOS:000333277500001 PM 24521094 ER PT J AU Tang, J Li, Y Lyon, K Camps, J Dalton, S Ried, T Zhao, S AF Tang, J. Li, Y. Lyon, K. Camps, J. Dalton, S. Ried, T. Zhao, S. TI Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer SO ONCOGENE LA English DT Article DE CRC driver-passenger distinction; sporadic canine CRCs; human-dog comparison; epithelial cell apicobasal polarity; genomic amplifications/deletions ID CELL POLARITY; TUMOR-SUPPRESSOR; DOMESTIC DOG; GENOME; SEQUENCE; PROTEIN; COLON; TRANSITION; NETWORK; BREAST AB Herein we report a proof-of-principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver-passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species, and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, although PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals. C1 [Tang, J.; Li, Y.; Lyon, K.; Dalton, S.; Zhao, S.] Univ Georgia, Inst Bioinformat, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [Camps, J.; Ried, T.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhao, S (reprint author), Univ Georgia, Inst Bioinformat, Dept Biochem & Mol Biol, B304B Life Sci Bldg,120 Green St, Athens, GA 30602 USA. EM szhao@bmb.uga.edu RI Tang, Jie/D-3764-2015 OI Tang, Jie/0000-0002-3991-2539 FU American Cancer Society; Georgia Cancer Coalition; NCI [P50 CA128613] FX We thank Ms Huan Xiong for her work; Dr Bert Vogelstein for providing various CRC lines and Dr Timothy A Chan of Memorial Sloan-Kettering Cancer Center for providing the IHA cells; and Drs Dong M Shin, J David Puett, Claiborne Glover, Georgia Chen, and Lisa J Stubb for their help and advice on this study. This work was funded by the American Cancer Society and the Georgia Cancer Coalition (principal investigator (PI): S Zhao), as well as NCI P50 CA128613 (PI: Dr Dong M Shin) and GM085354 (PI: Dr Stephen Dalton). NR 50 TC 3 Z9 4 U1 1 U2 8 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 FEB 13 PY 2014 VL 33 IS 7 BP 814 EP 822 DI 10.1038/onc.2013.17 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AB2MN UT WOS:000331626900002 PM 23416983 ER PT J AU Shukla, A Edwards, R Yang, Y Hahn, A Folkers, K Ding, J Padmakumar, VC Cataisson, C Suh, KS Yuspa, SH AF Shukla, A. Edwards, R. Yang, Y. Hahn, A. Folkers, K. Ding, J. Padmakumar, V. C. Cataisson, C. Suh, K. S. Yuspa, S. H. TI CLIC4 regulates TGF-beta-dependent myofibroblast differentiation to produce a cancer stroma SO ONCOGENE LA English DT Article DE CLIC; alpha-SMA; p38; microenvironment; PPM1a ID EPITHELIAL-MESENCHYMAL TRANSITION; CHLORIDE CHANNEL PROTEIN; MUSCLE ACTIN EXPRESSION; CONTRACTILE ACTIVITY; MOLECULAR-CLONING; CRYSTAL-STRUCTURE; CELL CARCINOMA; FIBROBLASTS; GROWTH; PHOSPHATASE AB Cancer stroma has a profound influence on tumor development and progression. The conversion of fibroblasts to activated myofibroblasts is a hallmark of reactive tumor stroma. Among a number of factors involved in this conversion, transforming growth factor (TGF)-beta has emerged as a major regulator. CLIC4, an integral protein in TGF-beta signaling, is highly upregulated in stroma of multiple human cancers, and overexpression of CLIC4 in stromal cells enhances the growth of cancer xenografts. In this study, we show that conditioned media from tumor cell lines induces expression of both CLIC4 and the myofibroblast marker alpha smooth muscle actin (alpha-SMA) in stromal fibroblasts via TGF-beta signaling. Genetic ablation of CLIC4 in primary fibroblasts prevents or reduces constitutive or TGF-beta-induced expression of alpha-SMA and extracellular matrix components that are markers of myofibroblasts. CLIC4 is required for the activation of p38 map kinase by TGF-beta, a pathway that signals myofibroblast conversion in stromal cells. This requirement involves the interaction of CLIC4 with PPM1a, the selective phosphatase of activated p38. Conditioned media from fibroblasts overexpressing CLIC4 increases tumor cell migration and invasion in a TGF-beta-dependent manner and promotes epithelial to mesenchymal transition indicating that high stromal CLIC4 serves to enhance tumor invasiveness and progression. Thus, CLIC4 is significantly involved in the development of a nurturing tumor microenvironment by enhancing TGF-beta signaling in a positive feedback loop. Targeting CLIC4 in tumor stroma should be considered as a strategy to mitigate some of the tumor enhancing effects of the cancer stroma. C1 [Shukla, A.; Edwards, R.; Yang, Y.; Hahn, A.; Folkers, K.; Padmakumar, V. C.; Cataisson, C.; Yuspa, S. H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Ding, J.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Suh, K. S.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, 37 Convent Dr, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov RI Shukla, Anjali/G-4046-2014 FU Center for Cancer Research, National Cancer Institute FX We thank Dr Lalage Wakefield, National Cancer Institute, Bethesda for providing Smad3 KO mice and MI, MII, MIII, MIV cell lines, Dr Ed Leof, Department of Biochemistry and Molecular Biology, Mayo Clinic, Minnesota for providing anti-phospho Smad3 antibody and Dr Akira Oshima, National Cancer Institute for help with immunofluorescence. This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute. NR 54 TC 15 Z9 17 U1 0 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 FEB 13 PY 2014 VL 33 IS 7 BP 842 EP 850 DI 10.1038/onc.2013.18 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AB2MN UT WOS:000331626900005 PM 23416981 ER PT J AU Okunola-Bakare, OM Cao, JJ Kopajtic, T Katz, JL Loland, CJ Shi, L Newman, AH AF Okunola-Bakare, Oluyomi M. Cao, Jianjing Kopajtic, Theresa Katz, Jonathan L. Loland, Claus J. Shi, Lei Newman, Amy Hauck TI Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DOPAMINE TRANSPORTER; SEROTONIN TRANSPORTER; ALIPHATIC DISULFIDES; CHEMISTRY; MUTAGENESIS; MEDICATION; INHIBITOR; COGNITION; BINDING; POTENT AB 2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (+/-)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (+/-)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (+/-)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SEAT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. C1 [Okunola-Bakare, Oluyomi M.; Cao, Jianjing; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Kopajtic, Theresa; Katz, Jonathan L.] NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Loland, Claus J.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-1165 Copenhagen, Denmark. [Shi, Lei] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. [Shi, Lei] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10065 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov RI Loland, Claus/E-5975-2014; OI Loland, Claus/0000-0002-1773-1446; Katz, Jonathan/0000-0002-1068-1159 FU National Institute on Drug Abuse Intramural Research Program; Lundbeck Foundation; Danish Council for Independent Research Sapere Aude program FX Support for this research was provided to A.H.N., O.M.O.-B., J.C., T.K., and J.L.K. by the National Institute on Drug Abuse Intramural Research Program. C.J.L. is supported by the Lundbeck Foundation and the Danish Council for Independent Research Sapere Aude program. NR 31 TC 6 Z9 6 U1 3 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 13 PY 2014 VL 57 IS 3 BP 1000 EP 1013 DI 10.1021/jm401754x PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AB0OW UT WOS:000331493000032 PM 24494745 ER PT J AU Foley, TL Rai, G Yasgar, A Daniel, T Baker, HL Attene-Ramos, M Kosa, NM Leister, W Burkart, MD Jadhav, A Simeonov, A Maloney, DJ AF Foley, Timothy L. Rai, Ganesha Yasgar, Adam Daniel, Thomas Baker, Heather L. Attene-Ramos, Matias Kosa, Nicolas M. Leister, William Burkart, Michael D. Jadhav, Ajit Simeonov, Anton Maloney, David J. TI 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)pi perazine-1-carbothioamide (ML267), a Potent Inhibitor of Bacterial Phosphopantetheinyl Transferase That Attenuates Secondary Metabolism and Thwarts Bacterial Growth SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CARRIER PROTEIN SYNTHASE; FATTY-ACID SYNTHESIS; SMALL-MOLECULE INHIBITION; CROSS-COUPLING REACTIONS; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; C-N; PSEUDOMONAS-AERUGINOSA; ANTIBACTERIAL DISCOVERY; BACILLUS-SUBTILIS AB 4'-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)-piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus, and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli. Additionally, we highlight the in vitro absorption, distribution, metabolism; and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor. C1 [Foley, Timothy L.; Rai, Ganesha; Yasgar, Adam; Daniel, Thomas; Baker, Heather L.; Attene-Ramos, Matias; Leister, William; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Kosa, Nicolas M.; Burkart, Michael D.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. RP Simeonov, A (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM asimeono@mail.nih.gov; maloneyd@mail.nih.gov FU National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681]; NIH [R21AI090213, R01GM094924] FX T.L.F., G.R., A.Y., T.D., H.L.B., M.A.-R., W.L., A.J., A.S., and D.J.M. were supported by the intramural research program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (Grant U54MH084681). N.M.K. and M.D.B. were supported by NIH Grants R21AI090213 and R01GM094924. We thank Sam Michael, Michael Balcom (deceased), and Richard Jones for automation support, Paul Shinn and Danielle van Leer for the assistance with compound management, Edward H. Kerns and Kimloan Nguyen for determination of in vitro ADME properties, Elizabeth Fernandez, Christopher Leclair, and Heather Baker for assistance with compound purification and processing, Mohamed Marahiel (Philipps-Universitat Marburg), the Bacillus Genomic Stock Center, and The National BioResource Project of the Japanese National Institute for Genetics for bacterial strains, Udo Oppermann (University of Oxford) for the human PPTase expression plasmid, and Victor Torres (Anti-infectives Screening Core, New York University) for MIC studies on clinical isolates of MRSA and conducting the mouse model of staphylococcal septicemia. NR 62 TC 11 Z9 11 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 13 PY 2014 VL 57 IS 3 BP 1063 EP 1078 DI 10.1021/jm401752p PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AB0OW UT WOS:000331493000037 PM 24450337 ER PT J AU Ferreyra, GA Elinoff, JM Demirkale, CY Starost, MF Buckley, M Munson, PJ Krakauer, T Danner, RL AF Ferreyra, Gabriela A. Elinoff, Jason M. Demirkale, Cumhur Y. Starost, Matthew F. Buckley, Marilyn Munson, Peter J. Krakauer, Teresa Danner, Robert L. TI Late Multiple Organ Surge in Interferon-Regulated Target Genes Characterizes Staphylococcal Enterotoxin B Lethality SO PLOS ONE LA English DT Article ID TOXIC-SHOCK-SYNDROME; A STREPTOCOCCAL INFECTIONS; MONKEYS MACACA-MULATTA; INNATE IMMUNE-RESPONSE; HUMAN T-CELLS; DENDRITIC CELLS; I INTERFERON; BACTERIAL SUPERANTIGENS; INTRANASAL EXPOSURE; ENDOTHELIAL-CELLS AB Background: Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB) challenge was investigated in six tissues. Results: The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC), spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RTPCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN)/antiviralresponse and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN)-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature. Conclusion: Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes. C1 [Ferreyra, Gabriela A.; Elinoff, Jason M.; Danner, Robert L.] NIH, Funct Genom & Prote Facil, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Demirkale, Cumhur Y.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Buckley, Marilyn; Krakauer, Teresa] US Army Med Res Inst Infect Dis, Integrated Toxicol Div, Ft Detrick, MD 21702 USA. RP Krakauer, T (reprint author), US Army Med Res Inst Infect Dis, Integrated Toxicol Div, Ft Detrick, MD 21702 USA. EM teresa.krakauer@us.army.mil; rdanner@nih.gov FU Defense Threat Reduction Agency [DTRA 3.10035]; Intramural Research Program of the Critical Care Medicine Department, NIH Clinical Center FX This research was entirely funded by The Defense Threat Reduction Agency (#DTRA 3.10035) and the Intramural Research Program of the Critical Care Medicine Department, NIH Clinical Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 7 Z9 7 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 13 PY 2014 VL 9 IS 2 AR e88756 DI 10.1371/journal.pone.0088756 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7GP UT WOS:000331266000062 PM 24551153 ER PT J AU Yin, HG Kosa, P Liu, XB Swaim, WD Lai, ZN Cabrera-Perez, J Di Pasquale, G Ambudkar, IS Bugge, TH Chiorini, JA AF Yin, Hongen Kosa, Peter Liu, Xibao Swaim, William D. Lai, Zhennan Cabrera-Perez, Javier Di Pasquale, Giovanni Ambudkar, Indu S. Bugge, Thomas H. Chiorini, John A. TI Matriptase Deletion Initiates a Sjogren's Syndrome-Like Disease in Mice SO PLOS ONE LA English DT Article ID SALIVARY-GLAND; NETHERTON-SYNDROME; TIGHT JUNCTION; ATOPIC-DERMATITIS; EPITHELIAL-CELLS; TRANSGENIC MICE; EXPRESSION; GENE; MUTATIONS; ICHTHYOSIS AB Objective: The objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model. Methods: Embryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers. Results: Embryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjogren's syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjogren's syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers. Conclusions: Our findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland dysfunction in the absence of inflammation while systemic deletion can induce a primary Sjogren's syndrome like phenotype with autoimmunity and loss of gland function. C1 [Yin, Hongen; Liu, Xibao; Swaim, William D.; Lai, Zhennan; Cabrera-Perez, Javier; Di Pasquale, Giovanni; Ambudkar, Indu S.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Kosa, Peter; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Yin, HG (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM yinho@mail.nih.gov; jchiorini@dir.nidcr.nih.gov FU National Institutes of Health (NIH); National Institute of Dental and Craniofacial Research (NIDCR) intramural grants FX This work is supported by National Institutes of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR) intramural grants to JAC and THB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 5 Z9 5 U1 0 U2 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 FEB 13 PY 2014 VL 9 IS 2 AR e82852 DI 10.1371/journal.pone.0082852 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7GP UT WOS:000331266000001 PM 24551030 ER PT J AU Baker, SG Kramer, BS Lindeman, KS AF Baker, Stuart G. Kramer, Barnett S. Lindeman, Karen S. TI The Randomized Registry Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Baker, Stuart G.; Kramer, Barnett S.] NIH, Bethesda, MD 20892 USA. [Lindeman, Karen S.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Baker, SG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 5 TC 3 Z9 3 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 13 PY 2014 VL 370 IS 7 BP 681 EP 682 DI 10.1056/NEJMc1315677 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AA6CX UT WOS:000331187500032 PM 24521130 ER PT J AU Fenalti, G Giguere, PM Katritch, V Huang, XP Thompson, AA Cherezov, V Roth, BL Stevens, RC AF Fenalti, Gustavo Giguere, Patrick M. Katritch, Vsevolod Huang, Xi-Ping Thompson, Aaron A. Cherezov, Vadim Roth, Bryan L. Stevens, Raymond C. TI Molecular control of delta-opioid receptor signalling SO NATURE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; X-RAY CRYSTALLOGRAPHY; SODIUM-IONS; CRYSTALLIZING MEMBRANE; ALLOSTERIC REGULATION; LIPIDIC MESOPHASES; INVERSE AGONISTS; ANTAGONISTS; DISCOVERY; BINDING AB Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 angstrom high-resolution crystal structure of the human delta-opioid receptor (delta-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive delta-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive beta-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical delta-opioid antagonists such as naltrindole into potent beta-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor. C1 [Fenalti, Gustavo; Katritch, Vsevolod; Thompson, Aaron A.; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Giguere, Patrick M.; Huang, Xi-Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Giguere, Patrick M.; Huang, Xi-Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Giguere, Patrick M.; Huang, Xi-Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM bryan_roth@med.unc.edu; stevens@scripps.edu RI Roth, Bryan/F-3928-2010; Cherezov, Vadim/L-9812-2013; Katritch, Vsevolod/Q-8357-2016; Stevens, Raymond/K-7272-2015 OI Cherezov, Vadim/0000-0002-5265-3914; Stevens, Raymond/0000-0002-4522-8725 FU National Institutes of Health [P50 GM073197, U54 GM094618, R01 DA017204]; NIMH Psychoactive Drug Screening Program; Michael Hooker Chair for Protein Therapeutics and Translational Proteomics; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104] FX This work was supported by the National Institutes of Health Common Fund grant P50 GM073197 for technology development (V. C. and R. C. S.), PSI:Biology grant U54 GM094618 for biological studies and structure production (target GPCR-39) (V. K., V. C. and R. C. S.), R01 DA017204 and the NIMH Psychoactive Drug Screening Program (P. G., X.-P. H., B. L. R.) and the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics to B. L. R. We thank J. Velasquez for help with molecular biology, T. Trinh and M. Chu for help with baculovirus expression, G. W. Han for help with structure analysis and quality control review, E. Abola for help with sodium site analysis, A. Walker for assistance with manuscript preparation and J. Smith, R. Fischetti and N. Sanishvili for assistance in development and use of the minibeam and beamtime at beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. NR 46 TC 135 Z9 137 U1 3 U2 68 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 FEB 13 PY 2014 VL 506 IS 7487 BP 191 EP 196 DI 10.1038/nature12944 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA5AK UT WOS:000331107700031 PM 24413399 ER PT J AU Smith, AA Kepka, D Yabroff, KR AF Smith, Alexandria A. Kepka, Deanna Yabroff, K. Robin TI Advanced practice registered nurses, physician assistants and cancer prevention and screening: a systematic review SO BMC HEALTH SERVICES RESEARCH LA English DT Review ID HEALTH-CARE PROVIDERS; CERVICAL-CANCER; UNITED-STATES; FOLLOW-UP; PRACTITIONERS; SERVICES; WOMEN; DISPARITIES; PATTERNS; OVERUSE AB Background: For more than two decades, integration of team-based approaches in primary care, including physicians, advanced practice registered nurses and physician assistants (APRN/PA), have been recommended for improving healthcare delivery, yet little is known about their roles in cancer screening and prevention. This study aims to review the current literature on the participation and roles of APRN/PAs in providing cancer screening and prevention recommendations in primary care settings in the United States. Methods: We searched MEDLINE and CINAHL to identify studies published in 1990-2011 reporting on cervical, breast, and colorectal cancer screening and smoking cessation, diet, and physical activity recommendations by APRN/PAs in the United States. A total of 15 studies met all of our eligibility criteria. Key study, provider, and patient characteristics were abstracted as were findings about APRN/PA recommendations for screening and prevention. Results: Most studies were cross-sectional, showed results from within a single city or state, had relatively small sample sizes, reported non-standardized outcome measures. Few studies reported any patient characteristics. APRN/PAs are involved in recommending cancer screening and prevention, although we found variation across screening tests and health behavior recommendations. Conclusions: Additional research on the cancer prevention and screening practices of APRN/PAs in primary care settings using standardized outcome measures in relation to evidence-based guidelines may help strengthen primary care delivery in the United States. C1 [Smith, Alexandria A.] Amer Legacy Fdn, Washington, DC USA. [Kepka, Deanna; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kepka, Deanna] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Kepka, Deanna] Huntsman Canc Inst, Salt Lake City, UT USA. RP Kepka, D (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM deanna.Kepka@hci.utah.edu OI Yabroff, K. Robin/0000-0003-0644-5572 NR 44 TC 4 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD FEB 12 PY 2014 VL 14 AR 68 DI 10.1186/1472-6963-14-68 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AC6DJ UT WOS:000332611300001 PM 24521264 ER PT J AU Wu, XS Wu, LG AF Wu, Xin-Sheng Wu, Ling-Gang TI The Yin and Yang of Calcium Effects on Synaptic Vesicle Endocytosis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium; endocytosis ID FROG NEUROMUSCULAR-JUNCTION; ADRENAL CHROMAFFIN CELLS; KISS-AND-RUN; NEUROTRANSMITTER RELEASE; AFFERENT SYNAPSE; NERVE-TERMINALS; TRAPEZOID BODY; MEDIAL NUCLEUS; CNS SYNAPSE; CA2+ AB A large number of studies suggest that calcium triggers and accelerates vesicle endocytosis at many synapses and non-neuronal secretory cells. However, many studies show that prolonging the duration of the stimulation train, which induces more calcium influx, slows down endocytosis; and several studies suggest that instead of triggering endocytosis, calcium actually inhibits endocytosis. Here we addressed this apparent conflict at a large nerve terminal, the calyx of Held in rat brainstem, in which recent studies suggest that transient calcium increase up to tens of micromolar concentration at the micro/nano domain triggers endocytosis. By dialyzing 0-1 mu M calcium into the calyx via a whole-cell pipette, we found that slow endocytosis was inhibited by calcium dialysis in a concentration-dependent manner. Thus, prolonged, small, and global calcium increase inhibits endocytosis, whereas transient and large calcium increase at the micro/nano domain triggers endocytosis and facilitates endocytosis. This yin and yang effect of calcium may reconcile apparent conflicts regarding whether calcium accelerates or inhibits endocytosis. Whether endocytosis is fast or slow depends on the net outcome between the yin and yang effect of calcium. C1 [Wu, Xin-Sheng; Wu, Ling-Gang] NINDS, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. We thank Drs. Fujun Luo, Jiansong Sheng, and Zhen Zhang for critical reading of this manuscript. NR 49 TC 11 Z9 11 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 12 PY 2014 VL 34 IS 7 BP 2652 EP 2659 DI 10.1523/JNEUROSCI.3582-13.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AB2HV UT WOS:000331614700026 PM 24523554 ER PT J AU Gazzinelli, RT Mendonca-Neto, R Lilue, J Howard, J Sher, A AF Gazzinelli, Ricardo T. Mendonca-Neto, Rondon Lilue, Jingtao Howard, Jonathan Sher, Alan TI Innate Resistance against Toxoplasma gondii: An Evolutionary Tale of Mice, Cats, and Men SO CELL HOST & MICROBE LA English DT Review ID TOLL-LIKE RECEPTORS; DENDRITIC CELLS; INFECTION; PROFILIN; IMMUNITY; MECHANISM; MONOCYTES; VIRULENCE; PROTEIN; GTPASES AB Recent studies have revealed remarkable species specificity of the Toll-like receptors (TLRs) TLR11 and TLR12 and the immunity-related GTPase (IRG) proteins that are essential elements for detection and immune control of Toxoplasma gondii in mice, but not in humans. The biological and evolutionary implications of these findings for the T. gondii host-pathogen relationship and for human disease are discussed. C1 [Gazzinelli, Ricardo T.] Oswaldo Cruz Fdn Minas Gerais, Rene Rachou Inst, Immunopathol Lab, BR-30190002 Belo Horizonte, MG, Brazil. [Gazzinelli, Ricardo T.; Mendonca-Neto, Rondon] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil. [Gazzinelli, Ricardo T.] Univ Massachusetts Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [Lilue, Jingtao; Howard, Jonathan] Univ Cologne, Inst Genet, D-50674 Cologne, Germany. [Howard, Jonathan] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal. [Sher, Alan] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Gazzinelli, RT (reprint author), Oswaldo Cruz Fdn Minas Gerais, Rene Rachou Inst, Immunopathol Lab, BR-30190002 Belo Horizonte, MG, Brazil. EM ritoga@cpqrr.fiocruz.br; jhoward@igc.gulbenkian.pt; asher@niaid.nih.gov OI Lilue, Jingtao/0000-0002-1958-0231 FU CAPES; David Rockefeller Center for Latin America Studies at the Harvard School of Public Health; National Institute of Science and Technology on Vaccines; National Institutes of Health [NIAID R01 AI071319-01]; German Research Council [SPP1399, SFB670, SFB680]; Intramural Program of the National Institutes of Allergy and Infectious Disease FX The authors apologize for not citing many of the important references that have contributed to this review owing to space limitations. We are grateful to the members of our laboratories as well as Sankar Ghosh, Greg Taylor, and Felix Yarovinsky for important discussions and their key contributions in defining the role of TLR11, TLR12, and IRG proteins in mouse resistance to T. gondii. We also thank Daniel Caffrey and Warrison Andrade for critically reading this manuscript and for discussions. R.T.G. is recipient of the Visiting Professor Scholarship from CAPES and the David Rockefeller Center for Latin America Studies at the Harvard School of Public Health and is supported by the National Institute of Science and Technology on Vaccines and the National Institutes of Health (NIAID R01 AI071319-01). J.H. is recipient of the SPP1399, SFB670, and SFB680 grants from the German Research Council, while A.S. is supported by the Intramural Program of the National Institutes of Allergy and Infectious Disease. NR 25 TC 17 Z9 17 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD FEB 12 PY 2014 VL 15 IS 2 BP 132 EP 138 DI 10.1016/j.chom.2014.01.004 PG 7 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AB0IT UT WOS:000331475900004 PM 24528860 ER PT J AU Campa, D Barrdahl, M Tsilidis, KK Severi, G Diver, WR Siddiq, A Chanock, S Hoover, RN Ziegler, RG Berg, CD Buys, SS Haiman, CA Henderson, BE Schumacher, FR Le Marchand, L Flesch-Janys, D Lindstrom, S Hunter, DJ Hankinson, SE Willett, WC Kraft, P Cox, DG Khaw, KT Tjonneland, A Dossus, L Trichopoulos, D Panico, S van Gils, CH Weiderpass, E Barricarte, A Sund, M Gaudet, MM Giles, G Southey, M Baglietto, L Chang-Claude, J Kaaks, R Canzian, F AF Campa, Daniele Barrdahl, Myrto Tsilidis, Konstantinos K. Severi, Gianluca Diver, W. Ryan Siddiq, Afshan Chanock, Stephen Hoover, Robert N. Ziegler, Regina G. Berg, Christine D. Buys, Saundra S. Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick R. Le Marchand, Loic Flesch-Janys, Dieter Lindstroem, Sara Hunter, David J. Hankinson, Susan E. Willett, Walter C. Kraft, Peter Cox, David G. Khaw, Kay-Tee Tjonneland, Anne Dossus, Laure Trichopoulos, Dimitrios Panico, Salvatore van Gils, Carla H. Weiderpass, Elisabete Barricarte, Aurelio Sund, Malin Gaudet, Mia M. Giles, Graham Southey, Melissa Baglietto, Laura Chang-Claude, Jenny Kaaks, Rudolf Canzian, Federico TI A Genome-Wide "Pleiotropy Scan'' Does Not Identify New Susceptibility Loci for Estrogen Receptor Negative Breast Cancer SO PLOS ONE LA English DT Article ID COMPLEX DISEASES; ASSOCIATION; TRAITS; RISK; METAANALYSIS AB Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER- positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER- negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5x10(-8)) to perform a secondary analysis of an ER- negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER- GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 x 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach''. C1 [Campa, Daniele; Barrdahl, Myrto; Chang-Claude, Jenny; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Tsilidis, Konstantinos K.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Severi, Gianluca; Giles, Graham; Southey, Melissa; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Severi, Gianluca; Giles, Graham; Southey, Melissa; Baglietto, Laura] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Sch Populat Hlth, Melbourne, Vic 3010, Australia. [Diver, W. Ryan; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Siddiq, Afshan; Cox, David G.] Univ London Imperial Coll Sci Technol & Med, London, England. [Chanock, Stephen; Hoover, Robert N.; Ziegler, Regina G.; Berg, Christine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Buys, Saundra S.] Univ Utah, Sch Med, Div Oncol, Huntsman Canc Inst, Salt Lake City, UT USA. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Flesch-Janys, Dieter] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometr & Epidemiol, Hamburg, Germany. [Lindstroem, Sara; Hunter, David J.; Hankinson, Susan E.; Willett, Walter C.; Kraft, Peter; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hankinson, Susan E.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Hankinson, Susan E.] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, Susan E.] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Cox, David G.] Univ Lyon 1, F-69365 Lyon, France. [Cox, David G.] Ctr Rech Cancerol Lyon, Inst Natl Sante & Rech Med, U1052, Lyon, France. [Cox, David G.] Ctr Rech Cancerol Lyon, Ctr Natl Rech Sci, UMR5286, Lyon, France. [Cox, David G.] Ctr Leon Berard, F-69373 Lyon, France. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Dossus, Laure] Hormones & Womens Hlth Team, Inst Natl Sante & Rech Med, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Dossus, Laure] Univ Paris 11, UMRS 1018, Villejuif, France. [Dossus, Laure] Inst Gustave Roussy, F-94805 Villejuif, France. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Panico, Salvatore] Univ Naples Federico II, Dipartimento Med Clin & Chirurg, Naples, Italy. [van Gils, Carla H.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Weiderpass, Elisabete] Arctic Univ Tromso, Dept Community Med, Fac Hlth Sci, Univ Tromso, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Barricarte, Aurelio] CIBERESP, Consortium Biomed Res Epidemiol & Publ Hlth, Madrid, Spain. [Sund, Malin] Umea Univ Hosp, Dept Surg, S-90185 Umea, Sweden. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. RP Campa, D (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. EM d.campa@dkfz.de RI Berg , Christine/K-1047-2014; Campa, Daniele/K-1617-2016; Weiderpass, Elisabete/M-4029-2016; Cox, David/A-2023-2009; Panico, Salvatore/K-6506-2016; OI Campa, Daniele/0000-0003-3220-9944; Weiderpass, Elisabete/0000-0003-2237-0128; Cox, David/0000-0002-2152-9259; Panico, Salvatore/0000-0002-5498-8312; Giles, Graham/0000-0003-4946-9099 FU US National Institutes of Health, National Cancer Institute [U01-CA98233-07, U01CA98710-06, U01-CA98216-06, U01-CA98758-07]; Intramural Research Program of National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the US National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233-07 to D.J.H.; U01CA98710-06 to M.J.T.; U01-CA98216-06 to E.R. and R.K.; and U01-CA98758-07 to B.E.H.); and Intramural Research Program of National Institutes of Health and National Cancer Institute, Division of Cancer Epidemiology and Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 6 Z9 6 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 11 PY 2014 VL 9 IS 2 AR e85955 DI 10.1371/journal.pone.0085955 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7DT UT WOS:000331258100006 PM 24523857 ER PT J AU Fletcher, CV Staskus, K Wietgrefe, SW Rothenberger, M Reilly, C Chipman, JG Beilman, GJ Khoruts, A Thorkelson, A Schmidt, TE Anderson, J Perkey, K Stevenson, M Perelson, AS Douek, DC Haase, AT Schacker, TW AF Fletcher, Courtney V. Staskus, Kathryn Wietgrefe, Stephen W. Rothenberger, Meghan Reilly, Cavan Chipman, Jeffrey G. Beilman, Greg J. Khoruts, Alexander Thorkelson, Ann Schmidt, Thomas E. Anderson, Jodi Perkey, Katherine Stevenson, Mario Perelson, Alan S. Douek, Daniel C. Haase, Ashley T. Schacker, Timothy W. TI Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug levels; pharmacokinetics; FDC network ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; LYMPHOID-TISSUES; PROTEASE INHIBITOR; INFECTED PATIENTS; RALTEGRAVIR INTENSIFICATION; IMMUNE RECONSTITUTION; DENDRITIC CELLS; UNITED-STATES; THERAPY AB Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution. C1 [Fletcher, Courtney V.] Univ Nebraska Med Ctr, Dept Pharm Practice, Coll Pharm, Omaha, NE USA. [Staskus, Kathryn; Wietgrefe, Stephen W.; Perkey, Katherine; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Rothenberger, Meghan; Khoruts, Alexander; Thorkelson, Ann; Schmidt, Thomas E.; Anderson, Jodi; Schacker, Timothy W.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Reilly, Cavan] Univ Minnesota, Dept Biostat, Minneapolis, MN 55455 USA. [Chipman, Jeffrey G.; Beilman, Greg J.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Stevenson, Mario] Univ Miami, Dept Med, Miami, FL 33136 USA. [Perelson, Alan S.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Schacker, TW (reprint author), Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. EM schacker@umn.edu OI Chipman, Jeffrey/0000-0002-0759-3705; Beilman, Gregory/0000-0001-5036-3027 FU National Institutes of Health [AI074340, AI028433] FX We thank Lisa Turnquist, Colleen O'Neil, and Tim Leonard for their contributions. Methods for IC and tissue assessment of drug concentration were developed in the C.V.F. laboratory by C.V.F., Dr. Brian L. Robbins, and Mr. Lee Winchester. This work was supported in part by National Institutes of Health Grants AI074340 and AI028433. NR 55 TC 150 Z9 150 U1 3 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 11 PY 2014 VL 111 IS 6 BP 2307 EP 2312 DI 10.1073/pnas.1318249111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA3NO UT WOS:000330999600058 PM 24469825 ER PT J AU Griner, LAM Guha, R Shinn, P Young, RM Keller, JM Liu, D Goldlust, IS Yasgar, A McKnight, C Boxer, MB Duveau, DY Jiang, JK Michael, S Mierzwa, T Huang, W Walsh, MJ Mott, BT Patela, P Leister, W Maloney, DJ Leclair, CA Rai, G Jadhav, A Peyser, BD Austin, CP Martin, SE Simeonov, A Ferrer, M Staudt, LM Thomas, CJ AF Griner, Lesley A. Mathews Guha, Rajarshi Shinn, Paul Young, Ryan M. Keller, Jonathan M. Liu, Dongbo Goldlust, Ian S. Yasgar, Adam McKnight, Crystal Boxer, Matthew B. Duveau, Damien Y. Jiang, Jian-Kang Michael, Sam Mierzwa, Tim Huang, Wenwei Walsh, Martin J. Mott, Bryan T. Patela, Paresma Leister, William Maloney, David J. Leclair, Christopher A. Rai, Ganesha Jadhav, Ajit Peyser, Brian D. Austin, Christopher P. Martin, Scott E. Simeonov, Anton Ferrer, Marc Staudt, Louis M. Thomas, Craig J. TI High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE translational research; PCI-32765; Imbruvica ID NF-KAPPA-B; ANTITUMOR-ACTIVITY; IN-VIVO; INHIBITOR; CANCER; COMBINATIONS; MALIGNANCIES; MUTATIONS; THERAPY; PATHWAY AB The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT- mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL. C1 [Griner, Lesley A. Mathews; Guha, Rajarshi; Shinn, Paul; Keller, Jonathan M.; Liu, Dongbo; Goldlust, Ian S.; Yasgar, Adam; McKnight, Crystal; Boxer, Matthew B.; Duveau, Damien Y.; Jiang, Jian-Kang; Michael, Sam; Mierzwa, Tim; Huang, Wenwei; Walsh, Martin J.; Mott, Bryan T.; Patela, Paresma; Leister, William; Maloney, David J.; Leclair, Christopher A.; Rai, Ganesha; Jadhav, Ajit; Austin, Christopher P.; Martin, Scott E.; Simeonov, Anton; Ferrer, Marc; Thomas, Craig J.] NCI, Div Preclin Innovat, NIH, Chem Genom Ctr,Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Young, Ryan M.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Peyser, Brian D.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Patela, Paresma] SAIC Frederick Inc, Basic Sci Program, Biol Chem Lab, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov; craigt@mail.nih.gov OI Peyser, Brian/0000-0002-3455-5181 FU Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of the National Human Genome Research Institute; Intramural Research Program of the National Cancer Institute, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E, U54CA143930] FX We thank Drs. Jack Taunton, Shaomeng Wang, Fed Bernal, James E. Bradner, Benjamin F. Cravatt, Daniel K. Nomura, Mark Tebbe, and Kenneth Bair for kind donations to the MIPE compound library. This work was supported by the Division of Preclinical Innovation, National Center for Advancing Translational Sciences; the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; the Intramural Research Program of the National Human Genome Research Institute; and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research and the Frederick National Laboratory for Cancer Research, National Institutes of Health, including Contract HHSN261200800001E and Grant U54CA143930. NR 52 TC 58 Z9 58 U1 2 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 11 PY 2014 VL 111 IS 6 BP 2349 EP 2354 DI 10.1073/pnas.1311846111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA3NO UT WOS:000330999600065 ER PT J AU Bittencourt, MS Blaha, MJ Blankstein, R Budoff, M Vargas, JD Blumenthal, RS Agatston, AS Nasir, K AF Bittencourt, Marcio Sommer Blaha, Michael J. Blankstein, Ron Budoff, Matthew Vargas, Jose D. Blumenthal, Roger S. Agatston, Arthur S. Nasir, Khurram TI Polypill Therapy, Subclinical Atherosclerosis, and Cardiovascular Events-Implications for the Use of Preventive Pharmacotherapy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE polypill; risk stratification; subclinical atherosclerosis ID CORONARY-ARTERY CALCIFICATION; ALL-CAUSE MORTALITY; POPULATION-BASED COHORT; C-REACTIVE PROTEIN; RISK-FACTORS; DOUBLE-BLIND; DISEASE; CALCIUM; INDIVIDUALS; PREDICTION AB Objectives This study examines whether the coronary artery calcium (CAC) score can be used to define the target population to treat with a polypill. Background Prior studies have suggested a single polypill to reduce cardiovascular disease (CVD) at the population level. Methods Participants from MESA (Multi-Ethnic Study of Atherosclerosis) were stratified using the criteria of 4 polypill studies (TIPS [The Indian Polycap Study], Poly-Iran, Wald, and the PILL [Program to Improve Life and Longevity] Collaboration). We compared coronary heart disease (CHD) and CVD event rates and calculated the 5-year number needed to treat (NNT) after stratification based on the CAC score. Results Among MESA participants eligible for TIPS, Poly-Iran, Wald, and the PILL Collaboration, CAC 0 was observed in 58.6%, 54.5%, 38.9%, and 40.8%, respectively. The rate of CHD events among those with CAC 0 varied from 1.2 to 1.9 events per 1,000 person-years, those with CAC scores from 1 to 100 had event rates ranging from 4.1 to 5.5, and in those with CAC scores > 100 the event rate ranged from 11.6 to 13.3. The estimated 5-year NNT to prevent 1 CVD event ranged from 81-130 for patients with CAC 0, 38-54 for those with CAC scores from 1 to 100, and 18-20 for those with CAC scores > 100. Conclusions In MESA, among individuals eligible for treatment with the polypill, the majority of CHD and CVD events occurred in those with CAC scores > 100. The group with CAC 0 had a very low event rate and a high projected NNT. The avoidance of treatment in individuals with CAC 0 could allow for significant reductions in the population considered for treatment, with a more selective use of the polypill and, as a result, avoidance of treatment in those who are unlikely to benefit. (J Am Coll Cardiol 2014; 63: 434-43) (c) 2014 by the American College of Cardiology Foundation C1 [Bittencourt, Marcio Sommer; Blankstein, Ron] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA. [Bittencourt, Marcio Sommer; Blankstein, Ron] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Bittencourt, Marcio Sommer; Blankstein, Ron] Harvard Univ, Sch Med, Boston, MA USA. [Blaha, Michael J.; Blumenthal, Roger S.; Nasir, Khurram] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Budoff, Matthew] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA 90509 USA. [Vargas, Jose D.] Johns Hopkins Univ Hosp, Cardiol Div, Baltimore, MD 21287 USA. [Vargas, Jose D.] NIH, Bethesda, MD 20892 USA. [Agatston, Arthur S.; Nasir, Khurram] Baptist Hlth Med Grp, Ctr Prevent & Wellness Res, Miami Beach, FL 33139 USA. [Agatston, Arthur S.; Nasir, Khurram] Florida Int Univ, Dept Med, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Dept Epidemiol, Robert Stempel Coll Publ Hlth, Miami, FL 33199 USA. [Nasir, Khurram] Baptist Hlth South Florida, Baptist Cardiovasc Inst, Miami, FL USA. RP Nasir, K (reprint author), Baptist Hlth Med Grp, Ctr Prevent & Wellness Res, 1691 Michigan Ave,Suite 500, Miami Beach, FL 33139 USA. EM knasir1@jhmi.edu RI Bittencourt, Marcio/C-1444-2011 OI Bittencourt, Marcio/0000-0002-3711-1754 FU NCATS NIH HHS [UL1 TR001079]; NHLBI NIH HHS [L30 HL110027] NR 30 TC 33 Z9 33 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 11 PY 2014 VL 63 IS 5 BP 434 EP 443 DI 10.1016/j.jacc.2013.08.1640 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 304BX UT WOS:000330721800006 PM 24161320 ER PT J AU Shuch, B Vourganti, S Ricketts, CJ Middleton, L Peterson, J Merino, MJ Metwalli, AR Srinivasan, R Linehan, WM AF Shuch, Brian Vourganti, Srinivas Ricketts, Christopher J. Middleton, Lindsay Peterson, James Merino, Maria J. Metwalli, Adam R. Srinivasan, Ramaprasad Linehan, W. Marston TI Defining Early-Onset Kidney Cancer: Implications for Germline and Somatic Mutation Testing and Clinical Management SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; HOGG-DUBE-SYNDROME; HEREDITARY LEIOMYOMATOSIS; GENETIC-BASIS; YOUNG-ADULTS; TRANSLOCATION; DISEASE; CHILDREN; SPECTRUM AB Purpose Approximately 5% to 8% of renal cell carcinoma (RCC) is hereditary. No guidelines exist for patient selection for RCC germline mutation testing. We evaluate how age of onset could indicate the need for germline mutation testing for detection of inherited forms of kidney cancer. Patients and Methods We analyzed the age distribution of RCC cases in the SEER-17 program and in our institutional hereditary kidney cancer population. The age distributions were compared by sex, race, histology, and hereditary cancer syndrome. Models were established to evaluate the specific age thresholds for genetic testing. Results The median age of patients with RCC in SEER-17 was 64 years, with the distribution closely approaching normalcy. Statistical differences were observed by race, sex, and subtype (P < .05). The bottom decile cutoff was 46 years of age and slightly differed by sex, race, and histology. The mean and median ages at presentation of 608 patients with hereditary kidney cancer were 39.3 years and 37 years, respectively. Although age varied by specific syndrome, 70% of these cases were found to lie at or below the bottom age decile. Modeling age-based genetic testing thresholds demonstrated that the 10th percentile maximized sensitivity and specificity. Conclusion Early age of onset might be a sign of hereditary RCC. Even in the absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should trigger consideration for genetic counseling/germline mutation testing and may serve as a useful cutoff when establishing genetic testing guidelines. (C) 2013 by American Society of Clinical Oncology C1 [Shuch, Brian; Vourganti, Srinivas; Ricketts, Christopher J.; Middleton, Lindsay; Peterson, James; Merino, Maria J.; Metwalli, Adam R.; Srinivasan, Ramaprasad; Linehan, W. Marston] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, NIH, CRC, 10 Ctr Dr,MSC 1107,Bldg 10,Room 1-5848, Bethesda, MD 20892 USA. EM linehanm@mail.nih.gov FU National Institutes of Health [ZIA1BC011028-05, ZIA BC011038-05, ZIA BC011043-05, ZID BC011089-05, ZIE BC 011023-05] FX Supported by Grants No. ZIA1BC011028-05, ZIA BC011038-05, ZIA BC011043-05, ZID BC011089-05, and ZIE BC 011023-05 from the National Institutes of Health. NR 28 TC 17 Z9 17 U1 1 U2 1 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 FEB 10 PY 2014 VL 32 IS 5 BP 431 EP 437 DI 10.1200/JCO.2013.50.8192 PG 7 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100014 PM 24378414 ER PT J AU Roschewski, M Stetler-Stevenson, M Yuan, C Mailankody, S Korde, N Landgren, O AF Roschewski, Mark Stetler-Stevenson, Maryalice Yuan, Constance Mailankody, Sham Korde, Neha Landgren, Ola TI Minimal Residual Disease: What Are the Minimum Requirements? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID STEM-CELL TRANSPLANTATION; MULTIPLE-MYELOMA; COMPLETE RESPONSE; FLOW-CYTOMETRY; HETEROGENEITY; DEXAMETHASONE; LENALIDOMIDE; COMBINATION; EXPRESSION; SURVIVAL C1 [Roschewski, Mark; Stetler-Stevenson, Maryalice; Yuan, Constance; Mailankody, Sham; Korde, Neha; Landgren, Ola] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 7 Z9 7 U1 0 U2 1 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 FEB 10 PY 2014 VL 32 IS 5 BP 475 EP 476 DI 10.1200/JCO.2013.52.1955 PG 2 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100021 PM 24419126 ER PT J AU Su, XL Dong, C Zhang, JL Su, LY Wang, XM Cui, HW Chen, Z AF Su, Xiulan Dong, Chao Zhang, Jialing Su, Liya Wang, Xuemei Cui, Hongwei Chen, Zhong TI Combination therapy of anti-cancer bioactive peptide with Cisplatin decreases chemotherapy dosing and toxicity to improve the quality of life in xenograft nude mice bearing human gastric cancer SO CELL AND BIOSCIENCE LA English DT Article DE Anti-cancer bioactive peptide (ACBP); Cisplatin; Tumor growth; Quality of life; Gastric cancer ID BCL-2 FAMILY PROTEINS; CYTOCHROME-C; CELL-DEATH; APOPTOSIS; TRIAL; PATHWAY; BAX AB Background: A great challenge of cancer chemotherapy is to eliminate cancer cells and concurrently maintain the quality of life (QOL) for cancer patients. Previously, we identified a novel anti-cancer bioactive peptide (ACBP), a peptide induced in goat spleen or liver following immunization with human gastric cancer protein extract. ACBP alone exhibited anti-tumor activity without measurable side effects. Thus, we hypothesize that ACBP and combined chemotherapy could improve the efficacy of treatment and lead to a better QOL. Results: In this study, ACBP was isolated and purified from immunized goat liver, and designated as ACBP-L. The anti-tumor activity was investigated in a previously untested human gastric cancer MGC-803 cell line and tumor model. ACBP-L inhibited cell proliferation in vitro in a dose and time dependent manner, titrated by MTT assay. The effect of ACBP-L on cell morphology was observed through light and scanning electron microscopy. In vivo ACBP-L alone significantly inhibited MGC-803 tumor growth in a xenograft nude mouse model without measurable side effects. Treatment with the full dosage of Cisplatin alone (5 mg/kg every 5 days) strongly suppressed tumor growth. However, the QOL in these mice had been significantly affected when measured by food intakes and body weight. The combinatory regiment of ACBP-L with a fewer doses of Cisplatin (5 mg/kg every 10 days) resulted in a similar anti-tumor activity with improved QOL. F-18-FDG PET/CT scan was used to examine the biological activity in tumors of live animals and indicated the consistent treatment effects. The tumor tissues were harvested after treatment, and ACBP-L and Cisplatin treatment suppressed Bcl-2, and induced Bax, Caspase 3, and Caspase 8 molecules as detected by RT-PCR and immunohistochemistry. The combinatory regiment induced stronger Bax and Caspase 8 protein expression. Conclusion: Our current finding in this gastric cancer xenograft animal model demonstrated that ACBP-L could lower Cisplatin dose to achieve a similar anti-tumor efficacy as the higher dose of Cisplatin alone, through enhanced modulation of apoptotic molecules. This newly developed combination regiment improved QOL in tumor bearing hosts, which could lead to clinical investigation for the new strategy of combination therapy. C1 [Su, Xiulan; Dong, Chao; Zhang, Jialing; Su, Liya; Cui, Hongwei] Inner Mongolia Med Univ, Affiliated Hosp, Clin Med Res Ctr, Hohhot 010050, Inner Mongolia, Peoples R China. [Wang, Xuemei] Inner Mongolia Med Univ, Affiliated Hosp, PET CT Ctr, Hohhot 010050, Inner Mongolia, Peoples R China. [Chen, Zhong] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Su, XL (reprint author), Inner Mongolia Med Univ, Affiliated Hosp, Clin Med Res Ctr, 1 Tongdao North St, Hohhot 010050, Inner Mongolia, Peoples R China. EM xlsu@hotmail.com; chenz@nidcd.nih.gov FU National Natural Science Foundation of China [China] [30860327]; Major Project of the Affiliated Hospital of Inner Mongolia Medical College [China] [ZD9809]; NIH/NIDCD [Z01-DC-000016] FX This work was supported by the National Natural Science Foundation of China [No. 30860327, China], Major Project of the Affiliated Hospital of Inner Mongolia Medical College [No. ZD9809, China], and NIH/NIDCD intramural research projects [No. Z01-DC-000016] for Zhong Chen. We thank Dr. Ke Yang from Beijing University Medical Health Center for helpful discussions and providing cell lines. We also thank Cindy Clark (NIH library) for helpful editing the manuscript. NR 35 TC 9 Z9 9 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD FEB 10 PY 2014 VL 4 AR 7 DI 10.1186/2045-3701-4-7 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB7LO UT WOS:000331971700001 PM 24507386 ER PT J AU Huang, HL Lamikanra, AA Alkaitis, MS Thezenas, ML Ramaprasad, A Moussa, E Roberts, DJ Casals-Pascual, C AF Huang, Honglei Lamikanra, Abigail A. Alkaitis, Matthew S. Thezenas, Marie L. Ramaprasad, Abhinay Moussa, Ehab Roberts, David J. Casals-Pascual, Climent TI Interleukin-10 Regulates Hepcidin in Plasmodium falciparum Malaria SO PLOS ONE LA English DT Article ID IRON; ANEMIA; INFLAMMATION; FERROPORTIN; INFECTION; IL-10; LIVER AB Background: Acute malarial anemia remains a major public health problem. Hepcidin, the major hormone controlling the availability of iron, is raised during acute and asymptomatic parasitemia. Understanding the role and mechanism of raised hepcidin and so reduced iron availability during infection is critical to establish evidence-based guidelines for management of malaria anemia. Our recent clinical evidence suggests a potential role of IL-10 in the regulation of hepcidin in patients with acute P. falciparum malaria. Methods: We have measured secretion of hepcidin by primary macrophages and the hepatoma cell line HepG2 stimulated with IL-10, IL-6 and Plasmodium falciparum-infected erythrocytes. Findings: We have observed that IL-10 and IL-6 production increased in primary macrophages when these cells were cocultured with Plasmodium falciparum-infected erythrocytes. We found that IL-10 induced hepcidin secretion in primary macrophages in a dose-dependent manner but not in HepG2 cells. These effects were mediated through signal transducer and activator of transcription (STAT) 3-phosphorylation and completely abrogated by a specific STAT3 inhibitor. Conclusion: IL-10 can directly regulate hepcidin in primary macrophages but not in HepG2 cells. This effect can be modulated by Plasmodium falciparum. The results are consistent with a role for IL-10 in modulating iron metabolism during acute phase of infection. C1 [Huang, Honglei; Thezenas, Marie L.; Ramaprasad, Abhinay; Moussa, Ehab; Casals-Pascual, Climent] Wellcome Trust Ctr Human Genet, Oxford, England. [Lamikanra, Abigail A.; Alkaitis, Matthew S.; Roberts, David J.] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford, England. [Lamikanra, Abigail A.; Alkaitis, Matthew S.; Roberts, David J.] John Radcliffe Hosp, Natl Hlth Serv Blood & Transplant, Oxford OX3 9DU, England. [Alkaitis, Matthew S.] NIAID, Lab Malaria & Vector Res, Rockville, MD USA. [Ramaprasad, Abhinay; Moussa, Ehab] King Abdullah Univ Sci & Technol, Jeddah, Saudi Arabia. RP Casals-Pascual, C (reprint author), Wellcome Trust Ctr Human Genet, Oxford, England. EM ccasals@well.ox.ac.uk RI Ramaprasad, Abhinay/D-1181-2013 OI Ramaprasad, Abhinay/0000-0001-9372-5526 FU Medical research Council [G0701885]; National Blood Service; National Institute for Health Research; Wellcome Trust Centre for Human Genetics (Oxford, UK) [077383/Z/05/Z]; National Health Service Blood and Transplant - Oxford Centre FX CC-P is supported by the Medical research Council (Clinician Scientist Fellowship: G0701885). DJR is supported by the National Blood Service, and the National Institute for Health Research. The research was carried out at the Wellcome Trust Centre for Human Genetics (Oxford, UK) [077383/Z/05/Z], and the National Health Service Blood and Transplant - Oxford Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 6 Z9 6 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2014 VL 9 IS 2 AR e88408 DI 10.1371/journal.pone.0088408 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7CL UT WOS:000331254600075 PM 24520384 ER PT J AU Wang, ZL Wang, Z Liu, DB Yan, XF Wang, F Niu, G Yang, M Chen, XY AF Wang, Zhongliang Wang, Zhe Liu, Dingbin Yan, Xuefeng Wang, Fu Niu, Gang Yang, Min Chen, Xiaoyuan TI Biomimetic RNA-Silencing Nanocomplexes: Overcoming Multidrug Resistance in Cancer Cells SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE biomimetics; drug design; gene regulation; gold; nanoparticles ID MODIFIED GOLD NANOPARTICLES; DELIVERY; INTERFERENCE; THERAPY; SIRNA; SIZE AB RNA interference (RNAi) is an RNA-dependent gene silencing approach controlled by an RNA-induced silencing complex (RISC). Herein, we present a synthetic RISC-mimic nanocomplex, which can actively cleave its target RNA in a sequence-specific manner. With high enzymatic stability and efficient self-delivery to target cells, the designed nanocomplex can selectively and potently induce gene silencing without cytokine activation. These nanocomplexes, which target multidrug resistance, are not only able to bypass the P-glycoprotein (Pgp) transporter, due to their nano-size effect, but also effectively suppress Pgp expression, thus resulting in successful restoration of drug sensitivity of OVCAR8/ADR cells to Pgp-transportable cytotoxic agents. This nanocomplex approach has the potential for both functional genomics and cancer therapy. C1 [Yang, Min] Jiangsu Inst Nucl Med, Minist Hlth, Jiangsu Key Lab Mol Nucl Med, Key Lab Nucl Med, Wuxi 214063, Peoples R China. [Wang, Zhongliang; Wang, Zhe; Liu, Dingbin; Yan, Xuefeng; Wang, Fu; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Yang, M (reprint author), Jiangsu Inst Nucl Med, Minist Hlth, Jiangsu Key Lab Mol Nucl Med, Key Lab Nucl Med, Wuxi 214063, Peoples R China. EM yangmin@jsinm.org; shawn.chen@nih.gov RI Wang, Zhongliang/J-8674-2012; OI Wang, Fu/0000-0001-9222-0833 FU National Natural Science Foundation [81171399, 81371596, 81101077]; CSC Foundation [2011832173]; National Significant New Drugs Creation Program [2012ZX09505-001-001]; National Basic Research Program of China (973 program) [2013CB733802, 2014CB744503]; Jiangsu Province Foundation [BK2011166, BE2012622, BL2012031, BM2012066]; Outstanding Professional Fund of Health Ministry in Jiangsu Province [RC2011095, H201028]; Intramural Research Program (IRP) of NIBIB/NIH FX This work was supported by the National Natural Science Foundation (81171399, 81371596 and 81101077), the CSC Foundation (2011832173), the National Significant New Drugs Creation Program (2012ZX09505-001-001), the National Basic Research Program of China (973 program, 2013CB733802 and 2014CB744503), the Jiangsu Province Foundation (BK2011166, BE2012622, BL2012031, and BM2012066), the Outstanding Professional Fund of Health Ministry in Jiangsu Province (RC2011095 and H201028), and the Intramural Research Program (IRP) of NIBIB/NIH. NR 35 TC 14 Z9 14 U1 8 U2 130 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD FEB 10 PY 2014 VL 53 IS 7 BP 1997 EP 2001 DI 10.1002/anie.201309985 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 303NE UT WOS:000330680400047 PM 24446433 ER PT J AU Tatem, AJ Huang, ZJ Narib, C Kumar, U Kandula, D Pindolia, DK Smith, DL Cohen, JM Graupe, B Uusiku, P Lourenco, C AF Tatem, Andrew J. Huang, Zhuojie Narib, Clothilde Kumar, Udayan Kandula, Deepika Pindolia, Deepa K. Smith, David L. Cohen, Justin M. Graupe, Bonita Uusiku, Petrina Lourenco, Christopher TI Integrating rapid risk mapping and mobile phone call record data for strategic malaria elimination planning SO MALARIA JOURNAL LA English DT Article DE Human mobility; Plasmodium falciparum malaria; Malaria elimination; Migration; Disease mapping; Spatial analysis; Satellite imagery; Mobile phones ID SUB-SAHARAN AFRICA; PLASMODIUM-FALCIPARUM; SPECIES DISTRIBUTIONS; MIGRATION PATTERNS; CHILD SURVIVAL; HUMAN MOVEMENT; TRANSMISSION; ZANZIBAR; BURDEN; KENYA AB Background: As successful malaria control programmes re-orientate towards elimination, the identification of transmission foci, targeting of attack measures to high-risk areas and management of importation risk become high priorities. When resources are limited and transmission is varying seasonally, approaches that can rapidly prioritize areas for surveillance and control can be valuable, and the most appropriate attack measure for a particular location is likely to differ depending on whether it exports or imports malaria infections. Methods/Results: Here, using the example of Namibia, a method for targeting of interventions using surveillance data, satellite imagery, and mobile phone call records to support elimination planning is described. One year of aggregated movement patterns for over a million people across Namibia are analyzed, and linked with case-based risk maps built on satellite imagery. By combining case-data and movement, the way human population movements connect transmission risk areas is demonstrated. Communities that were strongly connected by relatively higher levels of movement were then identified, and net export and import of travellers and infection risks by region were quantified. These maps can aid the design of targeted interventions to maximally reduce the number of cases exported to other regions while employing appropriate interventions to manage risk in places that import them. Conclusions: The approaches presented can be rapidly updated and used to identify where active surveillance for both local and imported cases should be increased, which regions would benefit from coordinating efforts, and how spatially progressive elimination plans can be designed. With improvements in surveillance systems linked to improved diagnosis of malaria, detailed satellite imagery being readily available and mobile phone usage data continually being collected by network providers, the potential exists to make operational use of such valuable, complimentary and contemporary datasets on an ongoing basis in infectious disease control and elimination. C1 [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Huang, Zhuojie; Pindolia, Deepa K.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Huang, Zhuojie; Kumar, Udayan; Pindolia, Deepa K.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Narib, Clothilde; Uusiku, Petrina; Lourenco, Christopher] Natl Vector Borne Dis Control Programme, Windhoek, Namibia. [Kumar, Udayan] Univ Florida, Dept Comp Sci, Gainesville, FL USA. [Kandula, Deepika; Cohen, Justin M.; Lourenco, Christopher] Clinton Hlth Access Initiat, Boston, MA USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Graupe, Bonita] Mobile Telecommun Ltd, Windhoek, Namibia. RP Tatem, AJ (reprint author), Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. EM A.J.Tatem@soton.ac.uk RI Emchi, Karma/Q-1952-2016; Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Cohen, Justin/0000-0003-4481-6784 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Bill and Melinda Gates Foundation [49446, 1032350] FX The work was undertaken under a data sharing agreement between MTC Namibia, the Namibian National Vector-borne Diseases Control Programme and the Clinton Health Access Initiative. The authors are grateful to MTC for sharing their data and help with extractions. This work represents part of the Human Mobility Mapping Project (http://www.thummp.org), Flowminder (www.flowminder.org) and the WorldPop population mapping project (http://www.worldpop.org.uk). AJT & DLS acknowledge funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and are also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#49446 and #1032350). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 36 Z9 37 U1 8 U2 36 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD FEB 10 PY 2014 VL 13 AR 52 DI 10.1186/1475-2875-13-52 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AA9IN UT WOS:000331407100001 PM 24512144 ER PT J AU Blydt-Hansen, TD Pierce, CB Cai, Y Samsonov, D Massengill, S Moxey-Mims, M Warady, BA Furth, SL AF Blydt-Hansen, Tom D. Pierce, Christopher B. Cai, Yi Samsonov, Dmitri Massengill, Susan Moxey-Mims, Marva Warady, Bradley A. Furth, Susan L. TI Medication Treatment Complexity and Adherence in Children with CKD SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; RENAL TUBULAR-ACIDOSIS; GLOMERULAR-FILTRATION-RATE; PILL BURDEN; ANTIRETROVIRAL THERAPY; OBSTRUCTIVE UROPATHY; PATHOGENESIS; TRANSPLANTATION; NONADHERENCE; PROGRESSION AB Background and objectives The complexity of CKD management in children is increased by the number of comorbid conditions. This study assessed the prevalence of comorbidities in pediatric CKD and the frequency with which multiple comorbidities present together by assessing prevalent medication use by CKD stage and diagnosis and their association with clinical or sociodemographic factors. The association between number and frequency of dosing of medications prescribed and self-report of nonadherence was also assessed. Design, setting, participants, & measurements In this cross-sectional analysis of the Chronic Kidney Disease in Children study, medication use at study entry grouped by indication was examined by CKD stage, diagnosis, age, race, ethnicity, income, and CKD duration. Multivariate adjusted predictors of medication use and clustering were examined. Nonadherence was assessed by self-report of missed medications in the past 7 days. Results The 558 eligible participants had a median age of 11 years and median GFR of 44 ml/min per 1.73 m(2); 62% of participants were male and 78% had nonglomerular kidney disease. The number of medications for treatment of CKD comorbidities increased with advanced CKD stage (2.5-fold for stages IV versus II; P<0.001) and glomerular disease (1.4-fold versus nonglomerular; P<0.001). Three distinct medication clusters were identified that corresponded to treatment of glomerular disease, advanced renal tubular dysfunction, and proteinuric complications, respectively. Nonadherence was associated with increased medication dosing frequency (administration>2 times/d; P<0.001) but not the number of medications. Conclusions Medical therapy for children with CKD is complex and is affected by glomerular diagnosis, CKD stage, and medication frequency. The need for CKD-related medication treatment cannot be easily predicted by CKD staging alone. Poorer adherence was associated with increased medication frequency, but not with the number of medical problems needing treatment. Consolidating medical treatment and reducing medication frequency may improve adherence rates in children with CKD. C1 [Blydt-Hansen, Tom D.] Univ Manitoba, Dept Pediat & Child Hlth, Childrens Hosp, Hlth Sci Ctr,Div Pediat Nephrol, Winnipeg, MB R3A 1S1, Canada. [Moxey-Mims, Marva] NIDDK, Bethesda, MD 20892 USA. RP Blydt-Hansen, TD (reprint author), Univ Manitoba, Dept Pediat & Child Hlth, Childrens Hosp, Hlth Sci Ctr,Div Pediat Nephrol, FE009 840 Sherbrook St, Winnipeg, MB R3A 1S1, Canada. EM tblydthansen@hsc.mb.ca FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX The CKiD study is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute. The study sponsors had a role in the study design, analysis, interpretation of data, writing this manuscript, and the decision to submit the manuscript for publication. NR 27 TC 4 Z9 4 U1 1 U2 3 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 FEB 7 PY 2014 VL 9 IS 2 BP 247 EP 254 DI 10.2215/CJN.05750513 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AI9FY UT WOS:000337238400007 PM 24262500 ER PT J AU Quail, MA Smith, M Jackson, D Leonard, S Skelly, T Swerdlow, HP Gu, Y Ellis, P AF Quail, Michael A. Smith, Miriam Jackson, David Leonard, Steven Skelly, Thomas Swerdlow, Harold P. Gu, Yong Ellis, Peter TI SASI-Seq: sample assurance Spike-Ins, and highly differentiating 384 barcoding for Illumina sequencing SO BMC GENOMICS LA English DT Article DE Next-generation sequencing; Indexing; Barcode; Illumina; Sample assurance; Spike-in; Contamination; Sample identity ID GENOME; CONTAMINATION; ERROR; DNA; MUTATIONS; LIBRARIES; GENOTYPE AB Background: A minor but significant fraction of samples subjected to next-generation sequencing methods are either mixed-up or cross-contaminated. These events can lead to false or inconclusive results. We have therefore developed SASI-Seq; a process whereby a set of uniquely barcoded DNA fragments are added to samples destined for sequencing. From the final sequencing data, one can verify that all the reads derive from the original sample(s) and not from contaminants or other samples. Results: By adding a mixture of three uniquely barcoded amplicons, of different sizes spanning the range of insert sizes one would normally use for Illumina sequencing, at a spike-in level of approximately 0.1%, we demonstrate that these fragments remain intimately associated with the sample. They can be detected following even the tightest size selection regimes or exome enrichment and can report the occurrence of sample mix-ups and cross-contamination. As a consequence of this work, we have designed a set of 384 eleven-base Illumina barcode sequences that are at least 5 changes apart from each other, allowing for single-error correction and very low levels of barcode misallocation due to sequencing error. Conclusion: SASI-Seq is a simple, inexpensive and flexible tool that enables sample assurance, allows deconvolution of sample mix-ups and reports levels of cross-contamination between samples throughout NGS workflows. C1 [Quail, Michael A.; Smith, Miriam; Jackson, David; Leonard, Steven; Swerdlow, Harold P.; Gu, Yong; Ellis, Peter] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Skelly, Thomas] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD 21702 USA. RP Quail, MA (reprint author), Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. EM mq1@sanger.ac.uk FU Wellcome Trust [098051]; European Union [262055] FX The authors thank the Wellcome Trust Sanger Institute core sequencing and informatics teams. This work was supported by the Wellcome Trust [grant number 098051] and from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 262055. We also thank Simon Harris of the Wellcome Trust Sanger Institute who analysed sequence data for false variant calls. NR 37 TC 11 Z9 11 U1 4 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 7 PY 2014 VL 15 AR 110 DI 10.1186/1471-2164-15-110 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AD8NU UT WOS:000333523700001 PM 24507442 ER PT J AU Koh, KH Pan, X Shen, HW Arnold, SLM Yu, AM Gonzalez, FJ Isoherranen, N Jeong, H AF Koh, Kwi Hye Pan, Xian Shen, Hong-Wu Arnold, Samuel L. M. Yu, Ai-Ming Gonzalez, Frank J. Isoherranen, Nina Jeong, Hyunyoung TI Altered Expression of Small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 Induction during Pregnancy in CYP2D6-humanized Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cytochrome P450; Drug Metabolism; Pregnancy; Retinoid; Transgenic Mice; HNF4; SHP ID NUCLEAR FACTOR 4-ALPHA; BILE-ACID CONCENTRATIONS; GENE-EXPRESSION; MOLECULAR-BASIS; X-RECEPTOR; TRANSCRIPTIONAL REGULATION; LIPID HOMEOSTASIS; DRUG-METABOLISM; HUMANIZED MOUSE; HEPATOCYTE-NUCLEAR-FACTOR-4-ALPHA AB Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4 (HNF4), did not change during pregnancy. However, HNF4 recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4 transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women. C1 [Koh, Kwi Hye; Jeong, Hyunyoung] Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL 60612 USA. [Pan, Xian; Jeong, Hyunyoung] Univ Illinois, Coll Pharm, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. [Shen, Hong-Wu; Yu, Ai-Ming] Univ Calif Davis, Med Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA. [Arnold, Samuel L. M.; Isoherranen, Nina] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Jeong, H (reprint author), Univ Illinois, Dept Pharm Practice MC 886, 833 S Wood St, Chicago, IL 60612 USA. EM yjeong@uic.edu FU National Institutes of Health [HD065532, K12HK055892] FX This work was supported, in whole or in part, by National Institutes of Health Grant HD065532 and Fellowship K12HK055892 (NICHD; to H. J.). NR 51 TC 16 Z9 16 U1 1 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 7 PY 2014 VL 289 IS 6 BP 3105 EP 3113 DI 10.1074/jbc.M113.526798 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA8TU UT WOS:000331368700001 PM 24318876 ER PT J AU Spruiell, K Richardson, RM Cullen, JM Awumey, EM Gonzalez, FJ Gyamfi, MA AF Spruiell, Krisstonia Richardson, Ricardo M. Cullen, John M. Awumey, Emmanuel M. Gonzalez, Frank J. Gyamfi, Maxwell A. TI Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Diabetes; Metabolic Syndrome; Nuclear Receptors; Obesity; Peroxisome Proliferator-activated Receptor (PPAR) ID ACTIVATED PROTEIN-KINASE; HIGH-FAT DIET; CONSTITUTIVE ANDROSTANE RECEPTOR; LOW PLASMA LEPTIN; NUCLEAR RECEPTOR; CROSS-TALK; INSULIN-RESISTANCE; INDUCED THERMOGENESIS; TARGETED DISRUPTION; HEPATIC STEATOSIS AB Background: PXR is a xenobiotic nuclear receptor that defends against toxic agents. Results: In male mice fed a HFD, the mouse PXR gene promoted obesity, whereas mice lacking the PXR or possessing the human transgene were hyperglycemic. Conclusion: The impact of PXR on HFD-induced obesity and hyperglycemia is species-dependent. Significance: The current data provide in vivo significance of PXR in metabolic syndrome. Clinical obesity is a complex metabolic disorder affecting one in three adults. Recent reports suggest that pregnane X receptor (PXR), a xenobiotic nuclear receptor important for defense against toxic agents and for eliminating drugs and other xenobiotics, may be involved in obesity. Noting differences in ligand specificities between human and mouse PXRs, the role of PXR in high fat diet (HFD)-induced obesity was examined using male PXR-humanized (hPXR) transgenic and PXR-knock-out (PXR-KO) mice in comparison to wild-type (WT) mice. After 16 weeks on either a control diet or HFD, WT mice showed greater weight gain, whereas PXR-KO mice gained less weight due to their resistance to HFD-induced decreases in adipose tissue peroxisome proliferator-activated receptor and induction of hepatic carnitine palmitoyltransferase 1, suggesting increased energy metabolism. Interestingly, control-fed PXR-KO mice exhibited hepatomegaly, hyperinsulinemia, and hyperleptinemia but hypoadiponectinemia and lower adiponectin receptor R2 mRNA levels relative to WT mice. Evaluation of these biologic indicators in hPXR mice fed a control diet or HFD revealed further differences between the mouse and human receptors. Importantly, although HFD-fed hPXR mice were resistant to HFD-induced obesity, both PXR-KO and hPXR mice exhibited impaired induction of glucokinase involved in glucose utilization and displayed elevated fasting glucose levels and severely impaired glucose tolerance. Moreover, the basal hepatic levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 were increased in hPXR mice compared with WT mice. Altogether, although the mouse PXR promotes HFD-induced obesity, the hPXR mouse carries a genetic predisposition for type 2 diabetes and thus provides a model for exploring the role of human PXR in the metabolic syndrome. C1 [Spruiell, Krisstonia; Richardson, Ricardo M.; Awumey, Emmanuel M.; Gyamfi, Maxwell A.] N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Durham, NC 27707 USA. [Cullen, John M.] N Carolina State Univ, North Carolina Coll Vet Med, Raleigh, NC 27607 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gyamfi, MA (reprint author), N Carolina Cent Univ, JLC Biomed Biotechnol Res Inst, Cardiovasc & Metab Dis Res Program, 700 George St, Durham, NC 27707 USA. EM mgyamfi@nccu.edu FU National Institutes of Health [U54 AA019765, SC1 HL099139, U54 CA156735, RO1 HL064761, R25HL059868, P20 MD000175]; National Cancer Institute Intramural Research Program FX This work was supported, in whole or in part, by National Institutes of Health Grants U54 AA019765, SC1 HL099139, U54 CA156735, RO1 HL064761, R25HL059868, and P20 MD000175, and the National Cancer Institute Intramural Research Program. NR 71 TC 16 Z9 18 U1 5 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 7 PY 2014 VL 289 IS 6 BP 3244 EP 3261 DI 10.1074/jbc.M113.494575 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA8TU UT WOS:000331368700013 PM 24362030 ER PT J AU Lee, JG Kim, W Gygi, S Ye, YH AF Lee, Jin-Gu Kim, Woong Gygi, Steven Ye, Yihong TI Characterization of the Deubiquitinating Activity of USP19 and Its Role in Endoplasmic Reticulum-associated Degradation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Deubiquitination; ER-associated Degradation; Hsp90; Membrane Proteins; Ubiquitin; USP19; Tail-anchored Protein Biogenesis ID UBIQUITIN LIGASE; CHAINS; MECHANISMS; INSERTION; PROTEINS; ENZYMES; ER AB Background: The regulation and function of USP19 is unknown. Results: We identify Hsp90 as a USP19 interactor and regulator. USP19 is predominantly localized in the cytosol despite having a transmembrane domain. Conclusion: USP19 is a Hsp90-regulated deubiquitinase dispensable for ERAD. Significance: The study reveals a novel means of DUB regulation involving chaperone association and membrane integration. Deubiquitinating enzymes (DUBs) regulate various cellular processes ranging from protein degradation to cellular signaling. USP19, the only DUB containing a carboxyl-terminal transmembrane domain, was proposed to function in endoplasmic reticulum-associated degradation (ERAD). Here we characterize the function and regulation of USP19. We identify Hsp90 as a specific partner that binds the catalytic domain of USP19 to promote substrate association. Intriguingly, although overexpressed USP19 interacts with Derlin-1 and other ERAD machinery factors in the membrane, endogenous USP19 is mostly in the cytosol where it binds Hsp90. Accordingly, we detect neither interaction of endogenous USP19 with Derlin-1 nor significant effect on ERAD by USP19 depletion. The USP19 transmembrane domain appears to be partially stabilized in the cytosol by an interaction with its own catalytic domain, resulting in auto-inhibition of its deubiquitinating activity. These results clarify the role of USP19 in ERAD and suggest a novel DUB regulation that involves chaperone association and membrane integration. Moreover, our study indicates that the localization of tail-anchored membrane proteins can be subject to regulation in cells. C1 [Lee, Jin-Gu; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kim, Woong; Gygi, Steven] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIDDK of the National Institutes of Health FX This research was supported by the Intramural Research Program of the NIDDK of the National Institutes of Health. NR 20 TC 11 Z9 11 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 7 PY 2014 VL 289 IS 6 BP 3510 EP 3517 DI 10.1074/jbc.M113.538934 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA8TU UT WOS:000331368700035 PM 24356957 ER PT J AU Khalaj, M Abbasi, A Yamanishi, H Akiyama, K Wakitani, S Kikuchi, S Hirose, M Yuzuriha, M Magari, M Degheidy, HA Abe, K Ogura, A Hashimoto, H Kunieda, T AF Khalaj, Maryam Abbasi, Abdolrahim Yamanishi, Hiroshi Akiyama, Kouyou Wakitani, Shuso Kikuchi, Sotaro Hirose, Michiko Yuzuriha, Misako Magari, Masaki Degheidy, Heba A. Abe, Kuniya Ogura, Atsuo Hashimoto, Hiroshi Kunieda, Tetsuo TI A Missense Mutation in Rev7 Disrupts Formation of Pol zeta, Impairing Mouse Development and Repair of Genotoxic Agent-induced DNA Lesions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cell Proliferation; DNA Polymerase; Embryo; Mouse Genetics; Mutant ID PRIMORDIAL GERM-CELLS; CROSS-LINK REPAIR; POLYMERASE-ZETA; FANCONI-ANEMIA; EMBRYONIC LETHALITY; CHROMOSOMAL INSTABILITY; GENOMIC INSTABILITY; CATALYTIC SUBUNIT; MAMMALIAN-CELLS; B-CELLS AB Background:Rev7 encodes a subunit of Pol for translesion DNA synthesis (TLS). Results: We found a Rev7 mutation in mice that causes developmental defects and increases susceptibility for genotoxicity. Conclusion:Rev7 is essential for mouse development through its function in cell proliferation. Significance: These findings demonstrate a unique function of Pol in development that is absent in other TLS polymerases. Repro22 is a mutant mouse produced via N-ethyl-N-nitrosourea-induced mutagenesis that shows sterility with germ cell depletion caused by defective proliferation of primordial germ cells, decreased body weight, and partial lethality during embryonic development. Using a positional cloning strategy, we identified a missense mutation in Rev7/Mad2l2 (Rev7(C70R)) and confirmed that the mutation is the cause of the defects in repro22 mice through transgenic rescue with normal Rev7. Rev7/Mad2l2 encodes a subunit of DNA polymerase (Pol), 1 of 10 translesion DNA synthesis polymerases known in mammals. The mutant REV7 did not interact with REV3, the catalytic subunit of Pol. Rev7(C70R/C70R) cells showed decreased proliferation, increased apoptosis, and arrest in S phase with extensive H2AX foci in nuclei that indicated accumulation of DNA damage after treatment with the genotoxic agent mitomycin C. The Rev7(C70R) mutation does not affect the mitotic spindle assembly checkpoint. These results demonstrated that Rev7 is essential in resolving the replication stalls caused by DNA damage during S phase. We concluded that Rev7 is required for primordial germ cell proliferation and embryonic viability and development through the translesion DNA synthesis activity of Pol preserving DNA integrity during cell proliferation, which is required in highly proliferating embryonic cells. C1 [Khalaj, Maryam; Abbasi, Abdolrahim; Yamanishi, Hiroshi; Wakitani, Shuso; Magari, Masaki] Okayama Univ, Grad Sch Nat Sci & Technol, Okayama 7008530, Japan. [Akiyama, Kouyou; Kunieda, Tetsuo] Okayama Univ, Grad Sch Environm & Life Sci, Okayama 7008530, Japan. [Khalaj, Maryam; Abbasi, Abdolrahim] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Kikuchi, Sotaro; Hashimoto, Hiroshi] Yokohama City Univ, Grad Sch Nanobiosci, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Hirose, Michiko; Yuzuriha, Misako; Abe, Kuniya; Ogura, Atsuo] RIKEN Bioresource Ctr, Tsukuba, Ibaraki 3050074, Japan. [Degheidy, Heba A.] US FDA, Div Biol, Silver Spring, MD 20993 USA. RP Abbasi, A (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM abbasiar@mail.nih.gov; tkunieda@cc.okayama-u.ac.jp RI Ogura, Atsuo/J-3916-2014 OI Ogura, Atsuo/0000-0003-0447-1988 FU Japan Society for the Promotion of Science FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported in part by grants from the Japan Society for the Promotion of Science. NR 60 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 7 PY 2014 VL 289 IS 6 BP 3811 EP 3824 DI 10.1074/jbc.M113.514752 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA8TU UT WOS:000331368700060 PM 24356953 ER PT J AU Teng, CT Beames, B Merrick, BA Martin, N Romeo, C Jetten, AM AF Teng, Christina T. Beames, Burton Merrick, B. Alex Martin, Negin Romeo, Charles Jetten, Anton M. TI Development of a stable cell line with an intact PGC-1 alpha/ERR alpha axis for screening environmental chemicals SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE PGC-1 alpha/ERR alpha; Stable cell line; XCT790; Luc reporter; Screen; EDC ID ESTROGEN-RELATED RECEPTOR; ERR-ALPHA; GENE-EXPRESSION; TRANSCRIPTIONAL CONTROL; ENERGY-EXPENDITURE; NUCLEAR RECEPTORS; INVERSE AGONIST; PGC-1-ALPHA; ORPHAN; COACTIVATOR AB The estrogen-related receptor alpha (ERR alpha) and the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha) play critical roles in the control of several physiological functions, including the regulation of genes involved in energy homeostasis. However, little is known about the ability of environmental chemicals to disrupt or modulate this important bioenergetics pathway in humans. The goal of this study was to develop a cell-based assay system with an intact PGC-1 alpha/ERR alpha axis that could be used as a screening assay for detecting such chemicals. To this end, we successfully generated several stable cell lines expressing PGC-1 alpha and showed that the reporter driven by the native ERRa hormone response unit (AAB-Luc) is active in these cell lines and that the activation is PGC-1 alpha-dependent. Furthermore, we show that this activation can be blocked by the ERR alpha selective inverse agonist, XCT790. In addition, we find that genistein and bisphenol A further stimulate the reporter activity, while kaempferol has minimal effect. These cell lines will be useful for identifying environmental chemicals that modulate this important pathway. Published by Elsevier Inc. C1 [Teng, Christina T.; Beames, Burton; Merrick, B. Alex] NIEHS, DNTP, Biomol Screening Branch, NIH, Res Triangle Pk, NC 27709 USA. [Martin, Negin; Romeo, Charles] NIEHS, DIR, Viral Core Lab, NIH, Res Triangle Pk, NC 27709 USA. [Jetten, Anton M.] NIEHS, DIR, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, DNTP, BSB, POB 12233,MD K2-17,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM teng1@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural Research Programs; Division of National Toxicology Program (DNTP); Division of Intramural Research (DIR); National Institute of Environmental Health Sciences, National Institutes of Health (NIH) FX We thank members of Dr. Anton Jetten's laboratory for technical advice and support. We appreciate comments on the manuscript by Drs. H. Kinyamu, S. Ferguson, and R. Tice. This research was supported by the Intramural Research Programs, Division of National Toxicology Program (DNTP) and Division of Intramural Research (DIR), the National Institute of Environmental Health Sciences, National Institutes of Health (NIH). NR 38 TC 2 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 7 PY 2014 VL 444 IS 2 BP 177 EP 181 DI 10.1016/j.bbrc.2014.01.033 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AB6TX UT WOS:000331923500012 PM 24457025 ER PT J AU Thomas, MA Demberg, T Vargas-Inchaustegui, DA Xiao, P Tuero, I Venzon, D Weiss, D Treece, J Robert-Guroff, M AF Thomas, Michael A. Demberg, Thorsten Vargas-Inchaustegui, Diego A. Xiao, Peng Tuero, Iskra Venzon, David Weiss, Deborah Treece, James Robert-Guroff, Marjorie TI Rhesus macaque rectal and duodenal tissues exhibit B-cell sub-populations distinct from peripheral blood that continuously secrete antigen-specific IgA in short-term explant cultures SO VACCINE LA English DT Article DE SIV/SHIV infected rhesus macaques; Mucosal explant cultures; Memory B-cells; IgA; AIDS vaccine ID IMMUNODEFICIENCY VIRUS-INFECTION; PLASMA-CELLS; GASTROINTESTINAL-TRACT; NONHUMAN-PRIMATES; IMMUNE-RESPONSES; IN-VITRO; MUCOSAL; SIV; HIV; VACCINE AB It is becoming increasingly obvious that evaluation of a vaccine aimed at preventing HIV infection should include assessment of induced immunity at mucosal sites of viral entry. Among the most salient immune responses are viral-specific antibodies. A recent report on IgA-secreting plasma cells in human duodenal explants prompted us to examine similar duodenal and rectal biopsies of rhesus macaques, a key animal model for pre-clinical HIV/SIV vaccine studies, and characterize the local resident B-cells. Here we report that non-human primate rectal explants possess similar levels of B-cells as duodenal explants. We characterize the antibody isotype expression on mucosal memory B-cells and show for the first time that the B-cell memory subsets of the duodenum and rectum are distinct from those of PBMC, not only by essentially lacking CD27(+) cells, as previously reported for uninfected macaques (Titanji et al., 2010), but also in being mostly IgD(-). SIV- and SHIV-infected macaques had fewer total IgA-secreting cells in rectal tissue compared to naive macaques. As expected, the fractions of B-cells with surface expression of IgA were dominant in the rectal and duodenal explants whereas in PBMC IgG surface expression was dominant among IgD- B-cells. Mucosal antibody secreting cells were found to be predominantly plasma cells/plasma blasts based on their lack of response to stimulation. Importantly, short-term culture of rectal explants of SIV- and SHIV-positive animals led to secretion of Env-specific IgA into the culture supernatant which could be easily measured by ELISA. Collection of such culture supernatant over several days allows for accumulation of mucosal antibody in amounts that should enable antibody purification, characterization, and use in functional assays. Rectal explants can be readily obtained and unequivocally identify the mucosal tissue as the source of antibody. Overall they facilitate evaluation of mucosal vaccines. Published by Elsevier Ltd. C1 [Thomas, Michael A.; Demberg, Thorsten; Vargas-Inchaustegui, Diego A.; Xiao, Peng; Tuero, Iskra; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Weiss, Deborah; Treece, James] Adv BioSci Labs Inc, Rockville, MD USA. RP Robert-Guroff, M (reprint author), Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural NIH HHS [ZIA BC011058-02] NR 42 TC 8 Z9 8 U1 1 U2 4 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 FEB 7 PY 2014 VL 32 IS 7 BP 872 EP 880 DI 10.1016/j.vaccine.2013.12.014 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AB0SI UT WOS:000331502000018 PM 24374153 ER PT J AU Langel, FD Chiang, CY Lane, D Kenny, T Ojeda, JF Zhong, Y Che, JW Zhou, YY Ribot, W Kota, KP Bavari, S Panchal, RG AF Langel, Felicia D. Chiang, Chih-Yuan Lane, Douglas Kenny, Tara Ojeda, Jenifer F. Zhong, Yang Che, Jianwei Zhou, Yingyao Ribot, Wilson Kota, Krishna P. Bavari, Sina Panchal, Rekha G. TI Alveolar Macrophages Infected with Ames or Sterne Strain of Bacillus anthracis Elicit Differential Molecular Expression Patterns SO PLOS ONE LA English DT Article ID NF-KAPPA-B; LETHAL FACTOR; REGULATORY FACTOR-3; GENE-EXPRESSION; KINASE-KINASE; TNF-ALPHA; IN-VIVO; ACTIVATION; INFLAMMATION; APOPTOSIS AB Alveolar macrophages (AMs) phagocytose Bacillus anthracis following inhalation and induce the production of proinflammatory cytokines and chemokines to mediate the activation of innate immunity. Ames, the virulent strain of B. anthracis, contains two plasmids that encode the antiphagocytic poly-gamma-d-glutamic acid capsule and the lethal toxin. The attenuated Sterne strain of B. anthracis, which lacks the plasmid encoding capsule, is widely adapted as a vaccine strain. Although differences in the outcome of infection with the two strains may have originated from the presence or absence of an anti-phagocytic capsule, the disease pathogenesis following infection will be manifested via the host responses, which is not well understood. To gain understanding of the host responses at cellular level, a microarray analysis was performed using primary rhesus macaque AMs infected with either Ames or Sterne spores. Notably, 528 human orthologs were identified to be differentially expressed in AMs infected with either strain of the B. anthracis. Meta-analyses revealed genes differentially expressed in response to B. anthracis infection were also induced upon infections with multiple pathogens such as Francisella Novicida or Staphylococcus aureus. This suggests the existence of a common molecular signature in response to pathogen infections. Importantly, the microarray and protein expression data for certain cytokines, chemokines and host factors provide further insights on how cellular processes such as innate immune sensing pathways, anti-apoptosis versus apoptosis may be differentially modulated in response to the virulent or vaccine strain of B. anthracis. The reported differences may account for the marked difference in pathogenicity between these two strains. C1 [Langel, Felicia D.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Chiang, Chih-Yuan; Ojeda, Jenifer F.; Bavari, Sina; Panchal, Rekha G.] US Army Med Res Inst Infect Dis, Mol & Translat Sci Div, Ft Detrick, MD 21702 USA. [Lane, Douglas; Kenny, Tara] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Zhong, Yang; Che, Jianwei; Zhou, Yingyao] Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Ribot, Wilson] US Army Med Res Inst Infect Dis, Bacteriol Div, Ft Detrick, MD USA. [Kota, Krishna P.] Perkin Elmer, Waltham, MA USA. RP Panchal, RG (reprint author), US Army Med Res Inst Infect Dis, Mol & Translat Sci Div, Ft Detrick, MD 21702 USA. EM rekha.g.panchal.civ@mail.mil FU Department of Defense Chemical Biological Defense Program through the Defense Threat Reduction Agency (DTRA) [JSTO-CBD 2.10019_09_RD_B]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was funded by the Department of Defense Chemical Biological Defense Program through the Defense Threat Reduction Agency (DTRA) JSTO-CBD 2.10019_09_RD_B (to R.G.P). 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 funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 0 Z9 0 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 7 PY 2014 VL 9 IS 2 AR e87201 DI 10.1371/journal.pone.0087201 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1CR UT WOS:000330834400011 PM 24516547 ER PT J AU Powers, JF Korgaonkar, PG Fliedner, S Giubellino, A Pacak, K Sahagian, GG Tischler, AS AF Powers, James F. Korgaonkar, Parimal G. Fliedner, Stephanie Giubellino, Alessio Pacak, Karel Sahagian, G. Gary Tischler, Arthur S. TI Cytocidal Activities of Topoisomerase 1 Inhibitors and 5-Azacytidine against Pheochromocytoma/Paraganglioma Cells in Primary Human Tumor Cultures and Mouse Cell Lines SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; DNA METHYLATION; IN-VIVO; CAMPTOTHECIN; PROMOTER; NANOPARTICLES; PARAGANGLIOMA; APOPTOSIS; THERAPY; CANCER AB There is currently no effective treatment for metastatic pheochromocytomas and paragangliomas. A deficiency in current chemotherapy regimens is that the metastases usually grow very slowly. Drugs that target dividing tumor cells have therefore had limited success. To improve treatment, new strategies and valid experimental models are required for preclinical testing. However, development of models has itself been hampered by the absence of human pheochromocytoma/paraganglioma cell lines for cultures or xenografts. Topoisomerase 1 (TOP1) inhibitors are drugs that interfere with mechanisms that maintain DNA integrity during transcription in both quiescent and dividing cells. We used primary cultures of representative human tumors to establish the cytotoxicity of camptothecin, a prototypical TOP1 inhibitor, against nondividing pheochromocytoma/paraganglioma cells, and then employed a mouse pheochromocytoma model (MPC) to show that efficacy of low concentrations of camptothecin and other TOP1 inhibitors is increased by intermittent coadministration of sub-toxic concentrations of 5-azacytidine, a DNA methylation inhibitor that modulates transcription. We then tested the same drugs against a clonal MPC derivative that expresses CMV reporter-driven luciferase and GFP, intended for in vivo drug testing. Unexpectedly, luciferase expression, bioluminescence and GFP expression were paradoxically increased by both camptothecin and SN38, the active metabolite of irinotecan, thereby masking cell death. Expression of chromogranin A, a marker for neuroendocrine secretory granules, was not increased, indicating that the drug effects on levels of luciferase and GFP are specific to the GFP-luciferase construct rather than generalized cellular responses. Our findings provide proof of principle for use of TOP1 inhibitors against pheochromocytoma/paraganglioma and suggest novel strategies for enhancing efficacy and reducing toxicity by optimizing the combination and timing of their use in conjunction with other drugs. The paradoxical effects of TOP1 inhibitors on luciferase and GFP dictate a need for caution in the use of CMV promoter-regulated constructs for cancer-related imaging studies. C1 [Powers, James F.; Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. [Korgaonkar, Parimal G.] Tufts Univ, Sch Med, Small Anim Imaging Preclin Testing Facil, Boston, MA 02111 USA. [Fliedner, Stephanie; Giubellino, Alessio] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Fliedner, Stephanie] Univ Med Ctr Schleswig Holstein Lubeck, Dept Med 1, Lubeck, Germany. RP Powers, JF (reprint author), Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. EM jpowers1@tuftsmedicalcenter.org FU Department of Defense [PR100171]; Pheo Para Alliance FX JF Powers and AS Tischler were supported by grant PR100171 from the Department of Defense and by a grant from the Pheo Para Alliance (http://www.pheo-para-alliance.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 4 Z9 4 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 7 PY 2014 VL 9 IS 2 AR e87807 DI 10.1371/journal.pone.0087807 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1CR UT WOS:000330834400018 PM 24516563 ER PT J AU Van Engelenburg, SB Shtengel, G Sengupta, P Waki, K Jarnik, M Ablan, SD Freed, EO Hess, HF Lippincott-Schwartz, J AF Van Engelenburg, Schuyler B. Shtengel, Gleb Sengupta, Prabuddha Waki, Kayoko Jarnik, Michal Ablan, Sherimay D. Freed, Eric O. Hess, Harald F. Lippincott-Schwartz, Jennifer TI Distribution of ESCRT Machinery at HIV Assembly Sites Reveals Virus Scaffolding of ESCRT Subunits SO SCIENCE LA English DT Article ID CYTOKINESIS; DYNAMICS; PROTEIN; COMPLEX; ABSCISSION; FILAMENTS; MIDBODY; RELEASE; TSG101; VPS4 AB The human immunodeficiency virus (HIV) hijacks the endosomal sorting complexes required for transport (ESCRT) to mediate virus release from infected cells. The nanoscale organization of ESCRT machinery necessary for mediating viral abscission is unclear. Here, we applied three-dimensional superresolution microscopy and correlative electron microscopy to delineate the organization of ESCRT components at HIV assembly sites. We observed ESCRT subunits localized within the head of budding virions and released particles, with head-localized levels of CHMP2A decreasing relative to Tsg101 and CHMP4B upon virus abscission. Thus, the driving force for HIV release may derive from initial scaffolding of ESCRT subunits within the viral bud interior followed by plasma membrane association and selective remodeling of ESCRT subunits. C1 [Van Engelenburg, Schuyler B.; Sengupta, Prabuddha; Jarnik, Michal; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Shtengel, Gleb; Hess, Harald F.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Waki, Kayoko; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [Z99 HD999999] NR 20 TC 56 Z9 56 U1 1 U2 48 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 7 PY 2014 VL 343 IS 6171 BP 653 EP 656 DI 10.1126/science.1247786 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB7QC UT WOS:000349821400001 PM 24436186 ER PT J AU Portnoy, DB Kaufman, AR Klein, WMP Doyle, TA de Groot, M AF Portnoy, David B. Kaufman, Annette R. Klein, William M. P. Doyle, Todd A. de Groot, Mary TI Cognitive and affective perceptions of vulnerability as predictors of exercise intentions among people with type 2 diabetes SO JOURNAL OF RISK RESEARCH LA English DT Article DE risk perception; worry; cognitive; affective; exercise; diabetes ID CORONARY-HEART-DISEASE; BREAST-CANCER RISK; PROTECTION MOTIVATION THEORY; HEALTH BELIEF MODEL; PERCEIVED RISK; WOMENS PERCEPTIONS; PERSONAL RISK; WORRY; BEHAVIOR; METAANALYSIS AB Most conventional measures of risk perception such as perceived likelihood address largely deliberative or cognitive perceptions of vulnerability. Nevertheless, affective perceptions of vulnerability such as worry may have different antecedents and consequences than do these conventional measures, serve as stronger predictors of behavior, and qualify effects of conventional deliberative risk perceptions on behavior. In this study, we assessed how worry - the most common measure of affective perceptions of vulnerability compared with three conventional measures of risk (absolute risk, comparative risk, and conditional risk) in predicting behavioral intentions. Participants were 83 adults with type 2 diabetes who assessed their risk of heart disease and reported their intentions to increase physical activity (which reduces heart disease risk). As predicted, worry was the only significant predictor of exercise intentions such that higher worry was associated with higher intentions. Importantly, this relationship was stronger among individuals who perceived their absolute risk to be relatively higher and those who perceived their comparative risk to be relatively lower, demonstrating that cognitive and affective perceptions interact. These findings highlight the importance of not conflating affective and cognitive perceptions of vulnerability when assessing perceived risk and suggest the need for more research on how to best conceptualize perceived risk in different samples and settings. C1 [Portnoy, David B.; Kaufman, Annette R.; Klein, William M. P.] NCI, Behav Res Program, Rockville, MD 20852 USA. [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. [Klein, William M. P.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Doyle, Todd A.] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. [de Groot, Mary] Indiana Univ, Sch Med, Indianapolis, IN USA. RP Portnoy, DB (reprint author), NCI, Behav Res Program, Rockville, MD 20852 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 FU NIDDK NIH HHS [P30 DK092949, R18 DK092765, R34 DK071545] NR 58 TC 5 Z9 5 U1 2 U2 29 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1366-9877 EI 1466-4461 J9 J RISK RES JI J. Risk Res. PD FEB 7 PY 2014 VL 17 IS 2 BP 177 EP 193 DI 10.1080/13669877.2013.794153 PG 17 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 272MR UT WOS:000328465400002 PM 24563609 ER PT J AU Spinner, MA Sanchez, LA Hsu, AP Shaw, PA Zerbe, CS Calvo, KR Arthur, DC Gu, WJ Gould, CM Brewer, CC Cowen, EW Freeman, AF Olivier, KN Uzel, G Zelazny, AM Daub, JR Spalding, CD Claypool, RJ Giri, NK Alter, BP Mace, EM Orange, JS Cuellar-Rodriguez, J Hickstein, DD Holland, SM AF Spinner, Michael A. Sanchez, Lauren A. Hsu, Amy P. Shaw, Pamela A. Zerbe, Christa S. Calvo, Katherine R. Arthur, Diane C. Gu, Wenjuan Gould, Christine M. Brewer, Carmen C. Cowen, Edward W. Freeman, Alexandra F. Olivier, Kenneth N. Uzel, Gulbu Zelazny, Adrian M. Daub, Janine R. Spalding, Christine D. Claypool, Reginald J. Giri, Neelam K. Alter, Blanche P. Mace, Emily M. Orange, Jordan S. Cuellar-Rodriguez, Jennifer Hickstein, Dennis D. Holland, Steven M. TI GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-2; ACUTE MYELOID-LEUKEMIA; FAMILIAL MYELODYSPLASTIC SYNDROME; NATURAL-KILLER-CELLS; HUMAN BREAST-TUMORS; MONOMAC SYNDROME; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; PRIMARY LYMPHEDEMA; GENE-EXPRESSION AB Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P=.038 and P=.006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P<.001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening. C1 [Spinner, Michael A.; Sanchez, Lauren A.; Hsu, Amy P.; Zerbe, Christa S.; Freeman, Alexandra F.; Olivier, Kenneth N.; Uzel, Gulbu; Zelazny, Adrian M.; Daub, Janine R.; Spalding, Christine D.; Claypool, Reginald J.; Cuellar-Rodriguez, Jennifer; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Arthur, Diane C.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Gu, Wenjuan] Frederick Natl Lab Canc Res, Support Biostat Res Branch, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Gould, Christine M.] Walter Reed Natl Mil Med Ctr, Dept Pediat, Bethesda, MD USA. [Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, Bethesda, MD USA. [Cowen, Edward W.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Giri, Neelam K.; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mace, Emily M.; Orange, Jordan S.] Texas Childrens Hosp, Baylor Coll Med, Ctr Human Immunobiol, Houston, TX 77030 USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI orange, jordan/0000-0001-7117-7725; Calvo, Katherine/0000-0002-0771-4191 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Cancer Institute FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases and National Cancer Institute. 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 104 Z9 104 U1 2 U2 19 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 6 PY 2014 VL 123 IS 6 BP 809 EP 821 DI 10.1182/blood-2013-07-515528 PG 13 WC Hematology SC Hematology GA AH0TY UT WOS:000335834600006 PM 24227816 ER PT J AU Tumbale, P Williams, JS Schellenberg, MJ Kunkel, TA Williams, RS AF Tumbale, Percy Williams, Jessica S. Schellenberg, Matthew J. Kunkel, Thomas A. Williams, R. Scott TI Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity SO NATURE LA English DT Article ID DISEASE PROTEIN APRATAXIN; RIBONUCLEOTIDE INCORPORATION; NEURODEGENERATIVE DISEASE; POLYMERASE; MUTATIONS; REMOVAL; REPAIR; GENE; REPLICATION; SUPERFAMILY AB Faithful maintenance and propagation of eukaryotic genomes is ensured by three-step DNA ligation reactions used by ATP-dependent DNA ligases(1,2). Paradoxically, when DNA ligases encounter nicked DNA structures with abnormal DNA termini, DNA ligase catalytic activity can generate and/or exacerbate DNA damage through abortive ligation that produces chemically adducted, toxic 5'-adenylated (5'-AMP) DNA lesions(3-6). Aprataxin (APTX) reverses DNA adenylation but the context for deadenylation repair is unclear. Here we examine the importance of APTX to RNase-H2-dependent excision repair (RER) of a lesion that is very frequently introduced into DNA, a ribonucleotide. We show that ligases generate adenylated 5' ends containing a ribose characteristic of RNase H2 incision. APTX efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response (RDDR), promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RER. Structure-function studies of human APTX-RNA-DNA-AMP-Zn complexes define a mechanism for detecting and reversing adenylation at RNA-DNA junctions. This involves A-form RNA binding, proper protein folding and conformational changes, all of which are affected by heritable APTX mutations in ataxia with oculomotor apraxia 1. Together, these results indicate that accumulation of adenylated RNA-DNA may contribute to neurological disease. C1 [Tumbale, Percy; Williams, Jessica S.; Schellenberg, Matthew J.; Kunkel, Thomas A.; Williams, R. Scott] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Williams, Jessica S.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Williams, RS (reprint author), NIEHS, Struct Biol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov RI Williams, Robert/A-6059-2015 FU US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765, Z01ES065070]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported by the intramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) projects 1Z01ES102765 to R.S.W. and Z01ES065070 to T.A.K. X-ray diffraction data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID (or 22-BM) beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract number W-31-109-Eng-38. We thank L. Pedersen of the NIEHS collaborative crystallography group, and the Advanced Photon Source (APS) Southeast Regional Collaborative Access Team (SER-CAT) staff for assistance with crystallographic data collection. We thank L. Pedersen and B. Wallace for critical reading of the manuscript, J. Krahn for assistance with movies, and T. Ellenberger and P. O'Brien for DNA ligase expression vectors. NR 38 TC 41 Z9 41 U1 0 U2 19 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 FEB 6 PY 2014 VL 506 IS 7486 BP 111 EP + DI 10.1038/nature12824 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 303BA UT WOS:000330648100042 PM 24362567 ER PT J AU Kulzer, JR Stitzel, ML Morken, MA Huyghe, JR Fuchsberger, C Kuusisto, J Laakso, M Boehnke, M Collins, FS Mohlke, KL AF Kulzer, Jennifer R. Stitzel, Michael L. Morken, Mario A. Huyghe, Jeroen R. Fuchsberger, Christian Kuusisto, Johanna Laakso, Markku Boehnke, Michael Collins, Francis S. Mohlke, Karen L. TI A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INSULIN-SECRETION; TRANSCRIPTIONAL REPRESSOR; GENE-EXPRESSION; SUSCEPTIBILITY LOCUS; ISLET PREPARATIONS; PROVIDES INSIGHTS; PLASMA-MEMBRANE; PAX4; ARF AB Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7.4 x 10(-5)). Measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAPI promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele. Collectively, these data suggest that the T2D-risk allele of rs11603334 could abrogate binding of a complex containing PAX6 and PAX4 and thus lead to increased promoter activity and ARAP1 expression in human pancreatic islets. This work suggests that increased ARAP1 expression might contribute to T2D susceptibility at this GWAS locus. C1 [Kulzer, Jennifer R.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Stitzel, Michael L.; Morken, Mario A.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Stitzel, Michael L.] Jackson Lab Genom Med, Farmington, CT 06030 USA. [Huyghe, Jeroen R.; Fuchsberger, Christian; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Huyghe, Jeroen R.; Fuchsberger, Christian; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. RP Mohlke, KL (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. EM mohlke@med.unc.edu OI Fuchsberger, Christian/0000-0002-5918-8947 FU National Institutes of Health (NIH) [R01DK072193, R21DA027040, R01DK093757, K99DK092251, R01DK062370]; NIH National Human Genome Research Institute (NHGRI) Division of Intramural Research project [Z01HG000024]; Academy of Finland [77299, 124243] FX We thank first and foremost the human organ donors whose pancreatic islets were used in this study. Islets were obtained from the Islet Cell Resource Center Basic Science Islet Distribution Program and Integrated Islet Distribution Program and the National Disease Research Interchange. This study was supported by National Institutes of Health (NIH) grants R01DK072193 (K.L.M.), R21DA027040 (K.L.M.), R01DK093757 (K.L.M.), K99DK092251 (M.L.S.), and R01DK062370 (M.B.), NIH National Human Genome Research Institute (NHGRI) Division of Intramural Research project number Z01HG000024 (F.S.C.), and Academy of Finland grants 77299 and 124243 (M.L.). The authors gratefully acknowledge the Genetics of Type 2 Diabetes Consortium for access to the reference Panel used for imputation, Michael R. Erdos (NHGRI) for assistance coordinating and preparing human islet samples, Yun Li (University of North Carolina at Chapel Hill) for providing linkage-disequilibrium data from the 1000 Genomes Project, Praveen Sethupathy (University of North Carolina at Chapel Hill) for helpful discussion and assistance generating motif prediction scores via PWM-Scan, Leslie Lange and Ethan Lange (University of North Carolina at Chapel Hill) for statistical advice, and Marie Fogarty (University of North Carolina at Chapel Hill) for helpful discussions. NR 66 TC 20 Z9 20 U1 0 U2 12 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 FEB 6 PY 2014 VL 94 IS 2 BP 186 EP 197 DI 10.1016/j.ajhg.2013.12.011 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AA9NF UT WOS:000331419500003 PM 24439111 ER PT J AU Peloso, GM Auer, PL Bis, JC Voorman, A Morrison, AC Stitziel, NO Brody, JA Khetarpal, SA Crosby, JR Fomage, M Isaacs, A Jakobsdottir, J Feitosa, MF Davies, G Huffman, JE Manichaikul, A Davis, B Lohman, K Joon, AY Smith, AV Grove, ML Zanoni, P Redon, V Demissie, S Lawson, K Peters, U Carlson, C Jackson, RD Ryckman, KK Mackey, RH Robinson, JG Siscovick, DS Schreiner, PJ Mychaleckyj, JC Pankow, JS Holman, A Uitterlinden, AG Harris, TB Taylor, KD Stafford, JM Reynolds, LM Marioni, RE Dehghan, A Franco, OH Patele, AP Lu, YC Hindy, G Gottesman, O Bottinger, EP Melander, O Orho-Melander, M Loos, RJF Duga, S Merlini, PA Farrall, M Goel, A Asselta, R Girelli, D Martinelli, N Shah, SH Kraus, WE Li, MY Rader, DJ Reilly, MP McPherson, R Watkins, H Ardissino, D Zhang, QY Wang, JD Tsai, MY Taylor, HA Correa, A Griswold, ME Lange, LA Starr, JM Rudan, I Eiriksdottir, G Launer, LJ Ordovas, JM Levy, D Chen, YDI Reiner, AP Hayward, C Polasek, O Deary, IJ Borecki, IB Liu, YM Gudnason, V Wilson, JG van Duijn, CM Kooperberg, C Rich, SS Psaty, BM Rotter, JI O'Donnell, CJ Rice, K Boerwinkle, E Kathiresan, S Cupples, LA AF Peloso, Gina M. Auer, Paul L. Bis, Joshua C. Voorman, Arend Morrison, Alanna C. Stitziel, Nathan O. Brody, Jennifer A. Khetarpal, Sumeet A. Crosby, Jacy R. Fomage, Myriam Isaacs, Aaron Jakobsdottir, Johanna Feitosa, Mary F. Davies, Gail Huffman, Jennifer E. Manichaikul, Ani Davis, Brian Lohman, Kurt Joon, Aron Y. Smith, Albert V. Grove, Megan L. Zanoni, Paolo Redon, Valeska Demissie, Serkalem Lawson, Kim Peters, Ulrike Carlson, Christopher Jackson, Rebecca D. Ryckman, Kelli K. Mackey, Rachel H. Robinson, Jennifer G. Siscovick, David S. Schreiner, Pamela J. Mychaleckyj, Josyf C. Pankow, James S. Holman, Albert Uitterlinden, Andre G. Harris, Tamara B. Taylor, Kent D. Stafford, Jeanette M. Reynolds, Lindsay M. Marioni, Riccardo E. Dehghan, Abbas Franco, Oscar H. Patele, Aniruddh P. Lu, Yingchang Hindy, George Gottesman, Omri Bottinger, Erwin P. Melander, Olle Orho-Melander, Marju Loos, Ruth J. F. Duga, Stefano Merlini, Piera Angelica Farrall, Martin Goel, Anuj Asselta, Rosanna Girelli, Domenico Martinelli, Nicola Shah, Svati H. Kraus, William E. Li, Mingyao Rader, Daniel J. Reilly, Muredach P. McPherson, Ruth Watkins, Hugh Ardissino, Diego Zhang, Qunyuan Wang, Judy Tsai, Michael Y. Taylor, Herman A. Correa, Adolfo Griswold, Michael E. Lange, Leslie A. Starr, John M. Rudan, Igor Eiriksdottir, Gudny Launer, Lenore J. Ordovas, Jose M. Levy, Daniel Chen, Y. -D. Ida Reiner, Alexander P. Hayward, Caroline Polasek, Ozren Deary, Ian J. Borecki, Ingrid B. Liu, Yongmei Gudnason, Vilmundur Wilson, James G. van Duijn, Cornelia M. Kooperberg, Charles Rich, Stephen S. Psaty, Bruce M. Rotter, Jerome I. O'Donnell, Christopher J. Rice, Kenneth Boerwinkle, Eric Kathiresan, Sekar Cupples, L. Adrienne CA NHLBI GO Exome Sequencing Project TI Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PLATELET-ACTIVATING-FACTOR; DENSITY-LIPOPROTEIN CHOLESTEROL; FACTOR ACETYLHYDROLASES; PCSK9; PROTEIN; TRAITS; LDL AB Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited. C1 [Peloso, Gina M.; Patele, Aniruddh P.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peloso, Gina M.; O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Peloso, Gina M.; Patele, Aniruddh P.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Auer, Paul L.; Peters, Ulrike; Carlson, Christopher; Reiner, Alexander P.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Bis, Joshua C.; Brody, Jennifer A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Voorman, Arend; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Morrison, Alanna C.; Crosby, Jacy R.; Fomage, Myriam; Davis, Brian; Grove, Megan L.; Lawson, Kim; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.; Feitosa, Mary F.; Zhang, Qunyuan; Wang, Judy; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Khetarpal, Sumeet A.; Zanoni, Paolo; Redon, Valeska; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Crosby, Jacy R.] Univ Texas Grad Sch Biomed Sci Houston, Dept Biostat Bioinformat & Syst Biol, Houston, TX 77030 USA. [Fomage, Myriam; Joon, Aron Y.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 CN Rotterdam, Netherlands. [Jakobsdottir, Johanna; Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Davies, Gail; Marioni, Riccardo E.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Davies, Gail; Marioni, Riccardo E.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, MRC IGMM, MRC Human Genet, Edinburgh EH4 2XU, Midlothian, Scotland. [Manichaikul, Ani; Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Manichaikul, Ani; Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Lohman, Kurt; Stafford, Jeanette M.; Reynolds, Lindsay M.; Liu, Yongmei] Wake Forest Sch Med, Winston Salem, NC 27106 USA. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Demissie, Serkalem; Levy, Daniel; O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Dept Internal Med, Columbus, OH 43210 USA. [Ryckman, Kelli K.; Robinson, Jennifer G.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. [Mackey, Rachel H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Siscovick, David S.; Reiner, Alexander P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schreiner, Pamela J.; Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Holman, Albert; Uitterlinden, Andre G.; Dehghan, Abbas; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CN Rotterdam, Netherlands. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Taylor, Kent D.; Chen, Y. -D. Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90502 USA. [Patele, Aniruddh P.] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Hindy, George; Melander, Olle] Lund Univ, Dept Clin Sci Malmo, Clin Res Ctr, S-20502 Malmo, Sweden. [Orho-Melander, Marju] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, S-20502 Malmo, Sweden. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, I-20133 Milan, Italy. [Merlini, Piera Angelica; Ardissino, Diego] ASTC, I-27100 Pavia, Italy. [Merlini, Piera Angelica] Osped Maggiore Niguarda, Div Cardiol, I-20162 Milan, Italy. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX3 7BN, England. [Girelli, Domenico; Martinelli, Nicola] Univ Verona, Sch Med, Dept Med, I-37134 Verona, Italy. [Shah, Svati H.] Duke Univ, Div Urogynecol, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Kraus, William E.] Duke Univ, Sch Med, Duke Mol Physiol Inst, Durham, NC 27701 USA. [Li, Mingyao] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Atherogen Lab, Ottawa, ON K1Y 4W7, Canada. [Watkins, Hugh] Merck Sharp & Dohme Corp, Rahway, NJ 07065 USA. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, I-43100 Parma, Italy. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS 39217 USA. [Taylor, Herman A.] Tougaloo Coll, Tougaloo, MS 39174 USA. [Taylor, Herman A.; Correa, Adolfo; Griswold, Michael E.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split 21000, Croatia. [Ordovas, Jose M.] Natl Ctr Cardiovasc Investigat, Dept Cardiovasc Epidemiol & Populat Genet, Madrid 28049, Spain. [Ordovas, Jose M.] IMDEA Alimentac, Madrid 28049, Spain. [Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, Medford, MA 02155 USA. [Ordovas, Jose M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split 21000, Croatia. [Wilson, James G.] Univ Mississippi, Dept Physiol & Biophys, Med Ctr, Jackson, MS 39216 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org; skathiresan@partners.org; adrienne@bu.edu RI Hindy, George/H-1864-2016; Duga, Stefano/F-8173-2014; Gudnason, Vilmundur/K-6885-2015; Polasek, Ozren/B-6002-2011; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Martinelli, Nicola/J-5622-2016; Hayward, Caroline/M-8818-2016; Feitosa, Mary/K-8044-2012; OI Mackey, Rachel/0000-0001-6088-2664; Hindy, George/0000-0002-7257-9299; Stitziel, Nathan/0000-0002-4963-8211; Manichaikul, Ani/0000-0002-5998-795X; Duga, Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Pankow, James/0000-0001-7076-483X; Dehghan, Abbas/0000-0001-6403-016X; Gudnason, Vilmundur/0000-0001-5696-0084; Polasek, Ozren/0000-0002-5765-1862; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Martinelli, Nicola/0000-0001-6465-5119; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Asselta, Rosanna/0000-0001-5351-0619; Reynolds, Lindsay/0000-0001-6157-0144 FU National Heart, Lung, and Blood Institute (NHLBI); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, T32HL007208]; National Heart, Lung, and Blood Institute [HL105756]; Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq; NIH [RC2 HL-102925]; Merck; NIH/NHLBI [K08-HL114642]; NWO grant (veni) [916.12.154]; EUR Fellowship FX The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Infrastructure for the CHARGE Consortium is supported, in part, by the National Heart, Lung, and Blood Institute (grant HL105756). G.M.P. is supported by award number T32HL007208 from the NHLBI. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. Exome Array genotyping in case-control studies of coronary heart disease was supported by NIH RC2 HL-102925 and an investigator-initiated research grant from Merck to S.K. N.O.S. is supported, in part, by a career development award from the NIH/NHLBI K08-HL114642. A.D. is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or NIH. A full listing of acknowledgements is provided in Supplemental Data. NR 28 TC 99 Z9 100 U1 2 U2 23 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 FEB 6 PY 2014 VL 94 IS 2 BP 223 EP 232 DI 10.1016/j.ajhg.2014.01.009 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AA9NF UT WOS:000331419500006 PM 24507774 ER PT J AU Lange, LA Hu, YN Zhang, H Xue, CY Schmidt, EM Tang, ZZ Bizon, C Lange, EM Smith, JD Turner, EH Jun, G Kang, HM Peloso, G Auer, P Li, KP Flannick, J Zhang, J Fuchsberger, C Gaulton, K Lindgren, C Locke, A Manning, A Sim, XL Rivas, MA Holmen, OL Gottesman, O Lu, YC Ruderfer, D Stah, EA Duan, Q Li, Y Durda, P Jiao, S Isaacs, A Hofman, A Bis, JC Correa, A Griswold, ME Jakobsdottir, J Smith, AV Schreiner, PJ Feitosa, ME Zhang, QY Huffman, JE Crosby, J Wasse, CL Do, R Franceschini, N Martin, LW Robinson, JG Assimes, TL Crosslin, DR Rosenthal, EA Tsai, M Rieder, MJ Farlow, DN Folsom, AR Lumley, T Fox, ER Carlson, CS Peters, U Jackson, RD Van Duijn, CM Uitterlinden, AG Levy, D Rotter, JI Taylor, HA Gudnason, V Siscovick, DS Fornage, M Borecki, IB Hayward, C Rudan, I Chen, YE Bottinger, EP Loos, RJF Strom, P Hveem, K Boehnke, M Groop, L McCarthy, M Meitinger, T Ballantyne, CM Gabriel, SB O'Donne, CJ Post, WS North, KE Reiner, AP Boerwinkle, E Psaty, BM Altshuler, D Kathiresan, S Lin, DY Jarvik, GP Cupples, LA Kooperberg, C Wilson, JG Nickerson, DA Abecasis, GR Rich, SS Tracy, RP Willer, CJ AF Lange, Leslie A. Hu, Youna Zhang, He Xue, Chenyi Schmidt, Ellen M. Tang, Zheng-Zheng Bizon, Chris Lange, Ethan M. Smith, Joshua D. Turner, Emily H. Jun, Goo Kang, Hyun Min Peloso, Gina Auer, Paul Li, Kuo-Ping Flannick, Jason Zhang, Ji Fuchsberger, Christian Gaulton, Kyle Lindgren, Cecilia Locke, Adam Manning, Alisa Sim, Xueling Rivas, Manuel A. Holmen, Oddgeir L. Gottesman, Omri Lu, Yingchang Ruderfer, Douglas Stah, Eli A. Duan, Qing Li, Yun Durda, Peter Jiao, Shuo Isaacs, Aaron Hofman, Albert Bis, Joshua C. Correa, Adolfo Griswold, Michael E. Jakobsdottir, Johanna Smith, Albert V. Schreiner, Pamela J. Feitosa, Mary E. Zhang, Qunyuan Huffman, Jennifer E. Crosby, Jacy Wasse, Christina L. Do, Ron Franceschini, Nora Martin, Lisa W. Robinson, Jennifer G. Assimes, Themistocles L. Crosslin, David R. Rosenthal, Elisabeth A. Tsai, Michael Rieder, Mark J. Farlow, Deborah N. Folsom, Aaron R. Lumley, Thomas Fox, Ervin R. Carlson, Christopher S. Peters, Ulrike Jackson, Rebecca D. Van Duijn, Cornelia M. Uitterlinden, Andre G. Levy, Daniel Rotter, Jerome I. Taylor, Herman A. Gudnason, Vilmundur, Jr. Siscovick, David S. Fornage, Myriam Borecki, Ingrid B. Hayward, Caroline Rudan, Igor Chen, Y. Eugene Bottinger, Erwin P. Loos, Ruth J. F. Strom, Pal Hveem, Kristian Boehnke, Michael Groop, Leif McCarthy, Mark Meitinger, Thomas Ballantyne, Christie M. Gabriel, Stacey B. O'Donne, Christopher J. Post, Wendy S. North, Kari E. Reiner, Alexander P. Boerwinkle, Eric Psaty, Bruce M. Altshuler, David Kathiresan, Sekar Lin, Dan-Yu Jarvik, Gail P. Cupples, L. Adrienne Kooperberg, Charles Wilson, James G. Nickerson, Deborah A. Abecasis, Goncalo R. Rich, Stephen S. Tracy, Russell P. Willer, Cristen J. CA NHLBI Grand Opportunity Exome Sequ TI Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN-CHOLESTEROL; HEART-DISEASE; DESIGN; PLASMA; OBJECTIVES; ATHEROSCLEROSIS; SUSCEPTIBILITY; ABSORPTION; SPECTRUM; RISK AB Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. C1 [Lange, Leslie A.; Lange, Ethan M.; Duan, Qing; Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hu, Youna; Jun, Goo; Kang, Hyun Min; Li, Kuo-Ping; Fuchsberger, Christian; Locke, Adam; Sim, Xueling; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Zhang, He; Zhang, Ji; Chen, Y. Eugene; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Xue, Chenyi; Schmidt, Ellen M.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Tang, Zheng-Zheng; Lange, Ethan M.; Li, Yun; Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Bizon, Chris] Renaissance Comp Inst, Chapel Hill, NC 27517 USA. [Smith, Joshua D.; Turner, Emily H.; Rieder, Mark J.; Jarvik, Gail P.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Peloso, Gina; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina; Manning, Alisa; Do, Ron; Gabriel, Stacey B.; Altshuler, David; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02141 USA. [Auer, Paul; Jiao, Shuo; Carlson, Christopher S.; Peters, Ulrike; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul; Manning, Alisa] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Flannick, Jason; Manning, Alisa; Farlow, Deborah N.] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA. [Flannick, Jason; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Gaulton, Kyle; Lindgren, Cecilia; Rivas, Manuel A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Manning, Alisa; Altshuler, David] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02138 USA. [Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth, HUNT Res Ctr, N-7600 Levanger, Norway. [Gottesman, Omri; Bottinger, Erwin P.] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Ruderfer, Douglas; Stah, Eli A.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Li, Yun] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Durda, Peter; Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT 05446 USA. [Isaacs, Aaron; Van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 DR Rotterdam, Netherlands. [Hofman, Albert] Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands. [Bis, Joshua C.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Correa, Adolfo; Griswold, Michael E.; Fox, Ervin R.; Taylor, Herman A.] Univ Mississippi Med Ctr, Dept Med, Jackson, MS 39216 USA. [Jakobsdottir, Johanna; Smith, Albert V.; Gudnason, Vilmundur, Jr.] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur, Jr.] Univ Iceland, IS-101 Reykjavik, Iceland. [Schreiner, Pamela J.; Tsai, Michael; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Feitosa, Mary E.; Zhang, Qunyuan; Borecki, Ingrid B.] Washington Univ, Div Stat Genom, Dept Genet, Sch Med, St Louis, MO 63110 USA. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, Med Res Ctr Human Genet, Med Res Ctr Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Crosby, Jacy; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Wasse, Christina L.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Martin, Lisa W.] George Washington Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20037 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Crosslin, David R.; Rosenthal, Elisabeth A.; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Crosslin, David R.; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1142, New Zealand. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol, Columbus, OH 43210 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Levy, Daniel; O'Donne, Christopher J.; Cupples, L. Adrienne] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90502 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Taylor, Herman A.] Tougaloo Coll, Jackson, MS 39174 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS 39217 USA. [Siscovick, David S.; Reiner, Alexander P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Med Ctr, Seattle, WA 98195 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Strom, Pal] Norwegian Univ Sci & Technol, Dept Comp & Informat Sci, N-7491 Trondheim, Norway. [Strom, Pal] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7489 Trondheim, Norway. [Groop, Leif] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Skane Univ Hosp, S-22100 Malmo, Sweden. [Groop, Leif] Glostrup Univ Hosp, Glostrup Res Inst, DK-2600 Glostrup, Denmark. [McCarthy, Mark] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [McCarthy, Mark] Univ Oxford, Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX1 2JD, England. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [O'Donne, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Post, Wendy S.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Willer, CJ (reprint author), Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. EM cristen@umich.edu RI Johnson, Andrew/G-6520-2013; Feitosa, Mary/K-8044-2012; Jun, Goo/F-1941-2017; Singleton, Andrew/C-3010-2009; Zhang, Ji/J-4009-2014; Jarvik, Gail/N-6476-2014; Altshuler, David/A-4476-2009; Hardy, John/C-2451-2009; Tang, Zheng-Zheng/F-6642-2014; de Bakker, Paul/B-8730-2009; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Ruderfer, Douglas/M-5795-2016; Hayward, Caroline/M-8818-2016 OI Martin, Lisa Warsinger/0000-0003-4352-0914; Locke, Adam/0000-0001-6227-198X; Turner, Emily/0000-0001-9040-9229; Saetrom, Pal/0000-0001-8142-7441; Shendure, Jay/0000-0002-1516-1865; Assimes, Themistocles/0000-0003-2349-0009; Feitosa, Mary/0000-0002-0933-2410; Jun, Goo/0000-0003-0891-0204; Quinlan, Aaron/0000-0003-1756-0859; Willer, Cristen/0000-0001-5645-4966; Seshadri, Sudha/0000-0001-6135-2622; Fuchsberger, Christian/0000-0002-5918-8947; Jarvik, Gail/0000-0002-6710-8708; Altshuler, David/0000-0002-7250-4107; Tang, Zheng-Zheng/0000-0003-3802-8087; de Bakker, Paul/0000-0001-7735-7858; Gudnason, Vilmundur/0000-0001-5696-0084; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Ruderfer, Douglas/0000-0002-2365-386X; Hayward, Caroline/0000-0002-9405-9550 FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; Northwest Institute of Genomic Medicine; Washington State Life Sciences Discovery Fund; National Institutes of Health [R01HL107816]; Amarin; Amgen; Astra-Zeneca; Daiichi-Sankyo; Esperion; F. Hoffman-La Roche; Glaxo-Smith Kline; Merck; Regeneron; Sanofi; Takeda; Zinfandel; [R01 HL67406]; [R00 HL94535]; [R01 HL109946] FX The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for the NHLBI Grand Opportunity (GO) Exome Sequencing Project was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (Women's Health Initiative Sequencing Project). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). G.J. is supported by R01 HL67406 and the Northwest Institute of Genomic Medicine, funded by the Washington State Life Sciences Discovery Fund. S.K.'s effort is funded through National Institutes of Health grant R01HL107816. C.J.W. is supported by R00 HL94535 and R01 HL109946. The University of Iowa receives financial support from Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Esperion, F. Hoffman-La Roche, Glaxo-Smith Kline, Merck, Regeneron and Sanofi, and Takeda and Zinfandel for J.G.R's research. B.M.P serves on the data and safety monitoring board of a clinical trial for Zoll LifeCor. Additional acknowledgements are provided in the Supplemental Data. NR 41 TC 87 Z9 89 U1 2 U2 19 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 FEB 6 PY 2014 VL 94 IS 2 BP 233 EP 245 DI 10.1016/j.ajhg.2014.01.010 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AA9NF UT WOS:000331419500007 PM 24507775 ER PT J AU Hong, JJ Feng, HQ Wang, F Ranjan, A Chen, JH Jiang, JS Ghirlando, R Xiao, TS Wu, C Bai, YW AF Hong, Jingjun Feng, Hanqiao Wang, Feng Ranjan, Anand Chen, Jianhong Jiang, Jiansheng Ghirlando, Rodolfo Xiao, T. Sam Wu, Carl Bai, Yawen TI The Catalytic Subunit of the SWR1 Remodeler Is a Histone Chaperone for the H2A.Z-H2B Dimer SO MOLECULAR CELL LA English DT Article ID H2A VARIANT HTZ1; CHROMOSOME STABILITY; CHROMATIN STRUCTURE; STRUCTURAL BASIS; COMPLEX; NUCLEOSOME; TRANSCRIPTION; RECOGNITION; HETEROCHROMATIN; HETERODIMER AB Histone variant H2A.Z-containing nucleosomes exist at most eukaryotic promoters and play important roles in gene transcription and genome stability. The multisubunit nucleosome-remodeling enzyme complex SWR1, conserved from yeast to mammals, catalyzes the ATP-dependent replacement of histone H2A in canonical nucleosomes with H2A.Z. How SWR1 catalyzes the replacement reaction is largely unknown. Here, we determined the crystal structure of the N-terminal region (599-627) of the catalytic subunit Swr1, termed Swr1-Z domain, in complex with the H2A.Z-H2B dimer at 1.78 A resolution. The Swr1-Z domain forms a 3-10 helix and an irregular chain. A conserved LxxLF motif in the Swr1-Z 310 helix specifically recognizes the alpha C helix of H2A.Z. Our results show that the Swr1-Z domain can deliver the H2A.Z-H2B dimer to the DNA-(H3-H4)2 tetrasome to form the nucleosome by a histone chaperone mechanism. C1 [Hong, Jingjun; Feng, Hanqiao; Wang, Feng; Ranjan, Anand; Chen, Jianhong; Wu, Carl; Bai, Yawen] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Jiang, Jiansheng; Xiao, T. Sam] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [Wu, Carl] Howard Hughes Med Inst, Ashburn, VA 20147 USA. RP Bai, YW (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov RI Xiao, Tsan/A-8590-2010; OI Xiao, Tsan/0000-0001-9688-475X FU National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Janelia Farm Research Campus of Howard Hughes Medical Institute; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; U.S. Department of Energy [DE-AC02-06CH11357] FX We thank the staff at the Advanced Photon Source (beamline 23-ID) for technical support, S. Li for protein purification, D. Wei for purification of SWR1, Dr. B. Zhou for assistance in ITC data collection and analysis, and Dr. J. Barrowman for editing the manuscript. This research was supported by the Intramural Research Programs of the National Cancer Institute (J.H., H.F., F.W., A.R., J.C., C.W., and Y.B.), the National Institute of Allergy and Infectious Diseases (J.J. and T.S.X.), and the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.), National Institutes of Health, the Janelia Farm Research Campus of Howard Hughes Medical Institute (C.W.) as well as National Cancer Institute grant Y1-CO-1020, National Institute of General Medical Sciences grant Y1-GM-1104, and U.S. Department of Energy grant DE-AC02-06CH11357 (Advanced Photon Source). NR 38 TC 20 Z9 21 U1 1 U2 13 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 FEB 6 PY 2014 VL 53 IS 3 BP 498 EP 505 DI 10.1016/j.molcel.2014.01.010 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AA2HL UT WOS:000330915600013 PM 24507717 ER PT J AU Fauci, AS Marston, HD AF Fauci, Anthony S. Marston, Hilary D. TI Ending AIDS - Is an HIV Vaccine Necessary? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INFECTION AB The numbers of AIDS-related deaths and new HIV infections have decreased dramatically, thanks to prevention and treatment tools. But to control the pandemic more quickly and sustain the success, a safe and at least moderately effective vaccine is essential. In the past decade, according to the 2013 Global Report of the Joint United Nations Program on HIV/AIDS (UNAIDS), the numbers of AIDS-related deaths and new human immunodeficiency virus (HIV) infections have fallen by about one third from their peaks accomplishments made possible by the accelerated implementation of effective prevention and treatment tools. Of particular note, the scale-up of antiretroviral therapy (ART) averted 5.4 million deaths in low- and middle-income countries between 1995 and 2012. HIV prevention efforts have expanded from a narrow agenda of providing condoms and clean needles to use of a comprehensive toolkit of preventive interventions ... C1 [Fauci, Anthony S.; Marston, Hilary D.] NIAID, Off Director, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Off Director, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 35 Z9 35 U1 3 U2 11 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 FEB 6 PY 2014 VL 370 IS 6 BP 495 EP 498 DI 10.1056/NEJMp1313771 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AA4NT UT WOS:000331073500004 PM 24499210 ER PT J AU Glass, RI Parashar, UD AF Glass, Roger I. Parashar, Umesh D. TI Rotavirus Vaccines - Balancing Intussusception Risks and Health Benefits SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID UNITED-STATES; VACCINATION; PENTAVALENT; EFFICACY; CHILDREN; MEXICO; SAFETY AB In January 2006, the Journal published two landmark articles reporting the safety and efficacy of two different vaccines RotaTeq (Merck), a pentavalent vaccine (RV5),(1) and Rotarix (GlaxoSmithKline), a monovalent vaccine (RV1)(2) to prevent rotavirus, the most common cause of severe childhood diarrhea worldwide and of deaths from diarrhea in low-income countries. Each trial enrolled more than 60,000 infants to determine whether these live oral vaccines caused intussusception, the rare complication that in 1999 forced the withdrawal of the first licensed rotavirus vaccine, RotaShield (Wyeth Lederle), less than a year after it was recommended for routine immunization of U.S. ... C1 [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Parashar, Umesh D.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 17 Z9 17 U1 0 U2 5 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 FEB 6 PY 2014 VL 370 IS 6 BP 568 EP 570 DI 10.1056/NEJMe1315836 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AA4NT UT WOS:000331073500014 PM 24422677 ER PT J AU Tripathi, V Popescu, NC Zimonjic, DB AF Tripathi, V. Popescu, N. C. Zimonjic, D. B. TI DLC1 induces expression of E-cadherin in prostate cancer cells through Rho pathway and suppresses invasion SO ONCOGENE LA English DT Article DE E-cadherin; DLC1; Rho; invasion; prostate cancer ID GTPASE-ACTIVATING PROTEIN; EPITHELIAL TUMOR-CELLS; HEPATOCELLULAR-CARCINOMA; ADHERENS JUNCTIONS; BREAST-CANCER; RHO/ROCK PATHWAY; GENE-EXPRESSION; FAMILY GTPASES; IN-VIVO; ADHESION AB E-cadherin is a cell-cell adhesion molecule that acts as a suppressor of cancer cell invasion and its expression is downregulated in many advanced, poorly differentiated, human cancers. In this study, we found that the expression of DLC1 (deleted in liver cancer 1) tumor-suppressor gene in metastatic prostate carcinoma (PCA) cells increased the expression of E-cadherin and resulted in an elevated rate of cell-cell aggregation as measured by aggregation assay. DLC1-mediated increase in E-cadherin expression was not dependent on alpha-catenin, a DLC1-binding protein associated with E-cadherin, and/or cellular density. The increase of E-cadherin expression occurred at mRNA level and relied on DLC1 RhoGAP function, leading to suppression of high level of RhoA-GTP and RhoC-GTP activity in metastatic PCA cells. Application of Rho/ROCK inhibitors produced the same effect as introduction of DLC1. Knocking down of RhoA produced a moderate increase in E-cadherin whereas knocking down of RhoC resulted in a significant increase of E-cadherin. Downregulation of E-cadherin caused by constitutively active RhoA(V14) and RhoC(V14) could not be reversed by expression of DLC1 in DLC1-negative cell line. DLC1-mediated suppression of metastatic PCA cells invasion was comparable with the one associated with ectopic E-cadherin expression, or caused by suppression of Rho pathway either by Rho/ROCK inhibitors, or by shRNA repression. This study demonstrates that DLC1 expression positively regulates E-cadherin and suppresses highly metastatic PCA cell invasion by modulating Rho pathway, which appears as a feasible therapeutic target in cancers with high activity of RhoGTPases. C1 [Tripathi, V.; Popescu, N. C.; Zimonjic, D. B.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 4128B,37 Convent Dr,MSC 4262, Bethesda, MD 20892 USA. EM popescun@mail.nih.gov FU National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. NR 57 TC 13 Z9 14 U1 1 U2 8 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 FEB 6 PY 2014 VL 33 IS 6 BP 724 EP 733 DI 10.1038/onc.2013.7 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AA5IL UT WOS:000331129200007 PM 23376848 ER PT J AU McCann, CP Rericha, EC Wang, CL Losert, W Parent, CA AF McCann, Colin P. Rericha, Erin C. Wang, Chenlu Losert, Wolfgang Parent, Carole A. TI Dictyostelium Cells Migrate Similarly on Surfaces of Varying Chemical Composition SO PLOS ONE LA English DT Article ID MYOSIN-II; TALIN HOMOLOG; LEADING-EDGE; WILD-TYPE; ADHESION; DISCOIDEUM; DYNAMICS; MORPHOGENESIS; CYTOKINESIS; SUBSTRATE AB During cell migration, cell-substrate binding is required for pseudopod anchoring to move the cell forward, yet the interactions with the substrate must be sufficiently weak to allow parts of the cell to de-adhere in a controlled manner during typical protrusion/retraction cycles. Mammalian cells actively control cell-substrate binding and respond to extracellular conditions with localized integrin-containing focal adhesions mediating mechanotransduction. We asked whether mechanotransduction also occurs during non-integrin mediated migration by examining the motion of the social amoeba Dictyostelium discoideum, which is thought to bind non-specifically to surfaces. We discovered that Dictyostelium cells are able to regulate forces generated by the actomyosin cortex to maintain optimal cell-surface contact area and adhesion on surfaces of various chemical composition and that individual cells migrate with similar speed and contact area on the different surfaces. In contrast, during collective migration, as observed in wound healing and metastasis, the balance between surface forces and protrusive forces is altered. We found that Dictyostelium collective migration dynamics are strongly affected when cells are plated on different surfaces. These results suggest that the presence of cell-cell contacts, which appear as Dictyostelium cells enter development, alter the mechanism cells use to migrate on surfaces of varying composition. C1 [McCann, Colin P.; Rericha, Erin C.; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [McCann, Colin P.; Rericha, Erin C.; Wang, Chenlu; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Losert, Wolfgang; Parent, Carole A.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Wang, Chenlu] Univ Maryland, Biophys Grad Program, College Pk, MD 20742 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research in the National Cancer Institute; Burroughs Wellcome Fund; NSF-Physics of Living Systems Program [PHY07A50371]; NSF-Cyber Physical Systems Grant [CPS0931508] FX This work was supported by the Intramural Research Program of the Center for Cancer Research in the National Cancer Institute. Erin Rericha holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. WL and ER acknowledge support from the NSF-Physics of Living Systems Program Grant PHY07A50371. WL and CW also received support from the NSF-Cyber Physical Systems Grant CPS0931508. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 3 Z9 3 U1 2 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 6 PY 2014 VL 9 IS 2 AR e87981 DI 10.1371/journal.pone.0087981 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1BH UT WOS:000330830700036 PM 24516575 ER PT J AU Wu, T Schwender, H Ruczinski, I Murray, JC Marazita, ML Munger, RG Hetmanski, JB Parker, MM Wang, P Murray, T Taub, M Li, S Redett, RJ Fallin, MD Liang, KY Wu-Chou, YH Chong, SS Yeow, V Ye, XQ Wang, H Huang, SZ Jabs, EW Shi, B Wilcox, AJ Jee, SH Scott, AF Beaty, TH AF Wu, Tao Schwender, Holger Ruczinski, Ingo Murray, Jeffrey C. Marazita, Mary L. Munger, Ronald G. Hetmanski, Jacqueline B. Parker, Margaret M. Wang, Ping Murray, Tanda Taub, Margaret Li, Shuai Redett, Richard J. Fallin, M. Daniele Liang, Kung Yee Wu-Chou, Yah Huei Chong, Samuel S. Yeow, Vincent Ye, Xiaoqian Wang, Hong Huang, Shangzhi Jabs, Ethylin W. Shi, Bing Wilcox, Allen J. Jee, Sun Ha Scott, Alan F. Beaty, Terri H. TI Evidence of Gene-Environment Interaction for Two Genes on Chromosome 4 and Environmental Tobacco Smoke in Controlling the Risk of Nonsyndromic Cleft Palate SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SYNDROMIC ORAL CLEFTS; SERUM URIC-ACID; OROFACIAL CLEFTS; CANDIDATE GENES; MATERNAL SMOKING; CARDIOVASCULAR-DISEASE; CIGARETTE-SMOKING; LIP; POPULATION AB Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6) Dm8 -> Tm5c form a hard-wired glutamatergic circuit that mediates UV preference by pooling similar to 16 R7 signals for transfer to the lobula, a higher visual center. C1 [Karuppudurai, Thangavel; Lin, Tzu-Yang; Ting, Chun-Yuan; Melnattur, Krishna V.; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Pursley, Randall; Pohida, Thomas] NIMH, Signal Proc & Instrumentat Sect, Div Computat Biosci, Ctr Informat Technol,NIH, Bethesda, MD 20892 USA. [Diao, Fengqiu; White, Benjamin H.] NIMH, Sect Neural Funct, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Macpherson, Lindsey J.; Gallio, Marco] Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. [Macpherson, Lindsey J.; Gallio, Marco] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov RI Karuppudurai, Thangavel/C-4831-2014; OI Gallio, Marco/0000-0003-2132-0639 FU Intramural Research Programs of the National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development [Z01-HD008776]; National Institute of Mental Health [1ZIA-MH-002800-07]; Center for Information Technology; NIH [RC1-NS069014, R01-NS076774] FX We thank Shinya Takemura and Dmitri Chklovskii for communicating results prior to publication; Tzumin Lee, Kristin Scott, Stephan Sigrist, Aaron DiAntonio, Gerald Rubin, and Claude Desplan for providing critical reagents; and Mark Mayer and Alan Hinnebusch for helpful discussion. This work was supported by the Intramural Research Programs of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant Z01-HD008776 to C.-H. L), National Institute of Mental Health (project 1ZIA-MH-002800-07 to B. H. W.), and Center for Information Technology (to R. P. and T. P.). L.J.M. and M.G.'s research was supported by NIH grants (RC1-NS069014 and R01-NS076774) to Charles Zuker. NR 42 TC 25 Z9 25 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD FEB 5 PY 2014 VL 81 IS 3 BP 603 EP 615 DI 10.1016/j.neuron.2013.12.010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AA3AO UT WOS:000330965500014 PM 24507194 ER PT J AU Neubert, FX Mars, RB Thomas, AG Sallet, J Rushworth, MFS AF Neubert, Franz-Xaver Mars, Rogier B. Thomas, Adam G. Sallet, Jerome Rushworth, Matthew F. S. TI Comparison of Human Ventral Frontal Cortex Areas for Cognitive Control and Language with Areas in Monkey Frontal Cortex SO NEURON LA English DT Article ID CONNECTIVITY-BASED PARCELLATION; COMPARATIVE CYTOARCHITECTONIC ANALYSIS; INTRINSIC FUNCTIONAL ARCHITECTURE; TRACTOGRAPHY-BASED PARCELLATION; INFERIOR PARIETAL LOBULE; PREFRONTAL CORTEX; MACAQUE MONKEY; BROCAS AREA; SOCIAL COGNITION; PREMOTOR CORTEX AB Human ventrolateral frontal cortex (vlFC) is identified with cognitive processes such as language and cognitive flexibility. The relationship between it and the vlFC of other primates has therefore been the subject of particular speculation. We used a combination of structural and functional neuroimaging methods to identify key components of human vlFC. We compared how vlFC areas interacted with other brain areas in 25 humans and 25 macaques using the same methods. We identified a core set of 11 vlFC components that interacted in similar ways with similar distributed circuits in both species and, in addition, one distinctively human component in ventrolateral frontal pole. Fundamental differences in interactions with posterior auditory association areas in the two species were also present-these were ubiquitous throughout posterior human vlFC but channeled to different frontal regions in monkeys. Finally, there were some differences in interregional interactions within vlFC in the two species. C1 [Neubert, Franz-Xaver; Mars, Rogier B.; Sallet, Jerome; Rushworth, Matthew F. S.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Mars, Rogier B.; Thomas, Adam G.; Rushworth, Matthew F. S.] John Radcliffe Hosp, Oxford Ctr Funct MRI Brain, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Thomas, Adam G.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Neubert, FX (reprint author), Univ Oxford, Dept Expt Psychol, 9 South Parks Rd, Oxford OX1 3UD, England. EM franz-xaver.neubert@psy.ox.ac.uk OI Thomas, Adam/0000-0002-2850-1419 FU Medical Research Council (United Kingdom) [G0802146]; Gustav Born Scholarship; Christopher Welch Scholarship FX This research was supported by Medical Research Council (United Kingdom) G0802146 (to M. F. S. R. and R. B. M.), a Gustav Born Scholarship (to F.-X.N.), and a Christopher Welch Scholarship (to F.-X.N.). We thank Vanessa M. Johnen for helpful comments on an earlier version of the manuscript. NR 59 TC 75 Z9 75 U1 4 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD FEB 5 PY 2014 VL 81 IS 3 BP 700 EP 713 DI 10.1016/j.neuron.2013.11.012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AA3AO UT WOS:000330965500022 PM 24485097 ER PT J AU George, SM Alfano, CM Groves, J Karabulut, Z Haman, KL Murphy, BA Matthews, CE AF George, Stephanie M. Alfano, Catherine M. Groves, Jay Karabulut, Zafer Haman, Kirsten L. Murphy, Barbara A. Matthews, Charles E. TI Objectively Measured Sedentary Time Is Related to Quality of Life among Cancer Survivors SO PLOS ONE LA English DT Article ID PHYSICAL-ACTIVITY; HEALTH; INTERVENTION; POSTURE; DISEASE; HUMANS; SF-36; MOVE AB Purpose: While exercise has been shown to be beneficial in improving health-related quality of life (HRQOL) among cancer survivors, evidence is limited on the independent role of sedentary behavior. We examined how objectively measured sedentary time was associated with HRQOL among long-term cancer survivors. Methods: This cross-sectional study included 54 cancer survivors, on average 3.4 years postdiagnosis, who were enrolled into an exercise trial designed to improve cognitive function. At baseline, we measured sedentary time and moderate-vigorous intensity physical activity with the ActivPal, cardiorespiratory fitness with treadmill testing, and self-reported HRQOL with an established scale (SF-36). In multivariate models, we regressed HRQOL on sedentary time (percent of waking time spent sitting and lying). Results: Survivors with higher sedentary time had significantly poorer physical functioning (beta = -0.50, p = 0.028), general health (beta = -0.75, ptrend = 0.004), and physical summary scores (beta = -0.34, p = 0.003). We did not observe associations between sedentary time and role-physical (p = 0.342), bodily-pain (p = 0.117), vitality (p = 0.095), social functioning (p = 0.407), role-emotional (p = 0.509), mental health (p = 0.494), or mental summary scores (p = 0.527). Conclusion: In this cross-sectional study of cancer survivors, we observed deleterious associations between sedentary time and aspects of physical HRQOL. Future prospective studies of sedentary time and HRQOL are needed to establish temporality and to facilitate the design of effective health promotion interventions for cancer survivors. C1 [George, Stephanie M.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Groves, Jay; Karabulut, Zafer] Vanderbilt Univ, Med Ctr, Vanderbilt Dayani Ctr Hlth & Wellness, Nashville, TN USA. [Haman, Kirsten L.] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Murphy, Barbara A.] Vanderbilt Univ, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. RP George, SM (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. EM Stephanie.george@nih.gov RI matthews, Charles/E-8073-2015 OI matthews, Charles/0000-0001-8037-3103 FU Lance Armstrong Foundation FX This study was funded by the Lance Armstrong Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 15 Z9 15 U1 0 U2 18 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 FEB 5 PY 2014 VL 9 IS 2 AR e87937 DI 10.1371/journal.pone.0087937 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1AT UT WOS:000330829200087 PM 24505335 ER PT J AU Ma, Y Chapman, J Levine, M Polireddy, K Drisko, J Chen, Q AF Ma, Yan Chapman, Julia Levine, Mark Polireddy, Kishore Drisko, Jeanne Chen, Qi TI High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VITAMIN-C PHARMACOKINETICS; TERMINAL HUMAN CANCER; I CLINICAL-TRIAL; CELL-DEATH; PANCREATIC-CANCER; DNA-DAMAGE; OXIDATIVE STRESS; PHARMACOLOGICAL CONCENTRATIONS; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT AB Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H2O2) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials. C1 [Ma, Yan; Polireddy, Kishore; Chen, Qi] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Ma, Yan; Polireddy, Kishore; Drisko, Jeanne; Chen, Qi] Univ Kansas, Med Ctr, KU Integrat Med, Kansas City, KS 66160 USA. [Chapman, Julia] Univ Kansas, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Kansas City, KS 66160 USA. [Levine, Mark] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. RP Chen, Q (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. EM jdrisko@kumc.edu; qchen@kumc.edu RI Bollu, Lakshmi/O-4992-2015; Chen, Qi/D-8278-2015 OI Bollu, Lakshmi/0000-0001-9596-6251; Chen, Qi/0000-0002-7173-8411 FU Gateway for Cancer Research Foundation; University of Kansas Endowment by the L. Charles Hilton Family Foundation; University of Kansas Research Institute; Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX Funding: This work was financially supported by Gateway for Cancer Research Foundation (formerly Cancer Treatment Research Foundation, Schaumburg, IL), a grant from the University of Kansas Endowment provided by the L. Charles Hilton Family Foundation, a bridging grant from the University of Kansas Research Institute, and the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 57 TC 42 Z9 43 U1 2 U2 24 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 5 PY 2014 VL 6 IS 222 AR 222ra18 DI 10.1126/scitranslmed.3007154 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AA4UF UT WOS:000331091100008 PM 24500406 ER PT J AU James, PA Oparil, S Carter, BL Cushman, WC Dennison-Himmelfarb, C Handler, J Lackland, DT LeFevre, ML MacKenzie, TD Ogedegbe, O Smith, SC Svetkey, LP Taler, SJ Townsend, RR Wright, JT Narva, AS Ortiz, E AF James, Paul A. Oparil, Suzanne Carter, Barry L. Cushman, William C. Dennison-Himmelfarb, Cheryl Handler, Joel Lackland, Daniel T. LeFevre, Michael L. MacKenzie, Thomas D. Ogedegbe, Olugbenga Smith, Sidney C., Jr. Svetkey, Laura P. Taler, Sandra J. Townsend, Raymond R. Wright, Jackson T., Jr. Narva, Andrew S. Ortiz, Eduardo TI 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID ISOLATED SYSTOLIC HYPERTENSION; LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; CONVERTING ENZYME-INHIBITOR; RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; CALCIUM-CHANNEL BLOCKER; CHRONIC RENAL-DISEASE; HIGH-RISK; OLDER PATIENTS AB Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient. C1 [James, Paul A.; Carter, Barry L.] Univ Iowa, Iowa City, IA 52242 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Cushman, William C.] Univ Tennessee, Memphis, TN USA. [Dennison-Himmelfarb, Cheryl] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Handler, Joel] Kaiser Permanente, Anaheim, CA USA. [Lackland, Daniel T.] Med Univ S Carolina, Charleston, SC USA. [LeFevre, Michael L.] Univ Missouri, Columbia, MO 65211 USA. [MacKenzie, Thomas D.] Denver Hlth & Hosp Author, Denver, CO USA. [MacKenzie, Thomas D.] Univ Colorado, Sch Med, Denver, CO USA. [Ogedegbe, Olugbenga] NYU, Sch Med, New York, NY USA. [Smith, Sidney C., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Svetkey, Laura P.] Duke Univ, Durham, NC USA. [Taler, Sandra J.] Mayo Clin, Coll Med, Rochester, MN USA. [Townsend, Raymond R.] Univ Penn, Philadelphia, PA 19104 USA. [Wright, Jackson T., Jr.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Narva, Andrew S.] NIDDK, Bethesda, MD 20892 USA. [Ortiz, Eduardo] NHLBI, Bethesda, MD 20892 USA. RP James, PA (reprint author), Univ Iowa, 200 Hawkins Dr,01286-D PFP, Iowa City, IA 52242 USA. EM paul-james@uiowa.edu FU National Heart, Lung, and Blood Institute (NHLBI) FX The evidence review for this project was funded by the National Heart, Lung, and Blood Institute (NHLBI). NR 45 TC 1872 Z9 2018 U1 55 U2 265 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 5 PY 2014 VL 311 IS 5 BP 507 EP 520 DI 10.1001/jama.2013.284427 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 302GF UT WOS:000330589800024 PM 24352797 ER PT J AU Coker, LH Espeland, MA Hogan, PE Resnick, SM Bryan, RN Robinson, JG Goveas, JS Davatzikos, C Kuller, LH Williamson, JD Bushnell, CD Shumaker, SA AF Coker, Laura H. Espeland, Mark A. Hogan, Patricia E. Resnick, Susan M. Bryan, R. Nick Robinson, Jennifer G. Goveas, Joseph S. Davatzikos, Christos Kuller, Lewis H. Williamson, Jeff D. Bushnell, Cheryl D. Shumaker, Sally A. CA WHIMS-MRI Study Grp TI Change in brain and lesion volumes after CEE therapies The WHIMS-MRI studies SO NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; POSTMENOPAUSAL HORMONE-THERAPY; RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; MITOCHONDRIAL BIOENERGETICS; MAGNETIC-RESONANCE; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; EQUINE ESTROGEN; WOMEN AB Objectives:To determine whether smaller brain volumes in older women who had completed Women's Health Initiative (WHI)-assigned conjugated equine estrogen-based hormone therapy (HT), reported by WHI Memory Study (WHIMS)-MRI, correspond to a continuing increased rate of atrophy an average of 6.1 to 7.7 years later in WHIMS-MRI2.Methods:A total of 1,230 WHI participants were contacted: 797 (64.8%) consented, and 729 (59%) were rescanned an average of 4.7 years after the initial MRI scan. Mean annual rates of change in total brain volume, the primary outcome, and rates of change in ischemic lesion volumes, the secondary outcome, were compared between treatment groups using mixed-effect models with adjustment for trial, clinical site, age, intracranial volumes, and time between MRI measures.Results:Total brain volume decreased an average of 3.22 cm(3)/y in the active arm and 3.07 cm(3)/y in the placebo arm (p = 0.53). Total ischemic lesion volumes increased in both arms at a rate of 0.12 cm(3)/y (p = 0.88).Conclusions:Conjugated equine estrogen-based postmenopausal HT, previously assigned at WHI baseline, did not affect rates of decline in brain volumes or increases in brain lesion volumes during the 4.7 years between the initial and follow-up WHIMS-MRI studies. Smaller frontal lobe volumes were observed as persistent group differences among women assigned to active HT compared with placebo. Women with a history of cardiovascular disease treated with active HT, compared with placebo, had higher rates of accumulation in white matter lesion volume and total brain lesion volume. Further study may elucidate mechanisms that explain these findings. C1 [Coker, Laura H.; Espeland, Mark A.; Hogan, Patricia E.; Shumaker, Sally A.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Williamson, Jeff D.] Wake Forest Sch Med, Dept Internal Med & Geriatr, Winston Salem, NC USA. [Bushnell, Cheryl D.] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [Resnick, Susan M.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Bryan, R. Nick; Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Internal Med & Epidemiol, Iowa City, IA USA. [Goveas, Joseph S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Coker, LH (reprint author), Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. EM lcoker@wakehealth.edu FU National Heart, Lung, and Blood Institute, NIH FX Supported by the National Heart, Lung, and Blood Institute, NIH. NR 29 TC 11 Z9 11 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 4 PY 2014 VL 82 IS 5 BP 427 EP 434 DI 10.1212/WNL.0000000000000079 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AH9WA UT WOS:000336494600014 PM 24384646 ER PT J AU Bedford, T Suchard, MA Lemey, P Dudas, G Gregory, V Hay, AJ McCauley, JW Russell, CA Smith, DJ Rambaut, A AF Bedford, Trevor Suchard, Marc A. Lemey, Philippe Dudas, Gytis Gregory, Victoria Hay, Alan J. McCauley, John W. Russell, Colin A. Smith, Derek J. Rambaut, Andrew TI Integrating influenza antigenic dynamics with molecular evolution SO ELIFE LA English DT Article ID A H1N1 VIRUSES; B VIRUSES; EPIDEMIC INFLUENZA; AMINO-ACID; HEMAGGLUTININ GENE; SEQUENCE-ANALYSIS; GENOMIC ANALYSES; UNITED-KINGDOM; DRIFT; VARIANTS AB Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. C1 [Bedford, Trevor; Dudas, Gytis; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, UCLA Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Louvain, Belgium. [Gregory, Victoria; Hay, Alan J.; McCauley, John W.] Natl Inst Med Res, MRC, Div Virol, London NW7 1AA, England. [Russell, Colin A.; Smith, Derek J.] Univ Cambridge, WHO Collaborating Ctr Modeling Evolut & Control E, Cambridge, England. [Russell, Colin A.] Univ Cambridge, Dept Vet Med, Cambridge, England. [Smith, Derek J.] Univ Cambridge, Dept Zool, Ctr Pathogen Evolut, Cambridge, England. [Smith, Derek J.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Rambaut, Andrew] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. RP Bedford, T (reprint author), Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. EM tbedford@fhcrc.org OI Bedford, Trevor/0000-0002-4039-5794; Russell, Colin/0000-0002-2113-162X; Rambaut, Andrew/0000-0003-4337-3707; Dudas, Gytis/0000-0002-0227-4158 FU Royal Society; National Institutes of Health [R01 HG006139, R01 AI107034, DP1-OD000490-01, HHSN266200700010C]; National Science Foundation [DMS126153, IIS1251151, EF-0423641]; European Commission [278433-PREDEMICS, 260864, 223498-EMPERIE, 278976-ANTIGONE]; Medical Research Council [U117512723]; Wellcome Trust [092807, 087982AIA]; Human Frontier Science Program [P0050/2008] FX Royal Society Newton International Fellowship Trevor Bedford; National Institutes of Health R01 HG006139 Marc A Suchard; National Institutes of Health R01 AI107034 Marc A Suchard; National Science Foundation DMS126153 Marc A Suchard; National Science Foundation IIS1251151 Marc A Suchard; European Commission 278433-PREDEMICS Marc A Suchard, Philippe Lemey, Andrew Rambaut; European Commission 260864 Marc A Suchard, Philippe Lemey, Andrew Rambaut; National Science Foundation EF-0423641 Marc A Suchard, Philippe Lemey, Andrew Rambaut; Medical Research Council U117512723 Victoria Gregory, Alan J Hay, John W McCauley; Wellcome Trust 092807 Andrew Rambaut; European Commission 223498-EMPERIE Colin A Russell, Derek J Smith; European Commission 278976-ANTIGONE Colin A Russell, Derek J Smith; Human Frontier Science Program P0050/2008 Colin A Russell, Derek J Smith; Wellcome Trust 087982AIA Colin A Russell, Derek J Smith; National Institutes of Health DP1-OD000490-01 Colin A Russell, Derek J Smith; National Institutes of Health HHSN266200700010C Colin A Russell, Derek J Smith; Royal Society University Research Fellowship Colin A Russell NR 78 TC 64 Z9 67 U1 5 U2 20 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 4 PY 2014 VL 3 AR e01914 DI 10.7554/eLife.01914 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AA7RF UT WOS:000331293900006 PM 24497547 ER PT J AU MacKinnon, AL Paavilainen, VO Sharma, A Hegde, RS Taunton, J AF MacKinnon, Andrew L. Paavilainen, Ville O. Sharma, Ajay Hegde, Ramanujan S. Taunton, Jack TI An allosteric Sec61 inhibitor traps nascent transmembrane helices at the lateral gate SO ELIFE LA English DT Article ID MEMBRANE-PROTEIN INTEGRATION; SIGNAL SEQUENCE RECOGNITION; CELL-ADHESION MOLECULE-1; ENDOPLASMIC-RETICULUM; COTRANSLATIONAL TRANSLOCATION; ER MEMBRANE; CONDUCTING CHANNEL; COMPLEX; INSERTION; TRANSPORT AB Membrane protein biogenesis requires the coordinated movement of hydrophobic transmembrane domains (TMD) from the cytosolic vestibule of the Sec61 channel into the lipid bilayer. Molecular insight into TMD integration has been hampered by the difficulty of characterizing intermediates during this intrinsically dynamic process. In this study, we show that cotransin, a substrate-selective Sec61 inhibitor, traps nascent TMDs in the cytosolic vestibule, permitting detailed interrogation of an early pre-integration intermediate. Site-specific crosslinking revealed the pre-integrated TMD docked to Sec61 near the cytosolic tip of the lateral gate. Escape from cotransin-arrest depends not only on cotransin concentration, but also on the biophysical properties of the TMD. Genetic selection of cotransin-resistant cancer cells uncovered multiple mutations clustered near the lumenal plug of Sec61 alpha, thus revealing cotransin's likely site of action. Our results suggest that TMD/lateral gate interactions facilitate TMD transfer into the membrane, a process that is allosterically modulated by cotransin binding to the plug. C1 [MacKinnon, Andrew L.; Paavilainen, Ville O.; Taunton, Jack] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Sharma, Ajay; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Taunton, Jack] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. RP Taunton, J (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM jack.taunton@ucsf.edu OI Paavilainen, Ville/0000-0002-3160-7767; Hegde, Ramanujan/0000-0001-8338-852X FU National Institutes of Health [GM081644]; Medical Research Council; Academy of Finland; Sigrid Juselius Foundation FX National Institutes of Health GM081644 Ramanujan S Hegde, Jack Taunton; Medical Research Council Ramanujan S Hegde; The Academy of Finland Ville O Paavilainen; Sigrid Juselius Foundation Ville O Paavilainen NR 51 TC 17 Z9 17 U1 1 U2 8 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 4 PY 2014 VL 3 AR e01483 DI 10.7554/eLife.01483 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AA7RF UT WOS:000331293900003 PM 24497544 ER PT J AU Pratt, CA Arteaga, S Loria, C AF Pratt, Charlotte A. Arteaga, Sonia Loria, Catherine TI Forging a Future of Better Cardiovascular Health Addressing Childhood Obesity SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT News Item DE cardiovascular health; childhood obesity; NHLBIQ ID ASSOCIATION; CHILDREN C1 [Pratt, Charlotte A.; Arteaga, Sonia; Loria, Catherine] NHLBI, Clin Applicat & Prevent Branch, Prevent & Populat Sci Program, NIH, Bethesda, MD 20892 USA. RP Pratt, CA (reprint author), NHLBI, Prevent & Populat Sci Program, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10118, Bethesda, MD 20892 USA. EM prattc@nhlbi.nih.gov NR 9 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 4 PY 2014 VL 63 IS 4 BP 369 EP 371 DI 10.1016/j.jacc.2013.07.088 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 297AM UT WOS:000330227200013 PM 24076288 ER PT J AU Zolla-Pazner, S deCamp, A Gilbert, PB Williams, C Yates, NL Williams, WT Howington, R Fong, YY Morris, DE Soderberg, KA Irene, C Reichman, C Pinter, A Parks, R Pitisuttithum, P Kaewkungwal, J Rerks-Ngarm, S Nitayaphan, S Andrews, C O'Connell, RJ Yang, ZY Nabel, GJ Kim, JH Michael, NL Montefiori, DC Liao, HX Haynes, BF Tomaras, GD AF Zolla-Pazner, Susan deCamp, Allan Gilbert, Peter B. Williams, Constance Yates, Nicole L. Williams, William T. Howington, Robert Fong, Youyi Morris, Daryl E. Soderberg, Kelly A. Irene, Carmela Reichman, Charles Pinter, Abraham Parks, Robert Pitisuttithum, Punnee Kaewkungwal, Jaranit Rerks-Ngarm, Supachai Nitayaphan, Sorachai Andrews, Charla O'Connell, Robert J. Yang, Zhi-yong Nabel, Gary J. Kim, Jerome H. Michael, Nelson L. Montefiori, David C. Liao, Hua-Xin Haynes, Barton F. Tomaras, Georgia D. TI Vaccine-Induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate with Decreased Risk of HIV-1 Infection SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; B-CELL RESPONSES; HIV-1-INFECTED INDIVIDUALS; CROSS-REACTIVITY; V1/V2 DOMAIN; ENVELOPE; NEUTRALIZATION; GP120; SEQUENCE AB In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008-0.05; estimated odds ratios of 0.53-0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection. C1 [Zolla-Pazner, Susan] New York Harbor Healthcare Syst, Dept Vet Affairs, New York, NY 10010 USA. [Zolla-Pazner, Susan; Williams, Constance] NYU, Sch Med, New York, NY USA. [deCamp, Allan; Gilbert, Peter B.; Fong, Youyi; Morris, Daryl E.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Yates, Nicole L.; Williams, William T.; Howington, Robert; Soderberg, Kelly A.; Parks, Robert; Montefiori, David C.; Liao, Hua-Xin; Haynes, Barton F.; Tomaras, Georgia D.] Duke Univ, Durham, NC USA. [Irene, Carmela; Reichman, Charles; Pinter, Abraham] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Pitisuttithum, Punnee; Kaewkungwal, Jaranit] Fac Trop Med, Mahidol, Thailand. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Bangkok, Thailand. [Nitayaphan, Sorachai] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Andrews, Charla; O'Connell, Robert J.; Kim, Jerome H.; Michael, Nelson L.] Walter Reed Army Inst Res, Mil HIV Res Program, Silver Spring, MD USA. [Yang, Zhi-yong; Nabel, Gary J.] NIAID, Virol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Zolla-Pazner, S (reprint author), New York Harbor Healthcare Syst, Dept Vet Affairs, New York, NY 10010 USA. EM zollas01@med.nyu.edu RI Tomaras, Georgia/J-5041-2016 FU National Institutes of Health [P01 AI100151, R01 HL59725, P01 AI64518]; Bill and Melinda Gates Foundation [1040758, 3830913]; Military HIV Research Program; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development; U.S. Army Medical Research and Material Command (USAMRMC) [Y1-AI-2642-12]; National Institutes of Allergy and Infectious Diseases [Y1-AI-2642-12]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense [W81XWH-07-2-0067] FX Supported in part by grant funds from the National Institutes of Health: P01 AI100151 (SZP), R01 HL59725 (SZP), P01 AI64518 (Duke Center for AIDS Research); from the Bill and Melinda Gates Foundation: 1040758 (BFH), and 3830913 (DCM); from the Military HIV Research Program, and research funds from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The work was also supported in part by an Interagency Agreement Y1-AI-2642-12 between the U.S. Army Medical Research and Material Command (USAMRMC) and the National Institutes of Allergy and Infectious Diseases and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 83 Z9 84 U1 2 U2 16 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 FEB 4 PY 2014 VL 9 IS 2 AR e87572 DI 10.1371/journal.pone.0087572 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302VA UT WOS:000330631800045 PM 24504509 ER PT J AU Berezhkovskii, AM Dagdug, L Lizunov, VA Zimmerberg, J Bezrukov, SM AF Berezhkovskii, Alexander M. Dagdug, Leonardo Lizunov, Vladimir A. Zimmerberg, Joshua Bezrukov, Sergey M. TI Trapping by Clusters of Channels, Receptors, and Transporters: Quantitative Description SO BIOPHYSICAL JOURNAL LA English DT Review ID 1ST PASSAGE TIME; LIGAND-BINDING; SPHINGOLIPID DOMAINS; ASYMPTOTIC ANALYSIS; PLASMA-MEMBRANES; RATE CONSTANTS; CELL-SURFACE; DIFFUSION; PROTEIN; HOMOGENIZATION AB Various membrane functional units such as receptors, transporters, and channels, whose action necessarily involves capturing diffusing molecules, are often organized into multimeric complexes forming clusters on the cell and organelle membranes. These functional units themselves are usually oligomers of several integral proteins, which have their own symmetry. Depending on the symmetry, they form clusters on different packing lattices. Moreover, local membrane inhomogeneities, e.g., the so-called membrane domains, rafts, stalks, etc., lead to different patterns even within the structures on the same packing lattice. Units in the cluster compete for diffusing molecules and screen each other. Here we propose a general approach that allows one to quantify the screening effects. The approach is used to derive simple approximate formulas giving the trapping rates of diffusing molecules by clusters of absorbers on lattices of different packing symmetries. The obtained results describe smooth variation of the trapping rate from the sum of the rates of individual absorbers forming the cluster to the effective collective rate. The latter shows how the trapping efficiency of an individual absorber decreases as the number of absorbers in the cluster increases and/or the inter-absorber distance decreases. Numerical tests demonstrate good agreement between the rates predicted by the theory and obtained from Brownian dynamics simulations for clusters of different shapes and sizes. C1 [Berezhkovskii, Alexander M.; Dagdug, Leonardo; Lizunov, Vladimir A.; Zimmerberg, Joshua; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.; Dagdug, Leonardo] NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Iztapalapa, Mexico. RP Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov FU Consejo Nacional de Ciencia y Tecnologia [176452]; National Institutes of Health, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX L.D. is grateful to the Consejo Nacional de Ciencia y Tecnologia for partial support by grant No. 176452. This study was supported by the Intramural Research Program of the National Institutes of Health, Center for Information Technology and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 34 TC 1 Z9 1 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 4 PY 2014 VL 106 IS 3 BP 500 EP 509 DI 10.1016/j.bpj.2013.12.015 PG 10 WC Biophysics SC Biophysics GA 304CV UT WOS:000330724800003 PM 24507591 ER PT J AU Gurnev, PA Yap, TL Pfefferkorn, CM Rostovtseva, TK Berezhkovskii, AM Lee, JC Parsegian, VA Bezrukov, SM AF Gurnev, Philip A. Yap, Thai Leong Pfefferkorn, Candace M. Rostovtseva, Tatiana K. Berezhkovskii, Alexander M. Lee, Jennifer C. Parsegian, V. Adrian Bezrukov, Sergey M. TI Alpha-Synuclein Lipid-Dependent Membrane Binding and Translocation through the alpha-Hemolysin Channel SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN TRANSLOCATION; PARKINSONS-DISEASE; ANTHRAX TOXIN; POLYNUCLEOTIDE MOLECULES; NANOPORE ANALYSIS; LEWY BODIES; PORE; HELIX; TRANSPORT; PEPTIDES AB Gauging the interactions of a natively unfolded Parkinson disease-related protein, alpha-synuclein (alpha-syn) with membranes and its pathways between and within cells is important for understanding its pathogenesis. Here, to address these questions, we use a robust beta-barrel channel, alpha-hemolysin, reconstituted into planar lipid bilayers. Transient, similar to 95% blockage of the channel current by alpha-syn was observed when 1), alpha-syn was added from the membrane side where the shorter (stem) part of the channel is exposed; and 2), the applied potential was lower on the side of alpha-syn addition. While the on- rate of alpha-syn binding to the channel strongly increased with the applied field, the off-rate displayed a turnover behavior. Statistical analysis suggests that at voltages >50 mV, a significant fraction of the alpha-syn molecules bound to the channel undergoes subsequent translocation. The observed on- rate varied by > 100 times depending on the bilayer lipid composition. Removal of the last 25 amino acids from the highly negatively charged C-terminal of alpha-syn resulted in a significant decrease in the binding rates. Taken together, these results demonstrate that beta-barrel channels may serve as sensitive probes of alpha-syn interactions with membranes as well as model systems for studies of channel-assisted protein transport. C1 [Gurnev, Philip A.; Parsegian, V. Adrian] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Gurnev, Philip A.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, Program Phys Biol, Bethesda, MD USA. [Yap, Thai Leong; Pfefferkorn, Candace M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Gurnev, PA (reprint author), Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. EM gurnev@physics.umass.edu RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; Center for Information Technology; National Institutes of Health; National Science Foundation EAGER [1249199] FX The work was supported by Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, and Center for Information Technology, National Institutes of Health, and by National Science Foundation EAGER award No. 1249199. NR 68 TC 9 Z9 9 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 4 PY 2014 VL 106 IS 3 BP 556 EP 565 DI 10.1016/j.bpj.2013.12.028 PG 10 WC Biophysics SC Biophysics GA 304CV UT WOS:000330724800008 PM 24507596 ER PT J AU Watts, M Sherman, A AF Watts, Margaret Sherman, Arthur TI Modeling the Pancreatic alpha-Cell: Dual Mechanisms of Glucose Suppression of Glucagon Secretion SO BIOPHYSICAL JOURNAL LA English DT Article ID SENSITIVE K+ CHANNEL; BETA-CELLS; HUMAN ISLETS; DELTA-CELLS; POSTPRANDIAL HYPERGLYCEMIA; ENDOPLASMIC-RETICULUM; ELECTRICAL-ACTIVITY; ENDOCRINE PANCREAS; IDENTIFIED ALPHA; INTACT ISLETS AB The mechanism by which glucose induces insulin secretion in beta-cells is fairly well understood. Despite years of research, however, the mechanism of glucagon secretion in alpha-cells is still not well established. It has been proposed that glucose regulates glucagon secretion by decreasing the conductance of either outward ATP-dependent potassium channels (K(ATP)) or an inward store-operated current (SOC). We have developed a mathematical model based on mouse data to test these hypotheses and found that both mechanisms are possible. Glucose metabolism closes K(ATP) channels, which depolarizes the cell but paradoxically reduces calcium influx by inactivating voltage-dependent calcium and sodium channels and decreases secretion. Glucose metabolism also activates SERCA pumps, which fills the endoplasmic reticulum and hyperpolarizes the cells by reducing the inward current through SOC channels and again suppresses glucagon secretion. We find further that the two mechanisms can combine to account for the nonmonotonic dependence of secretion on glucose observed in some studies, an effect that cannot be obtained with either mechanism alone. C1 [Watts, Margaret; Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Sherman, A (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM artiesherman@gmail.com FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. NR 58 TC 12 Z9 12 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 4 PY 2014 VL 106 IS 3 BP 741 EP 751 DI 10.1016/j.bpj.2013.11.4504 PG 11 WC Biophysics SC Biophysics GA 304CV UT WOS:000330724800027 PM 24507615 ER PT J AU Berezhkovskii, AM Shvartsman, SY AF Berezhkovskii, Alexander M. Shvartsman, Stanislav Y. TI On the GFP-Based Analysis of Dynamic Concentration Profiles SO BIOPHYSICAL JOURNAL LA English DT Article ID MORPHOGEN GRADIENT; FLUORESCENCE; SYSTEM AB Studies with GFP-tagged proteins can be used to investigate the dynamics of concentration profiles of regulatory proteins in cells and tissues. Analysis of these experiments must account for the finite rate with which the GFP-tagged proteins mature to the fluorescent state. Toward this end, we present an analytical framework that provides an explicit connection between the apparent kinetics of concentration gradients and the rates of GFP maturation. C1 [Berezhkovskii, Alexander M.] NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. [Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. RP Shvartsman, SY (reprint author), Princeton Univ, Dept Chem & Biol Engn, Princeton, NJ 08544 USA. EM stas@princeton.edu FU National Institute of General Medical Sciences [R01BM086537] FX This work was supported by grant R01BM086537 from the National Institute of General Medical Sciences. NR 15 TC 1 Z9 1 U1 5 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 4 PY 2014 VL 106 IS 3 BP L13 EP L15 DI 10.1016/j.bpj.2013.12.007 PG 3 WC Biophysics SC Biophysics GA 304CV UT WOS:000330724800001 PM 24507618 ER PT J AU Longo, VD Mattson, MP AF Longo, Valter D. Mattson, Mark P. TI Fasting: Molecular Mechanisms and Clinical Applications SO CELL METABOLISM LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; LIFE-SPAN EXTENSION; I IGF-I; DIETARY RESTRICTION; CALORIE RESTRICTION; INSULIN-RESISTANCE; BODY-COMPOSITION; ENERGY-INTAKE; CAENORHABDITIS-ELEGANS; SUPEROXIDE-DISMUTASE AB Fasting has been practiced for millennia, but, only recently, studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and bolster cellular protection. In lower eukaryotes, chronic fasting extends longevity, in part, by reprogramming metabolic and stress resistance pathways. In rodents intermittent or periodic fasting protects against diabetes, cancers, heart disease, and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma, and rheumatoid arthritis. Thus, fasting has the potential to delay aging and help prevent and treat diseases while minimizing the side effects caused by chronic dietary interventions. C1 [Longo, Valter D.] Univ So Calif, Longev Inst, Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Mattson, Mark P.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Longo, VD (reprint author), Univ So Calif, Longev Inst, Davis Sch Gerontol, Los Angeles, CA 90089 USA. EM vlongo@usc.edu; mark.mattson@nih.gov FU National Institute on Aging; Glenn Foundation for Medical Research; NIH/NIA [AG20642, AG025135, AG034906] FX We thank Min Wei for all the assistance with the preparation of the manuscript. We thank Yvon Le Maho for providing valuable information about fasting and a picture of penguins. We thank Matt Kaeberlein and Matthew Piper for panels for Figure 1. We thank William Mair for helpful discussions on fasting in Drosophila and thank Jay Mitchell for helpful comments on the manuscript. This work was supported, in part, by the Intramural Research Program of the National Institute on Aging; by the Glenn Foundation for Medical Research; and by the NIH/NIA grants AG20642, AG025135, and AG034906 to V.D.L. NR 103 TC 110 Z9 112 U1 25 U2 137 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD FEB 4 PY 2014 VL 19 IS 2 BP 181 EP 192 DI 10.1016/j.cmet.2013.12.008 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 304CE UT WOS:000330722600005 PM 24440038 ER PT J AU Lee, P Linderman, JD Smith, S Brychta, RJ Wang, J Idelson, C Perron, RM Werner, CD Phan, GQ Kammula, US Kebebew, E Pacak, K Chen, KY Celi, FS AF Lee, Paul Linderman, Joyce D. Smith, Sheila Brychta, Robert J. Wang, Juan Idelson, Christopher Perron, Rachel M. Werner, Charlotte D. Phan, Giao Q. Kammula, Udai S. Kebebew, Electron Pacak, Karel Chen, Kong Y. Celi, Francesco S. TI Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans SO CELL METABOLISM LA English DT Article ID GROWTH-FACTOR 21; ADIPOSE-TISSUE; ADULT HUMANS; INDUCED THERMOGENESIS; HEALTHY-ADULTS; EXERCISE; TEMPERATURE; ADIPOCYTES; EXPRESSION; EXPOSURE AB Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development. C1 [Lee, Paul; Linderman, Joyce D.; Smith, Sheila; Brychta, Robert J.; Wang, Juan; Idelson, Christopher; Perron, Rachel M.; Werner, Charlotte D.; Chen, Kong Y.; Celi, Francesco S.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Phan, Giao Q.; Kammula, Udai S.] NIH, Surg Branch, Bethesda, MD 20892 USA. [Kebebew, Electron] NIH, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Pacak, Karel] NCI, NIH, Bethesda, MD 20892 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM fsceli@vcu.edu OI Chen, Kong/0000-0002-0306-1904 FU Australian National Health Medical Research Council (NHMRC) Early Career Fellowship; Royal Australasian College of Physicians (RACP) Foundations Diabetes Australia Fellowship; School of Medicine, University of Queensland, Australia; NIDDK [Z01-DK047057-02, Z01-DK071044, Z01-DK071013, Z01-DK071014] FX P.L. was supported by an Australian National Health Medical Research Council (NHMRC) Early Career Fellowship; the Royal Australasian College of Physicians (RACP) Foundations Diabetes Australia Fellowship and Bushell Travelling Fellowship; and the School of Medicine, University of Queensland, Australia. This study was supported by the Intramural Research Program of NIDDK, programs Z01-DK047057-02, Z01-DK071044, Z01-DK071013, and Z01-DK071014. NR 32 TC 187 Z9 192 U1 15 U2 78 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD FEB 4 PY 2014 VL 19 IS 2 BP 302 EP 309 DI 10.1016/j.cmet.2013.12.017 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 304CE UT WOS:000330722600015 PM 24506871 ER PT J AU Iyer, LM Zhang, DP de Souza, RF Pukkila, PJ Rao, A Aravind, L AF Iyer, Lakshminarayan M. Zhang, Dapeng de Souza, Robson F. Pukkila, Patricia J. Rao, Anjana Aravind, L. TI Lineage-specific expansions of TET/JBP genes and a new class of DNA transposons shape fungal genomic and epigenetic landscapes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE methylcytosine; fungal evolution; DNA modification; genomic association ID COPRINUS-CINEREUS; COMPLEX MODIFICATIONS; STRUCTURE PREDICTION; PHYLOGENETIC TREES; EVOLUTION; METHYLATION; ELEMENTS; SYSTEMS; TRANSCRIPTION; ELIMINATION AB TET/JBP dioxygenases oxidize methylpyrimidines in nucleic acids and are implicated in generation of epigenetic marks and potential intermediates for DNA demethylation. We show that TET/JBP genes are lineage-specifically expanded in all major clades of basidiomycete fungi, with the majority of copies predicted to encode catalytically active proteins. This pattern differs starkly from the situation in most other organisms that possess just a single or a few copies of the TET/JBP family. In most basidiomycetes, TET/JBP genes are frequently linked to a unique class of transposons, KDZ (Kyakuja, Dileera, and Zisupton) and appear to have dispersed across chromosomes along with them. Several of these elements typically encode additional proteins, including a divergent version of the HMG domain. Analysis of their transposases shows that they contain a previously uncharacterized version of the RNase H fold with multiple distinctive Zn-chelating motifs and a unique insert, which are predicted to play roles in structural stabilization and target sequence recognition, respectively. We reconstruct the complex evolutionary history of TET/JBPs and associated transposons as involving multiple rounds of expansion with concomitant lineage sorting and loss, along with several capture events of TET/JBP genes by different transposon clades. On a few occasions, these TET/JBP genes were also laterally transferred to certain Ascomycota, Glomeromycota, Viridiplantae, and Amoebozoa. One such is an inactive version, calnexin-independence factor 1 (Cif1), from Schizosaccharomyces pombe, which has been implicated in inducing an epigenetically transmitted prion state. We argue that this unique transposon-TET/JBP association is likely to play important roles in speciation during evolution and epigenetic regulation. C1 [Iyer, Lakshminarayan M.; Zhang, Dapeng; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [de Souza, Robson F.] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, BR-05508900 Sao Paulo, Brazil. [Pukkila, Patricia J.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Rao, Anjana] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. [Rao, Anjana] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. RP Rao, A (reprint author), Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. EM arao@liai.org; aravind@ncbi.nlm.nih.gov FU Intramural Research Program of the US Department of Health and Human Services, National Institutes of Health, National Library of Medicine FX This work was funded by the Intramural Research Program of the US Department of Health and Human Services, National Institutes of Health, National Library of Medicine (L.M.I., D.Z., and L.A.). NR 42 TC 11 Z9 11 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 4 PY 2014 VL 111 IS 5 BP 1676 EP 1683 DI 10.1073/pnas.1321818111 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302FL UT WOS:000330587600024 PM 24398522 ER PT J AU Liu, Y Yang, YR Tang, TS Zhang, H Wang, ZF Friedberg, E Yang, W Guo, CX AF Liu, Yang Yang, Yeran Tang, Tie-Shan Zhang, Hui Wang, Zhifeng Friedberg, Errol Yang, Wei Guo, Caixia TI Variants of mouse DNA polymerase. reveal a mechanism of efficient and accurate translesion synthesis past a benzo[a] pyrene dG adduct SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE translesion DNA synthesis; polycyclic aromatic hydrocarbons ID ERROR-FREE BYPASS; Y-FAMILY; MAMMALIAN-CELLS; LESION-BYPASS; ACTIVE-SITE; STRUCTURAL BASIS; DIOL EPOXIDE; KAPPA; OPPOSITE; REPLICATION AB DNA polymerase kappa (Pol kappa) is the only known Y-family DNA polymerase that bypasses the 10S (+)-trans-anti-benzo[a] pyrene diol epoxide (BPDE)-N-2-deoxyguanine adducts efficiently and accurately. The unique features of Pol kappa, a large structure gap between the catalytic core and little finger domain and a 90-residue addition at the N terminus known as the N-clasp, may give rise to its special translesion capability. We designed and constructed two mouse Pol kappa variants, which have reduced gap size on both sides [Pol kappa Gap Mutant (PGM) 1] or one side flanking the template base (PGM2). These Pol kappa variants are nearly as efficient as WT in normal DNA synthesis, albeit with reduced accuracy. However, PGM1 is strongly blocked by the 10S (+)-trans-anti-BPDE-N-2-dG lesion. Steady-state kinetic measurements reveal a significant reduction in efficiency of dCTP incorporation opposite the lesion by PGM1 and a moderate reduction by PGM2. Consistently, Pol.-deficient cells stably complemented with PGM1 GFP-Pol kappa remained hypersensitive to BPDE treatment, and complementation with WT or PGM2 GFP-Pol kappa restored BPDE resistance. Furthermore, deletion of the first 51 residues of the N-clasp in mouse Pol kappa (mPol(kappa 52-516)) leads to reduced polymerization activity, and the mutant PGM2(52-516) but not PGM1(52-516) can partially compensate the N-terminal deletion and restore the catalytic activity on normal DNA. However, neither WT nor PGM2 mPol(kappa 52-516) retains BPDE bypass activity. We conclude that the structural gap physically accommodates the bulky aromatic adduct and the N-clasp is essential for the structural integrity and flexibility of Pol. during translesion synthesis. C1 [Liu, Yang; Yang, Yeran; Zhang, Hui; Wang, Zhifeng; Guo, Caixia] Chinese Acad Sci, Beijing Inst Genom, Lab Canc Genom & Individualized Med, Beijing 100101, Peoples R China. [Tang, Tie-Shan] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China. [Friedberg, Errol] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM weiy@mail.nih.gov; guocx@big.ac.cn RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU Chinese National 973 Project [2013CB945000, 2011CB944302, 2012CB944702]; Natural Science Foundation of China [30970588, 31170730, 81371415, 31300658, 31100557]; National Institutes of Health Intramural Program [DK036146-07]; Chinese Academy of Sciences "OneHundred-Talent Program"; State Key Laboratory of Biomembrane and Membrane Biotechnology FX The authors thank Dr. N. Geacintov for providing the BPDE modified oligodeoxynucleotide and advice on fidelity assay, Drs. S. Broyde and L. Lior-Hoffmann for the molecular simulated models of Pol.-BPDE-dG complex, Dr. H. Wang for BPDE reagents, Dr. T. Ogi for advice on establishment of stable cell lines, X. Zhang for assistance in cell culture, and Drs. Y. Zhang and P. Fischhaber for helpful discussion. This work was supported by Chinese National 973 Project Grants 2013CB945000, 2011CB944302, and 2012CB944702; Natural Science Foundation of China Grants 30970588, 31170730, 81371415, 31300658, and 31100557; National Institutes of Health Intramural Program DK036146-07; the Chinese Academy of Sciences "OneHundred-Talent Program"; and the State Key Laboratory of Biomembrane and Membrane Biotechnology. NR 49 TC 15 Z9 15 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 4 PY 2014 VL 111 IS 5 BP 1789 EP 1794 DI 10.1073/pnas.1324168111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302FL UT WOS:000330587600043 PM 24449898 ER PT J AU Keadle, SK Lyden, K Hickey, A Ray, EL Fowke, JH Freedson, PS Matthews, CE AF Keadle, Sarah Kozey Lyden, Kate Hickey, Amanda Ray, Evan L. Fowke, Jay H. Freedson, Patty S. Matthews, Charles E. TI Validation of a previous day recall for measuring the location and purpose of active and sedentary behaviors compared to direct observation SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Exposure measurement; Physical activity; Behavioral epidemiology ID ECOLOGICAL MOMENTARY ASSESSMENT; PHYSICAL-ACTIVITY; WEARABLE CAMERAS; BUILT ENVIRONMENT; UNITED-STATES; TIME SPENT; ADULTS; HEALTH; ACCELEROMETER; QUESTIONNAIRES AB Purpose: Gathering contextual information (i.e., location and purpose) about active and sedentary behaviors is an advantage of self-report tools such as previous day recalls (PDR). However, the validity of PDR's for measuring context has not been empirically tested. The purpose of this paper was to compare PDR estimates of location and purpose to direct observation (DO). Methods: Fifteen adult (18-75 y) and 15 adolescent (12-17 y) participants were directly observed during at least one segment of the day (i.e., morning, afternoon or evening). Participants completed their normal daily routine while trained observers recorded the location (i.e., home, community, work/school), purpose (e. g., leisure, transportation) and whether the behavior was sedentary or active. The day following the observation, participants completed an unannounced PDR. Estimates of time in each context were compared between PDR and DO. Intra-class correlations (ICC), percent agreement and Kappa statistics were calculated. Results: For adults, percent agreement was 85% or greater for each location and ICC values ranged from 0.71 to 0.96. The PDR-reported purpose of adults' behaviors were highly correlated with DO for household activities and work (ICCs of 0.84 and 0.88, respectively). Transportation was not significantly correlated with DO (ICC = -0.08). For adolescents, reported classification of activity location was 80.8% or greater. The ICCs for purpose of adolescents' behaviors ranged from 0.46 to 0.78. Participants were most accurate in classifying the location and purpose of the behaviors in which they spent the most time. Conclusions: This study suggests that adults and adolescents can accurately report where and why they spend time in behaviors using a PDR. This information on behavioral context is essential for translating the evidence for specific behavior-disease associations to health interventions and public policy. C1 [Keadle, Sarah Kozey; Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Keadle, Sarah Kozey] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Lyden, Kate] Univ Colorado Denver, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA. [Hickey, Amanda; Freedson, Patty S.] Univ Massachusetts, Dept Kinesiol, Amherst, MA 01003 USA. [Ray, Evan L.] Univ Massachusetts, Dept Math & Stat, Amherst, MA 01003 USA. [Fowke, Jay H.] Vanderbilt Univ, Ctr Med, Dept Med, Div Epidemiol, Nashville, TN 37232 USA. RP Keadle, SK (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM sarah.keadle@nih.gov RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Keadle, Sarah/0000-0002-9569-9306 FU [R01 NR011477] FX Funded by: R01 NR011477. NR 41 TC 5 Z9 5 U1 4 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD FEB 3 PY 2014 VL 11 AR 12 DI 10.1186/1479-5868-11-12 PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA AD0NR UT WOS:000332931600001 ER PT J AU Appaiahgari, MB Glass, R Singh, S Taneja, S Rongsen-Chandola, T Bhandari, N Mishra, S Vrati, S AF Appaiahgari, Mohan Babu Glass, Roger Singh, Shakti Taneja, Sunita Rongsen-Chandola, Temsunaro Bhandari, Nita Mishra, Sukhdev Vrati, Sudhanshu TI Transplacental rotavirus IgG interferes with immune response to live oral rotavirus vaccine ORV-116E in Indian infants SO VACCINE LA English DT Article DE Maternal antibody; Dose; Seroconversion; IgA; Rotavirus; Vaccine ID ATTENUATED HUMAN ROTAVIRUS; B-CELL RESPONSES; MATERNAL ANTIBODIES; CONTROLLED-TRIAL; SAFETY; IMMUNOGENICITY; INFECTION; EFFICACY; TITER; IMMUNIZATION AB The lower immune response and efficacy of live oral rotavirus (RV) vaccines tested in developing countries maybe due in part to high levels of pre-existing RV antibodies transferred to the infant from mother via the placenta. The candidate RV vaccine strain 116E was isolated from a newborn indicating that it might grow well even in the presence of this transplacental rotavirus antibody. Since the immune response to this vaccine among infants in the Indian subcontinent has been greater than that of the commercially licensed vaccines, we questioned whether this might be due to the ability of RV 116E to grow well in infants despite the presence of maternal RV antibody. To this end, we tested pre-immunization sera from Indian infants enrolled in a phase Ia/IIb trial of candidate RV vaccine ORV-116E for transplacental RV IgG to see whether it affected the immune responses and seroconversion to the vaccine. We found that the high titers of transplacental RV IgG diminished the immune responses of infants to ORV-116E vaccine. However, the vaccine was able to overcome the inhibitory effect of this RV IgG in a dose-dependent manner. This report clearly demonstrates the interference of maternal antibody on RV vaccine immunogenicity in infants in a field study as well as the ability of ORV-116E to overcome this interference when used at a higher dose. (C) 2013 Published by Elsevier Ltd. C1 [Appaiahgari, Mohan Babu; Vrati, Sudhanshu] Translat Hlth Sci & Technol Inst, Vaccine & Infect Dis Res Ctr, Gurgaon 122016, India. [Glass, Roger] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Singh, Shakti; Taneja, Sunita; Rongsen-Chandola, Temsunaro; Bhandari, Nita] Soc Appl Studies, New Delhi 110016, India. [Mishra, Sukhdev] Translat Hlth Sci & Technol Inst, Clin Dev Serv Agcy, Gurgaon 122016, India. [Vrati, Sudhanshu] Natl Inst Immunol, New Delhi 110067, India. RP Vrati, S (reprint author), Translat Hlth Sci & Technol Inst, Vaccine & Infect Dis Res Ctr, 496 Udyog Vihar Phase III, Gurgaon 122016, India. EM vrati@thsti.res.in RI singh, shakti/D-4070-2014 OI singh, shakti/0000-0001-6521-0998 FU Department of Biotechnology, Govt. of India FX We thank Duncan Steele and John Clemens for critical reading of the manuscript and valuable comments. This work was supported by the core grant provided by the Department of Biotechnology, Govt. of India to the National Institute of Immunology and the Translational Health Science and Technology Institute. NR 40 TC 19 Z9 19 U1 1 U2 6 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 FEB 3 PY 2014 VL 32 IS 6 BP 651 EP 656 DI 10.1016/j.vaccine.2013.12.017 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AB0SH UT WOS:000331501900003 PM 24374502 ER PT J AU Johnson, MJ Bjorkstrom, NK Petrovas, C Liang, F Gall, JGD Lore, K Koup, RA AF Johnson, Matthew J. Bjorkstrom, Niklas K. Petrovas, Constantinos Liang, Frank Gall, Jason G. D. Lore, Karin Koup, Richard A. TI Type I interferon-dependent activation of NK cells by rAd28 or rAd35, but not rAd5, leads to loss of vector-insert expression SO VACCINE LA English DT Article DE Adenovirus; rAd28; rAd35 ID PLASMACYTOID DENDRITIC CELLS; APOPTOTIC CELLS; IMMUNE-RESPONSES; VACCINE VECTOR; T-CELLS; GENE; IMMUNOGENICITY; SEROPREVALENCE; CYTOKINE; REGIONS AB Vaccines constructed from rare-serotype recombinant adenovirus vectors (rAd) such as rAd serotype 28 (rAd28) and rAd35 are currently being explored as alternatives to rAd5-based vaccines because they circumvent the problems with pre-existing immunity that complicate the effectiveness of rAd5 vaccines. However, previous work has demonstrated that the immunogenicity of rAd28 and rAd35 is substantially lower than rAd5. Here we show that rAd28 and rAd35 increase apoptosis of antigen presenting cells (APCs), such as monocytes, relative to rAd5 and mock infected controls. APCs undergoing apoptosis showed an increased loss of vector-insert expression. Loss of vector-insert expression correlated with activation of NK cells, which resulted in apoptosis of co-cultured monocytes. Finally, we show that activation of NK cells is dependent on IFN alpha which is produced by exposure to rAd28 or rAd35, but not to rAd5. Taken together, these data demonstrate that IFN alpha-induced activation of NK cells leads to increased monocyte apoptosis and subsequent vector-insert loss. This may be a possible mechanism that results in reduced immunogenicity of rAd28 and rAd35-based vectors. Published by Elsevier Ltd. C1 [Johnson, Matthew J.; Petrovas, Constantinos; Liang, Frank; Lore, Karin; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Johnson, Matthew J.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. [Bjorkstrom, Niklas K.; Liang, Frank; Lore, Karin] Karolinska Inst, Ctr Infect Med, Dept Pathol, S-14186 Stockholm, Sweden. [Bjorkstrom, Niklas K.; Liang, Frank; Lore, Karin] Karolinska Inst, Dept Med, S-14186 Stockholm, Sweden. [Gall, Jason G. D.] GenVec Inc, Gaithersburg, MD 20878 USA. RP Koup, RA (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov OI Bjorkstrom, Niklas/0000-0002-0967-076X FU Intramural NIH HHS [ZIA AI005073-10] NR 26 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD FEB 3 PY 2014 VL 32 IS 6 BP 717 EP 724 DI 10.1016/j.vaccine.2013.11.055 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AB0SH UT WOS:000331501900013 PM 24325826 ER PT J AU Murphy, AP Leopold, DA Welchman, AE AF Murphy, Aidan P. Leopold, David A. Welchman, Andrew E. TI Perceptual memory drives learning of retinotopic biases for bistable stimuli SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE bistable; ambiguous figures; perceptual stabilization; cue recruitment; associative learning ID AMBIGUOUS PATTERNS; VISUAL-ADAPTATION; SENSORY MEMORY; EXPERIENCE; MOTION; COMPETITION AB The visual system exploits past experience at multiple timescales to resolve perceptual ambiguity in the retinal image. For example, perception of a bistable stimulus can be biased toward one interpretation over another when preceded by a brief presentation of a disambiguated version of the stimulus (positive priming) or through intermittent presentations of the ambiguous stimulus (stabilization). Similarly, prior presentations of unambiguous stimuli can be used to explicitly "train" a long-lasting association between a percept and a retinal location (perceptual association). These phenonema have typically been regarded as independent processes, with short-term biases attributed to perceptual memory and longer-term biases described as associative learning. Here we tested for interactions between these two forms of experience-dependent perceptual bias and demonstrate that short-term processes strongly influence long-term outcomes. We first demonstrate that the establishment of long-term perceptual contingencies does not require explicit training by unambiguous stimuli, but can arise spontaneously during the periodic presentation of brief, ambiguous stimuli. Using rotating Necker cube stimuli, we observed enduring, retinotopically specific perceptual biases that were expressed from the outset and remained stable for up to 40 min, consistent with the known phenomenon of perceptual stabilization. Further, bias was undiminished after a break period of 5 min, but was readily reset by interposed periods of continuous, as opposed to periodic, ambiguous presentation. Taken together, the results demonstrate that perceptual biases can arise naturally and may principally reflect the brain's tendency to favor recent perceptual interpretation at a given retinal location. Further, they suggest that an association between retinal location and perceptual state, rather than a physical stimulus, is sufficient to generate long-term biases in perceptual organization. C1 [Murphy, Aidan P.; Welchman, Andrew E.] Univ Birmingham, Sch Psychol, Binocular Vis Lab, Birmingham B15 2TT, W Midlands, England. [Murphy, Aidan P.; Leopold, David A.] NIMH, Neuropsychol Lab, Sect Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. [Welchman, Andrew E.] Univ Cambridge, Dept Psychol, Cambridge, England. RP Murphy, AP (reprint author), NIMH, Neuropsychol Lab, Sect Cognit Neurophysiol & Imaging, Room B1-C60,Bldg 49,49 Convent Dr, Bethesda, MD 20892 USA. EM murphyap@mail.nih.gov RI Welchman, Andrew/B-7542-2013; OI Welchman, Andrew/0000-0002-7559-3299; Leopold, David/0000-0002-1345-6360 FU Wellcome Trust [095183] NR 42 TC 1 Z9 1 U1 1 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD FEB 3 PY 2014 VL 5 AR 60 DI 10.3389/fpsyg.2014.00060 PG 11 WC Psychology, Multidisciplinary SC Psychology GA AA7MC UT WOS:000331280500001 PM 24550874 ER PT J AU Meyer, V Dinkel, PD Luo, Y Yu, X Wei, GH Zheng, J Eaton, GR Ma, BY Nussinov, R Eaton, SS Margittai, M AF Meyer, Virginia Dinkel, Paul D. Luo, Yin Yu, Xiang Wei, Guanghong Zheng, Jie Eaton, Gareth R. Ma, Buyong Nussinov, Ruth Eaton, Sandra S. Margittai, Martin TI Single Mutations in Tau Modulate the Populations of Fibril Conformers through Seed Selection SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE Alzheimer's disease; conformation analysis; EPR spectroscopy; proteins; tau fibrils ID PAIRED HELICAL FILAMENTS; NEURODEGENERATIVE-DISEASES; FRONTOTEMPORAL DEMENTIA; AMYLOID FIBRILS; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; BETA-STRUCTURE; 4-REPEAT TAU; PROTEIN; PROPAGATION AB Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer's disease and other neurodegenerative disorders. Self-assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron-electron resonance spectroscopy was used to investigate the conformational ensemble of four-repeat tau fibrils. Single point mutations at key positions in the protein (K280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template-assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation. C1 [Meyer, Virginia; Dinkel, Paul D.; Eaton, Gareth R.; Eaton, Sandra S.; Margittai, Martin] Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA. [Luo, Yin; Wei, Guanghong] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. [Luo, Yin; Wei, Guanghong] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Yu, Xiang; Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Ma, Buyong; Nussinov, Ruth] NCI, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick Natl Lab, Frederick, MD 21702 USA. RP Margittai, M (reprint author), Univ Denver, Dept Chem & Biochem, Denver, CO 80208 USA. EM martin.margittai@du.edu RI Margittai, Martin/D-5039-2014; Ma, Buyong/F-9491-2011; Zheng, Jie/B-5057-2013; OI Margittai, Martin/0000-0003-1903-5927; Ma, Buyong/0000-0002-7383-719X; Zheng, Jie/0000-0003-1547-3612; Eaton, Gareth R/0000-0001-7429-8469; Eaton, Sandra S/0000-0002-2731-7986 FU National Institute of Neurological Disorders and Stroke [R01NS076619]; National Cancer Institute [HHSN261200800001E]; National Cancer Institute Center for Cancer Research, National Science Foundation (CAREER) [CBET-0952624, CBET-1158447]; National Natural Science Foundation of China [11074047, 11274075, 91227102] FX This project was supported by the National Institute of Neurological Disorders and Stroke Grant R01NS076619 (to M. M.). This work was also supported by the National Cancer Institute Contract (HHSN261200800001E), the intramural research program of the National Cancer Institute Center for Cancer Research, National Science Foundation (CAREER Award CBET-0952624 and CBET-1158447; to J.Z.), and the National Natural Science Foundation of China Grant (11074047, 11274075, and 91227102; to G. W.). We thank Dr. Eric Hustedt for his assistance using GLADD, and helpful discussions regarding analysis of DEER data. NR 43 TC 17 Z9 17 U1 0 U2 28 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD FEB 3 PY 2014 VL 53 IS 6 BP 1590 EP 1593 DI 10.1002/anie.201308473 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 301UU UT WOS:000330558400022 PM 24453187 ER PT J AU Luo, Q Cheng, X Holroyd, T Xu, D Carver, F Blair, RJ AF Luo, Qian Cheng, Xi Holroyd, Tom Xu, Duo Carver, Frederick Blair, R. James TI Theta band activity in response to emotional expressions and its relationship with gamma band activity as revealed by MEG and advanced beamformer source imaging SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE MEG; theta; gamma; emotion; event-related synchronization ID PRIMARY VISUAL-CORTEX; WORKING-MEMORY TASK; NEURONAL OSCILLATIONS; NEURAL MECHANISMS; CORTICAL NETWORKS; BEHAVING RAT; SYNCHRONIZATION; AMYGDALA; FREQUENCY; ALPHA AB Neuronal oscillations in the theta and gamma bands have been shown to be important for cognition. Here we examined the temporal and spatial relationship between the two frequency bands in emotional processing using magnetoencephalography and an advanced dynamic beamformer source imaging method called synthetic aperture magnetometry. We found that areas including the amygdala, visual and frontal cortex showed significant event-related synchronization in both bands, suggesting a functional association of neuronal oscillations in the same areas in the two bands. However, while the temporal profile in both bands was similar in the amygdala, the peak in gamma band power was much earlier within both visual and frontal areas. Our results do not support a traditional view that the localizations of lower and higher frequencies are spatially distinct. Instead, they suggest that in emotional processing, neuronal oscillations in the gamma and theta bands may reflect, at least in visual and frontal cortex either different but related functional processes or, perhaps more probably, different computational components of the same functional process. C1 [Luo, Qian; Xu, Duo] St Louis Univ, Sch Med, Dept Neurosurg, St Louis, MO 63104 USA. [Luo, Qian; Blair, R. James] NIMH, Unit Affect Cognit Neurosci, Bethesda, MD 20892 USA. [Cheng, Xi] Lieber Inst Brain Dev, Baltimore, MD USA. [Holroyd, Tom; Carver, Frederick] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. RP Luo, Q (reprint author), St Louis Univ, Sch Med, Dept Neurosurg, 1320 South Grand Blvd,1st Floor ODonnell Hall, St Louis, MO 63104 USA. EM RBBT_L@yahoo.com FU NIMH Intramural Research Program FX This study is supported by NIMH Intramural Research Program. NR 52 TC 2 Z9 2 U1 2 U2 8 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 3 PY 2014 VL 7 AR 940 DI 10.3389/fnhum.2013.00940 PG 8 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 302XM UT WOS:000330638400001 ER PT J AU Romero, R Hassan, SS Gajer, P Tarca, AL Fadrosh, DW Nikita, L Galuppi, M Lamont, RF Chaemsaithong, P Miranda, J Chaiworapongsa, T Ravel, J AF Romero, Roberto Hassan, Sonia S. Gajer, Pawel Tarca, Adi L. Fadrosh, Douglas W. Nikita, Lorraine Galuppi, Marisa Lamont, Ronald F. Chaemsaithong, Piya Miranda, Jezid Chaiworapongsa, Tinnakorn Ravel, Jacques TI The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women SO MICROBIOME LA English DT Article DE Community stability; Longitudinal sampling; Pregnancy; Vaginal microbiome; Lactobacillus; Dynamics ID 16S RIBOSOMAL-RNA; FEMALE GENITAL-TRACT; IMMUNODEFICIENCY-VIRUS TYPE-1; GRADIENT GEL-ELECTROPHORESIS; LOW-BIRTH-WEIGHT; ASYMPTOMATIC BACTERIAL VAGINOSIS; CHLAMYDIA-TRACHOMATIS INFECTION; CULTIVATION-INDEPENDENT METHODS; SEXUALLY-TRANSMITTED-DISEASES; HORMONE REPLACEMENT THERAPY AB Background: This study was undertaken to characterize the vaginal microbiota throughout normal human pregnancy using sequence-based techniques. We compared the vaginal microbial composition of non-pregnant patients with a group of pregnant women who delivered at term. Results: A retrospective case-control longitudinal study was designed and included non-pregnant women (n = 32) and pregnant women who delivered at term (38 to 42 weeks) without complications (n = 22). Serial samples of vaginal fluid were collected from both non-pregnant and pregnant patients. A 16S rRNA gene sequence-based survey was conducted using pyrosequencing to characterize the structure and stability of the vaginal microbiota. Linear mixed effects models and generalized estimating equations were used to identify the phylotypes whose relative abundance was different between the two study groups. The vaginal microbiota of normal pregnant women was different from that of non-pregnant women (higher abundance of Lactobacillus vaginalis, L. crispatus, L. gasseri and L. jensenii and lower abundance of 22 other phylotypes in pregnant women). Bacterial community state type (CST) IV-B or CST IV-A characterized by high relative abundance of species of genus Atopobium as well as the presence of Prevotella, Sneathia, Gardnerella, Ruminococcaceae, Parvimonas, Mobiluncus and other taxa previously shown to be associated with bacterial vaginosis were less frequent in normal pregnancy. The stability of the vaginal microbiota of pregnant women was higher than that of non-pregnant women; however, during normal pregnancy, bacterial communities shift almost exclusively from one CST dominated by Lactobacillus spp. to another CST dominated by Lactobacillus spp. Conclusion: We report the first longitudinal study of the vaginal microbiota in normal pregnancy. Differences in the composition and stability of the microbial community between pregnant and non-pregnant women were observed. Lactobacillus spp. were the predominant members of the microbial community in normal pregnancy. These results can serve as the basis to study the relationship between the vaginal microbiome and adverse pregnancy outcomes. C1 [Romero, Roberto; Hassan, Sonia S.; Tarca, Adi L.; Nikita, Lorraine; Galuppi, Marisa; Lamont, Ronald F.; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Program Perinatal Res & Obstet,Perinatol Res Bran, Bethesda, MD 20892 USA. [Romero, Roberto; Hassan, Sonia S.; Tarca, Adi L.; Nikita, Lorraine; Galuppi, Marisa; Lamont, Ronald F.; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Program Perinatal Res & Obstet,Perinatol Res Bran, Bethesda, MD 20892 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI USA. [Hassan, Sonia S.; Galuppi, Marisa; Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. [Gajer, Pawel; Fadrosh, Douglas W.; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Gajer, Pawel; Ravel, Jacques] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Lamont, Ronald F.] Univ Southern Denmark, Dept Obstet & Gynaecol, Odense, Denmark. [Lamont, Ronald F.] UCL, Northwick Pk Inst Med Res Campus, Div Surg, London, England. RP Romero, R (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Program Perinatal Res & Obstet,Perinatol Res Bran, Bldg 10, Bethesda, MD 20892 USA. EM romeror@mail.nih.gov; jravel@som.umaryland.edu OI Ravel, Jacques/0000-0002-0851-2233 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This work was funded, in part, by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. The authors wish to acknowledge the contributions of the patients who volunteered for these studies, the medical and healthcare personnel involved in the research effort, and colleagues who contributed to the discussions which eventually led to the conduct of the study. We are particularly grateful to Dr Sharon Hillier of the University of Pittsburgh, Dr Jack Sobel of Wayne State University, Dr David Relman of Stanford University and Dr Sorin Draghici of Wayne State University. NR 271 TC 80 Z9 85 U1 11 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD FEB 3 PY 2014 VL 2 AR 4 DI 10.1186/2049-2618-2-4 PG 19 WC Microbiology SC Microbiology GA CU0EN UT WOS:000363188900001 PM 24484853 ER PT J AU Patterson, MC Brown, TM Zaccariello, MJ Thurm, A Porter, FD AF Patterson, Marc C. Brown, Tanya M. Zaccariello, Michael J. Thurm, Audrey Porter, Forbes D. TI Longitudinal study of cognition in Niemann-Pick disease type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 10th Annual Research Meeting and World Symposium of the Lysosomal-Disease-Network (LDN) CY FEB 10-13, 2014 CL San Diego, CA SP Lysosomal Dis Network C1 [Patterson, Marc C.; Brown, Tanya M.; Zaccariello, Michael J.] Mayo Clin, Rochester, MN USA. [Thurm, Audrey; Porter, Forbes D.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2014 VL 111 IS 2 MA 192 BP S85 EP S85 DI 10.1016/j.ymgme.2013.12.204 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 304KO UT WOS:000330746000193 ER PT J AU Brown, ML Klabunde, CN Cronin, KA White, MC Richardson, LC McNeel, TS AF Brown, Martin L. Klabunde, Carrie N. Cronin, Kathy A. White, Mary C. Richardson, Lisa C. McNeel, Timothy S. TI Challenges in Meeting Healthy People 2020 Objectives for Cancer-Related Preventive Services, National Health Interview Survey, 2008 and 2010 SO PREVENTING CHRONIC DISEASE LA English DT Article ID UNITED-STATES; PUBLIC-HEALTH; METAANALYSIS; PHYSICIANS; ACCURACY; TRENDS AB Introduction Healthy People (HP) is the US program that formulates and tracks national health objectives for the nation. The National Health Interview Survey (NHIS) is a designated data source for setting and evaluating several HP targets in cancer. We used data from the 2008 and 2010 NHIS to provide a benchmark for national performance toward meeting HP 2020 cancer-related objectives. Methods HP 2020 cancer screening, provider counseling, and health care access objectives were selected. For each objective, NHIS measures for the overall population and several sociodemographic subgroups were calculated; the findings were compared with established HP 2020 targets. Results From 2008 to 2010, rates of breast and cervical cancer screening declined slightly while colorectal cancer screening rates increased by 7 percentage points. Rates of cancer screening and provider counseling were below HP targets. Meeting HP targets seems less likely for subgroups characterized by low income, no health insurance, or no usual source of care. Meeting HP targets for access to health services will require an increase of 18 percentage points in the proportion of persons under age 65 with health insurance coverage and an increase of 10 percentage points in the proportion aged 18 to 64 with a usual source of care. Conclusion Whether HP objectives for cancer screening and health care access are met may depend on implementation of health care reform measures that improve access to and coordination of care. Better integration of clinical health care and community-based efforts for delivering high-quality screening and treatment services and elimination of health disparities are also needed. C1 [Brown, Martin L.; Cronin, Kathy A.] NCI, Bethesda, MD 20892 USA. [White, Mary C.; Richardson, Lisa C.] Ctr Dis Control & Prevent, Atlanta, GA 30322 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Beltsville, MD 20705 USA. RP Klabunde, CN (reprint author), 9606 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM KlabundC@mail.nih.gov RI White, Mary /C-9242-2012 OI White, Mary /0000-0002-9826-3962 NR 28 TC 8 Z9 8 U1 0 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD FEB PY 2014 VL 11 AR 130174 DI 10.5888/pcd11.130174 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR3XE UT WOS:000343521700003 PM 24576396 ER PT J AU Hurtado, M Spinner, JR Yang, MS Evensen, C Windham, A Ortiz, G Tracy, R Ivy, ED AF Hurtado, Margarita Spinner, Jovonni R. Yang, Manshu Evensen, Christian Windham, Amy Ortiz, Gloria Tracy, Rachael Ivy, Edward Donnell TI Knowledge and Behavioral Effects in Cardiovascular Health: Community Health Worker Health Disparities Initiative, 2007-2010 SO PREVENTING CHRONIC DISEASE LA English DT Article ID HEART-DISEASE; STROKE AB Introduction Cardiovascular disease is the leading cause of death in the United States, and disparities in cardiovascular health exist among African Americans, American Indians, Hispanics, and Filipinos. The Community Health Worker Health Disparities Initiative of the National Heart, Lung, and Blood Institute (NHLBI) includes culturally tailored curricula taught by community health workers (CHWs) to improve knowledge and heart-healthy behaviors in these racial/ethnic groups. Methods We used data from 1,004 community participants in a 10-session curriculum taught by CHWs at 15 sites to evaluate the NHLBI's health disparities initiative by using a 1-group pretest posttest design. The curriculum addressed identification and management of cardiovascular disease risk factors. We used linear mixed effects and generalized linear mixed effects models to examine results. Results Average participant age was 48; 75% were female, 50% were Hispanic, 35% were African American, 8% were Filipino, and 7% were American Indian. Twenty-three percent reported a history of diabetes, and 37% reported a family history of heart disease. Correct pretest to posttest knowledge scores increased from 48% to 74% for heart healthy knowledge. The percentage of participants at the action or maintenance stage of behavior change increased from 41% to 85%. Conclusion Using the CHW model to implement community education with culturally tailored curricula may improve heart health knowledge and behaviors among minorities. Further studies should examine the influence of such programs on clinical risk factors for cardiovascular disease. C1 [Spinner, Jovonni R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Hurtado, Margarita; Yang, Manshu; Evensen, Christian; Windham, Amy] Amer Inst Res, Washington, DC USA. [Ortiz, Gloria; Tracy, Rachael; Ivy, Edward Donnell] NIH, Bethesda, MD 20892 USA. RP Spinner, JR (reprint author), NHLBI, NIH, 31 Ctr Dr,MSC 2480,Room 4A29D, Bethesda, MD 20892 USA. EM Jovonni.spinner@nih.gov FU National Institutes of Health, NHLBI [GS-10E-0112J] FX This research was supported by the National Institutes of Health, NHLBI contract GS-10E-0112J (Division for the Application of Research Discoveries [DARD] [Program Evaluation]). We thank Dr Denise Simons-Morton, Ms Karen Donato, and Dr Robinson Fulwood of NHLBI DARD for their support of the research and review of the manuscript. We also gratefully acknowledge the participation of the community sites, the CHWs, and the program participants, without whom this research could not have been carried out. NR 21 TC 2 Z9 2 U1 1 U2 9 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD FEB PY 2014 VL 11 AR 130250 DI 10.5888/pcd11.130250WJ PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR3XE UT WOS:000343521700006 PM 24524426 ER PT J AU Sanchez, M Purcell, EP Michie, JS Tsakraklides, SP La Porta, M Vinson, C AF Sanchez, Michael Purcell, E. Peyton Michie, Joan S. Tsakraklides, Sophia P. La Porta, Madeline Vinson, Cynthia TI Building Cancer Control Capacity: a Mixed-Method Evaluation of the Research to Reality (R2R) Mentorship Program SO PREVENTING CHRONIC DISEASE LA English DT Article ID INTERVENTIONS; HEALTH AB In 2011, the National Cancer Institute launched the Research to Reality (R2R) Pilot Mentorship Program to enhance mentees' core evidence-based public health (EBPH) competencies. In this article, we describe the program and its evaluation results and the program's ability to improve participants' EBPH competencies and appropriateness of program components. Program evaluation consisted of a pre/post program competency questionnaire and interviews with mentees, mentors, mentees' supervisors, and program staff. Mentees reported the same or higher rating in every competency at end of the program, with average increase of 0.6 points on a 4-point scale; the greatest improvements were seen in policy development/program planning Mentorship programs are a promising strategy to develop EBPH competencies, provide guidance, and disseminate and adapt evidence-based interventions within real-world context. C1 [Sanchez, Michael; La Porta, Madeline; Vinson, Cynthia] NCI, Rockville, MD 20850 USA. [Purcell, E. Peyton] SAIC Frederick Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. [Michie, Joan S.; Tsakraklides, Sophia P.] WESTAT Corp, Rockville, MD 20850 USA. RP Sanchez, M (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM sanchezgarciama@mail.nih.gov FU NCI, National Institutes of Health [HHSN261200800001E] FX This project was funded in whole or in part with federal funds from the NCI, 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 US government. NR 11 TC 0 Z9 0 U1 0 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD FEB PY 2014 VL 11 AR 130275 DI 10.5888/pcd11.130275 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR3XE UT WOS:000343521700008 ER PT J AU Clarke, LP Nordstrom, RJ Zhang, HM Tandon, P Zhang, YT Redmond, G Farahani, K Kelloff, G Henderson, L Shankar, L Deye, J Capala, J Jacobs, P AF Clarke, Laurence P. Nordstrom, Robert J. Zhang, Huiming Tandon, Pushpa Zhang, Yantian Redmond, George Farahani, Keyvan Kelloff, Gary Henderson, Lori Shankar, Lalitha Deye, James Capala, Jacek Jacobs, Paula TI The Quantitative Imaging Network: NCI's Historical Perspective and Planned Goals SO TRANSLATIONAL ONCOLOGY LA English DT Article AB The purpose of this editorial is to provide a brief history of National Institutes of Health National Cancer Institute (NCI) workshops as related to quantitative imaging within the oncology setting. The editorial will then focus on the recently supported NCI initiatives, including the Quantitative Imaging Network (QIN) initiative and its organizational structure, including planned research goals and deliverables. The publications in this issue of Translational Oncology come from many of the current members of this QIN research network. C1 [Clarke, Laurence P.; Nordstrom, Robert J.; Zhang, Huiming; Tandon, Pushpa; Zhang, Yantian; Redmond, George; Farahani, Keyvan; Kelloff, Gary; Henderson, Lori; Shankar, Lalitha; Deye, James; Capala, Jacek; Jacobs, Paula] NCI, Bethesda, MD 20892 USA. RP Clarke, LP (reprint author), Suite 6066,EPN 6130 Executive Blvd, Bethesda, MD 20892 USA. EM lclarke@mail.nih.gov NR 6 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 1 EP 4 DI 10.1593/tlo.13832 PG 4 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300001 PM 24772201 ER PT J AU Kalpathy-Cramer, J Freymann, JB Kirby, JS Kinahan, PE Prior, FW AF Kalpathy-Cramer, Jayashree Freymann, John Blake Kirby, Justin Stephen Kinahan, Paul Eugene Prior, Fred William TI Quantitative Imaging Network: Data Sharing and Competitive Algorithm Validation Leveraging The Cancer Imaging Archive SO TRANSLATIONAL ONCOLOGY LA English DT Article ID RESOURCE; THERAPY; SYSTEMS AB The Quantitative Imaging Network (QIN), supported by the National Cancer Institute, is designed to promote research and development of quantitative imaging methods and candidate biomarkers for the measurement of tumor response in clinical trial settings. An integral aspect of the QIN mission is to facilitate collaborative activities that seek to develop best practices for the analysis of cancer imaging data. The QIN working groups and teams are developing new algorithms for image analysis and novel biomarkers for the assessment of response to therapy. To validate these algorithms and biomarkers and translate them into clinical practice, algorithms need to be compared and evaluated on large and diverse data sets. Analysis competitions, or "challenges," are being conducted within the QIN as a means to accomplish this goal. The QIN has demonstrated, through its leveraging of The Cancer Imaging Archive (TCIA), that data sharing of clinical images across multiple sites is feasible and that it can enable and support these challenges. In addition to Digital Imaging and Communications in Medicine (DICOM) imaging data, many TCIA collections provide linked clinical, pathology, and "ground truth" data generated by readers that could be used for further challenges. The TCIA-QIN partnership is a successful model that provides resources for multisite sharing of clinical imaging data and the implementation of challenges to support algorithm and biomarker validation. C1 [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 01940 USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, Boston, MA USA. [Freymann, John Blake; Kirby, Justin Stephen] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, CMRP, Clin Res Directorate, Frederick, MD USA. [Kinahan, Paul Eugene] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Prior, Fred William] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Kalpathy-Cramer, J (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 01940 USA. EM kalpathy@nmr.mgh.harvard.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH grants [U01CA154602, R00LM009889, ST13-4130]; NIH grant [U01CA148131, 24XS036-004] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), 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 US Government. J.K.-C. is funded in part by the NIH grants U01CA154602 and R00LM009889 and a contract ST13-4130. P.E.K. is funded in part by the NIH grant U01CA148131 and Contract 24XS036-004. NR 33 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 147 EP 152 DI 10.1593/tlo.13862 PG 6 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300018 PM 24772218 ER PT J AU Bolnick, AD Bolnick, JM Kilburn, BA Armant, DR AF Bolnick, Alan D. Bolnick, Jay M. Kilburn, Brian A. Armant, D. Randall TI Low Molecular Weight Heparin Promotes Extravillous Differentiation and Prevents Apoptosis of First Trimester Human Trophoblast Cells Through HBEGF-mediated Signaling SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) CY MAR 19-23, 2014 CL Indian Wells, CA SP Pacific Coast Reprod Soc C1 [Bolnick, Alan D.; Bolnick, Jay M.; Kilburn, Brian A.; Armant, D. Randall] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 SU S MA P-3 BP E8 EP E8 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AP8SX UT WOS:000342350300012 ER PT J AU Bolnick, JM Bolnick, AD Kilburn, BA Armant, DR AF Bolnick, Jay M. Bolnick, Alan D. Kilburn, Brian A. Armant, D. Randall TI Sildenafil Rescues First Trimester Trophoblasts from Acute Alcohol Exposure Through Downstream Protein kinase G Signaling SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) CY MAR 19-23, 2014 CL Indian Wells, CA SP Pacific Coast Reprod Soc C1 [Bolnick, Jay M.; Bolnick, Alan D.; Kilburn, Brian A.; Armant, D. Randall] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI USA. [Armant, D. Randall] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Anat & Cell Biol, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 SU S MA P-29 BP E19 EP E20 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AP8SX UT WOS:000342350300038 ER PT J AU Gulley, JL Madan, RA Tsang, KY Jochems, C Marte, JL Farsaci, B Tucker, JA Hodge, JW Liewehr, DJ Steinberg, SM Heery, CR Schlom, J AF Gulley, James L. Madan, Ravi A. Tsang, Kwong Y. Jochems, Caroline Marte, Jennifer L. Farsaci, Benedetto Tucker, Jo A. Hodge, James W. Liewehr, David J. Steinberg, Seth M. Heery, Christopher R. Schlom, Jeffrey TI Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID PHASE-I TRIAL; T-CELLS; ANTITUMOR RESPONSES; PERIPHERAL-BLOOD; ANTIGEN CASCADE; VIRAL VACCINE; TUMOR; SURVIVAL; COMBINATION; LYMPHOCYTES AB PSA-TRICOM (PROSTVAC) is a novel vector-based vaccine designed to generate a robust immune response against prostate-specific antigen (PSA)-expressing tumor cells. The purpose of this report is to present an overview of both published studies and new data in the evaluation of immune responses to the PSA-TRICOM vaccine platform, currently in phase III testing. Of 104 patients tested for T-cell responses, 57% (59/104) demonstrated a >= 2-fold increase in PSA-specific T cells 4 weeks after vaccine (median 5-fold increase) compared with pre-vaccine, and 68% (19/28) of patients tested mounted post-vaccine immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). The PSA-specific immune responses observed 28 days after vaccine (i.e., likely memory cells) are quantitatively similar to the levels of circulating T cells specific for influenza seen in the same patients. Measurements of systemic immune response to PSA may underestimate the true therapeutic immune response (as this does not account for cells that have trafficked to the tumor) and does not include antigen spreading. Furthermore, although the entire PSA gene is the vaccine, only one epitope of PSA is evaluated in the T-cell responses. Because this therapeutic vaccine is directed at generating a cellular/Th1 immune response (T-cell costimulatory molecules and use of a viral vector), it is not surprising that less than 0.6% of patients (2/349) tested have evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. An ongoing phase III study will evaluate the systemic immune responses and correlation with clinical outcomes. (C) 2013 AACR. C1 [Gulley, James L.; Madan, Ravi A.; Tsang, Kwong Y.; Jochems, Caroline; Marte, Jennifer L.; Farsaci, Benedetto; Tucker, Jo A.; Hodge, James W.; Heery, Christopher R.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,13N208,MSC-1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Farsaci, Benedetto/L-9837-2014; Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Farsaci, Benedetto/0000-0001-8275-2561; Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 41 TC 39 Z9 39 U1 0 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 FEB PY 2014 VL 2 IS 2 BP 133 EP 141 DI 10.1158/2326-6066.CIR-13-0108 PG 9 WC Oncology; Immunology SC Oncology; Immunology GA AM7FU UT WOS:000340031200007 PM 24778277 ER PT J AU Compton, MT Kelley, ME Ionescu, DF AF Compton, Michael T. Kelley, Mary E. Ionescu, Dawn F. TI Subtyping first-episode non-affective psychosis using four early-course features: potentially useful prognostic information at initial presentation SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Article DE age at onset; first-episode psychosis; premorbid functioning; prodrome; schizophrenia ID EARLY-ONSET SCHIZOPHRENIA; NEGATIVE SYNDROME SCALE; MINI-MENTAL-STATE; AGE-OF-ONSET; PREMORBID ADJUSTMENT; UNTREATED PSYCHOSIS; 1ST EPISODE; SYMPTOMS; PATTERNS; DURATION AB Aim: Heterogeneity of symptoms, course and outcomes in primary psychotic disorders complicates prognosis, treatment and diverse aspects of research. This study aimed to identify interpretable subtypes of first-episode non-affective psychosis based on four early-course features (premorbid academic functioning, premorbid social functioning, duration of the prodrome and age at onset of psychosis). Methods: Data from 200 well-characterized patients hospitalized in public-sector inpatient units for first-episode non-affective psychosis were used in latent profile analyses. Derived subtypes were then compared along a number of clinical dimensions using analyses of variance. Results: Using four early-course features, three classes were derived. A good premorbid/short prodrome subtype was characterized by a lower severity of positive symptoms, better social/occupational/global functioning, and a shorter duration of untreated psychosis; a poor premorbid/early onset subtype demonstrated greater negative and preoccupation symptoms, as well as greater psychosocial problems; and a long prodrome/late onset subtype was characterized by greater dysphoric symptoms. Conclusions: Findings indicate a need for further research with first-episode samples on the utility of subtyping based on early-course (premorbid, prodromal and onset-related) characteristics. Such efforts could enhance the parsing of heterogeneity, thereby advancing clinical practice and research. C1 [Compton, Michael T.] George Washington Univ, Sch Med & Hlth Sci, Dept Psychiat & Behav Sci, Washington, DC 20037 USA. [Kelley, Mary E.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Ionescu, Dawn F.] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. RP Compton, MT (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Psychiat & Behav Sci, 2120 L St,Suite 600 NW, Washington, DC 20037 USA. EM mcompton@mfa.gwu.edu RI Ionescu, Dawn/K-5675-2015 FU National Institute of Mental Health [K23 MH067589, R01 MH081011] FX This research was supported by grants K23 MH067589 and R01 MH081011 to the first author from the National Institute of Mental Health. NR 70 TC 1 Z9 1 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 EI 1751-7893 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD FEB PY 2014 VL 8 IS 1 BP 50 EP 58 DI 10.1111/eip.12026 PG 9 WC Psychiatry SC Psychiatry GA AM4CD UT WOS:000339798600007 PM 23343467 ER PT J AU Mete, O Tischler, AS de Krijger, R McNicol, AM Eisenhofer, G Pacak, K Ezzat, S Asa, SL AF Mete, Ozgur Tischler, Arthur S. de Krijger, Ronald McNicol, Anne Marie Eisenhofer, Graeme Pacak, Karel Ezzat, Shereen Asa, Sylvia L. TI Protocol for the Examination of Specimens From Patients With Pheochromocytomas and Extra-Adrenal Paragangliomas SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID NEUROENDOCRINE TUMORS; GERMLINE MUTATIONS; GENE-MUTATIONS; SDHB; LOCALIZATION; DIAGNOSIS; PEPTIDES; FEATURES; PROGRESS; HEAD AB During the last decade there have been revolutionary breakthroughs in understanding the biology of pheochromocytomas and extra-adrenal paragangliomas. Discoveries of new susceptibility genes and genotype-phenotype correlations have led to the realization that appropriate patient care requires a complete integration of clinical, genetic, biochemical, imaging, and pathology findings. Clinical practice has in many cases not kept pace with the rate of discovery, underscoring a need for updated procedures for evaluation of patient specimens and reporting of data. We therefore propose a new synoptic reporting approach for pheochromocytomas and extra-adrenal paragangliomas that will provide clear and uniform information to pathologists and clinicians, in order to advance the diagnosis of these neoplasms and optimize patient care. C1 [Mete, Ozgur; Asa, Sylvia L.] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Ezzat, Shereen] Univ Hlth Network, Dept Med, Toronto, ON M5G 2C4, Canada. [Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol, Boston, MA USA. [de Krijger, Ronald] Erasmus MC Univ, Med Ctr, Dept Pathol, Rotterdam, Netherlands. [McNicol, Anne Marie] Univ Queensland, Royal Brisbane & Womens Hosp, Clin Res Ctr, Dept Mol & Cellular Pathol, Brisbane, Qld, Australia. [Eisenhofer, Graeme] Univ Dresden, Inst Clin Chem & Lab Med, Dresden, Germany. [Eisenhofer, Graeme] Univ Dresden, Dept Med 3, Dresden, Germany. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Hlth, Program Reprod & Adult Endocrinol, Bethesda, MD USA. RP Mete, O (reprint author), Univ Hlth Network, Dept Pathol, 200 Elizabeth St,11th Floor, Toronto, ON M5G 2C4, Canada. EM ozgur.mete2@uhn.ca FU Intramural NIH HHS [ZIA HD008735-12] NR 49 TC 20 Z9 20 U1 0 U2 1 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2014 VL 138 IS 2 BP 182 EP 188 DI 10.5858/arpa.2012-0551-OA PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA AM0QF UT WOS:000339550000011 PM 24476517 ER PT J AU Wolff, AC Hammond, MEH Hicks, DG Dowsett, M McShane, LM Allison, KH Allred, DC Bartlett, JMS Bilous, M Fitzgibbons, P Hanna, W Jenkins, RB Mangu, PB Paik, S Perez, EA Press, MF Spears, PA Vance, GH Viale, G Hayes, DF AF Wolff, Antonio C. Hammond, M. Elizabeth H. Hicks, David G. Dowsett, Mitch McShane, Lisa M. Allison, Kimberly H. Allred, Donald C. Bartlett, John M. S. Bilous, Michael Fitzgibbons, Patrick Hanna, Wedad Jenkins, Robert B. Mangu, Pamela B. Paik, Soonmyung Perez, Edith A. Press, Michael F. Spears, Patricia A. Vance, Gail H. Viale, Giuseppe Hayes, Daniel F. TI Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID IN-SITU HYBRIDIZATION; HER2 GENE AMPLIFICATION; RABBIT MONOCLONAL-ANTIBODY; CORE NEEDLE-BIOPSY; TIME RT-PCR; ASCO/CAP HER2-POSITIVITY CRITERIA; ADJUVANT TRASTUZUMAB BENEFIT; TISSUE MICROARRAY TECHNOLOGY; POLYMERASE CHAIN-REACTION; ESTROGEN-RECEPTOR AB Purpose. To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods. ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results. The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations. The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. C1 [Wolff, Antonio C.] Johns Hopkins Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [McShane, Lisa M.] NCI, Bethesda, MD 20892 USA. [Hammond, M. Elizabeth H.] Univ Utah, Sch Med & Intermt Healthcare, Salt Lake City, UT USA. [Hicks, David G.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Dowsett, Mitch] Royal Marsden Hosp, London SW3 6JJ, England. [Allison, Kimberly H.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Fitzgibbons, Patrick] St Jude Med Ctr, Fullerton, CA USA. [Press, Michael F.] Univ So Calif, Los Angeles, CA USA. [Allred, Donald C.] Washington Univ, Sch Med, St Louis, MO USA. [Bartlett, John M. S.] Ontario Inst Canc Res, Toronto, ON, Canada. [Hanna, Wedad] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Bilous, Michael] Univ Western Sydney & Healthscope Pathol, Sydney, NSW, Australia. [Jenkins, Robert B.] Mayo Clin, Rochester, MN USA. [Mangu, Pamela B.] Amer Soc Clin Oncol, Alexandria, VA USA. [Paik, Soonmyung] Natl Surg Adjuvant Breast & Bowel Project, Pitsburgh, PA USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Spears, Patricia A.] N Carolina State Univ, Raleigh, NC 27695 USA. [Vance, Gail H.] Indiana Univ, Med Ctr, Indianapolis, IN USA. [Viale, Giuseppe] Univ Milan, European Inst Oncol, Milan, Italy. [Hayes, Daniel F.] Univ Michigan, Comprehens Canc Care Ctr, Ann Arbor, MI 48109 USA. RP Wolff, AC (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Fitzgibbons, Patrick/0000-0002-2998-6913; Wolff, Antonio/0000-0003-3734-1063 FU Roche UK; Roche; Abbott FX Other Remuneration: John M. S. Bartlett, Roche UK; Wedad Hanna, Roche; Robert B. Jenkins, Abbott. NR 155 TC 198 Z9 211 U1 4 U2 24 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2014 VL 138 IS 2 BP 241 EP 256 DI 10.5858/arpa.2013-0953-SA PG 16 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA AM0QF UT WOS:000339550000019 PM 24099077 ER PT J AU Mash, C Bornstein, MH Banerjee, A AF Mash, Clay Bornstein, Marc H. Banerjee, Abhilasha TI Development of Object Control in the First Year: Emerging Category Discrimination and Generalization in Infants' Adaptive Selection of Action SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE action selection; categorization; infancy; motor control; generalization ID INDUCTIVE GENERALIZATION; CATEGORIZATION; INFORMATION; IDENTIFICATION; REPRESENTATION; INDIVIDUATION; COORDINATION; MANIPULATION; PERCEPTION; TRANSITION AB This research examined the development of adaptive generalization in infants' object-directed actions. Infants ages 9 and 12 months participated in an object manipulation task with stimulus objects from 2 categories that differed in shape and weight and that bore a consistent shape or weight correspondence. Weight differences between categories affected infants' actions required to handle objects effectively. Infants manually explored objects from both categories and then were tested for their selection of different actions between categories and their generalization to novel exemplars within categories. Nine-month-olds provided no evidence of category differentiation and generalization; however, 12-month-olds adapted their actions selectively for objects of each category and generalized those actions to novel objects within categories. A second sample of 9-month-olds who were examined in a simplified task with just one object per weight level successfully adapted their actions by weight. Together, the findings provide evidence for the development of selection and generalization in manipulative action across the second half of the first year of life. C1 [Mash, Clay; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Child & Family Res, NIH, Bethesda, MD USA. [Banerjee, Abhilasha] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. RP Mash, C (reprint author), NICHD, 6705 Rockledge Dr, Bethesda, MD 20892 USA. EM mashc@mail.nih.gov FU Intramural NIH HHS [ZIA HD001119-26] NR 50 TC 1 Z9 1 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 EI 1939-0599 J9 DEV PSYCHOL JI Dev. Psychol. PD FEB PY 2014 VL 50 IS 2 BP 325 EP 335 DI 10.1037/a0033234 PG 11 WC Psychology, Developmental SC Psychology GA AM5EF UT WOS:000339878300001 PM 23772823 ER PT J AU Knebel, AR Sharpe, VA Danis, M Toomey, LM Knickerbocker, DK AF Knebel, Ann R. Sharpe, Virginia A. Danis, Marion Toomey, Lauren M. Knickerbocker, Deborah K. TI Informing the Gestalt: An Ethical Framework for Allocating Scarce Federal Public Health and Medical Resources to States During Disasters SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE ethical issues; politics; state/local issues ID ISSUES AB During catastrophic disasters, government leaders must decide how to efficiently and effectively allocate scarce public health and medical resources. The literature about triage decision making at the individual patient level is substantial, and the National Response Framework provides guidance about the distribution of responsibilities between federal and state governments. However, little has been written about the decision-making process of federal leaders in disaster situations when resources are not sufficient to meet the needs of several states simultaneously. We offer an ethical framework and logic model for decision making in such circumstances. We adapted medical triage and the federalism principle to the decision-making process for allocating scarce federal public health and medical resources. We believe that the logic model provides a values-based framework that can inform the gestalt during the iterative decision process used by federal leaders as they allocate scarce resources to states during catastrophic disasters. C1 [Knebel, Ann R.] NINR, NIH, Bethesda, MD 20892 USA. [Danis, Marion] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Sharpe, Virginia A.] Vet Hlth Adm, Natl Ctr Eth Hlth Care, Washington, DC USA. [Toomey, Lauren M.; Knickerbocker, Deborah K.] US Dept HHS, Off Assistant Secretary Preparedness & Response, Off Emergency Management, Washington, DC 20201 USA. RP Knebel, AR (reprint author), NINR, NIH, 31 Ctr Dr,Bldg 31,Rm 5B05, Bethesda, MD 20892 USA. EM ann.knebel@hhs.gov NR 33 TC 1 Z9 1 U1 5 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD FEB PY 2014 VL 8 IS 1 BP 79 EP 88 DI 10.1017/dmp.2014.9 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AL3XG UT WOS:000339064300012 PM 24612854 ER PT J AU Stender, SR Brown, RJ Cochran, E Baez, E Gumus, P Lacassie, Y AF Stender, S. R. Brown, R. J. Cochran, E. Baez, E. Gumus, P. Lacassie, Y. TI LEPTIN DEFICIENCY PRESENTING AS NEW ONSET DIABETES MELLITUS IN AN 11 YEAR OLD BOY WITH PROGEROID APPEARANCE SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Stender, S. R.; Baez, E.; Gumus, P.; Lacassie, Y.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Brown, R. J.; Cochran, E.] NIDDK, NIH, DEOB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2014 VL 62 IS 2 MA 506 BP 558 EP 559 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL3SH UT WOS:000339048800516 ER PT J AU Fulop, T Tapolyai, M Zsom, L Hickson, DA Lirette, S Flessner, MF Griswold, M AF Fueloep, T. Tapolyai, M. Zsom, L. Hickson, D. A. Lirette, S. Flessner, M. F. Griswold, M. TI URINARY ELCTROLYTE EXCRETION AND SERUM POTASSIUM AMONG AFRICAN-AMERICANS; THE JACKSON HEART STUDY SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Fueloep, T.; Zsom, L.; Hickson, D. A.; Lirette, S.; Griswold, M.] Univ Mississippi Med Ctr, Jackson, MS USA. [Tapolyai, M.] Univ S Carolina, WJB Dorn VA Med Ctr, Columbia, SC 29208 USA. [Hickson, D. A.; Griswold, M.] Jackson Heart Study, Jackson, MS USA. [Hickson, D. A.] Jackson State Univ, Jackson, MS USA. [Flessner, M. F.] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2014 VL 62 IS 2 MA 560 BP 574 EP 575 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL3SH UT WOS:000339048800569 ER PT J AU Uittenbogaard, AM Myers-Morales, T Gorman, AA Welsh, E Wulff, C Hinnebusch, BJ Korhonen, TK Straley, SC AF Uittenbogaard, Annette M. Myers-Morales, Tanya Gorman, Amanda A. Welsh, Erin Wulff, Christine Hinnebusch, B. Joseph Korhonen, Timo K. Straley, Susan C. TI Temperature-dependence of yadBC phenotypes in Yersinia pestis SO MICROBIOLOGY-SGM LA English DT Article ID BORNE TRANSMISSION; SURFACE PROTEASE; OUTER-MEMBRANE; BUBONIC PLAGUE; VIRULENCE; CELLS; GENES; PATHOGENESIS; NEUTROPHILS; EXPRESSION AB YadB and YadC are putative trimeric autotransporters present only in the plague bacterium Yersinia pestis and its evolutionary predecessor, Yersinia pseudotuberculosis. Previously, yadBC was found to promote invasion of epithelioid cells by Y. pestis grown at 37 degrees C. In this study, we found that yadBC also promotes uptake of 37 degrees C-grown Y. pestis by mouse monocyte/macrophage cells. We tested whether yadBC might be required for lethality of the systemic stage of plague in which the bacteria would be pre-adapted to mammalian body temperature before colonizing internal organs and found no requirement for early colonization or growth over 3 days. We tested the hypothesis that YadB and YadC function on ambient temperature-grown Y. pestis in the flea vector or soon after infection of the dermis in bubonic plague. We found that yadBC did not promote uptake by monocyte/macrophage cells if the bacteria were grown at 28 degrees C, nor was there a role of yadBC in colonization of fleas by Y. pestis grown at 21 C. However, the presence of yadBC did promote recoverability of the bacteria from infected skin for 28 degrees C-grown Y. pestis. Furthermore, the gene for the proinflammatory chemokine CXCL1 was upregulated in expression if the infecting Y. pestis lacked yadBC but not if yadBC was present. Also, yadBC was not required for recoverability if the bacteria were grown at 37 degrees C. These findings imply that thermally induced virulence properties dominate over effects of yadBC during plague but that yadBC has a unique function early after transmission of Y. pestis to skin. C1 [Uittenbogaard, Annette M.; Myers-Morales, Tanya; Gorman, Amanda A.; Welsh, Erin; Wulff, Christine; Straley, Susan C.] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA. [Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Korhonen, Timo K.] Univ Helsinki, Dept Biosci, Div Gen Microbiol, Helsinki, Finland. RP Straley, SC (reprint author), Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA. EM scstraO1@uky.edu FU PHS (NIAID) ARRA [R21 AI083861]; PHS (NIAID) [R01 AI48491]; University of Kentucky Faculty Research Support grant FX This study was supported by PHS (NIAID) ARRA grant R21 AI083861, PHS (NIAID) grant R01 AI48491, and by a University of Kentucky Faculty Research Support grant, all to S. C. S. The authors acknowledge Christopher Jester (Department of Biology, University of Kentucky) for measuring survival of Y. pestis in PMNs. None of the authors has any conflict of interest that would affect this work. NR 34 TC 1 Z9 1 U1 3 U2 8 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD FEB PY 2014 VL 160 BP 396 EP 405 DI 10.1099/mic.0.073205-0 PN 2 PG 10 WC Microbiology SC Microbiology GA AK7IX UT WOS:000338603100015 PM 24222617 ER PT J AU Bhatnagar, S Hoberman, A Kearney, DH Shaikh, N Moxey-Mims, MM Chesney, RW Carpenter, MA Greenfield, SP Keren, R Mattoo, TK Mathews, R Gravens-Mueller, L Ivanova, A AF Bhatnagar, Sonika Hoberman, Alejandro Kearney, Diana H. Shaikh, Nader Moxey-Mims, Marva M. Chesney, Russell W. Carpenter, Myra A. Greenfield, Saul P. Keren, Ron Mattoo, Tej K. Mathews, Ranjiv Gravens-Mueller, Lisa Ivanova, Anastasia TI Development and Impact of an Intervention to Boost Recruitment in a Multicenter Pediatric Randomized Clinical Trial SO CLINICAL PEDIATRICS LA English DT Article DE recruitment; intervention; clinical trial ID RETENTION AB Objectives. Our primary objective was to develop and evaluate an intervention to increase recruitment in a multicenter pediatric randomized clinical trial (RCT). Our secondary objective was to assess the impact beyond 120 days. Methods. The study was conducted at 17 academic centers participating in a pediatric RCT. The intervention consisted of utilizing a recruitment assessment tool at a site visit or teleconference with key site personnel. Results. We found a significant increase in the number of individuals enrolled for all 17 sites at 120 days postintervention (mean = 1.12 per site; median = 1 per site; 95% confidence interval = 1-2; P = .04). No significant differences were apparent beyond the first 120 days postintervention. Conclusions. Successful recruitment in RCTs is essential to the quality, generalizability, and cost-effectiveness of clinical research. Implementation of this recruitment intervention may effectively increase recruitment in RCTs. Beyond the first 120 days postintervention, repeated interventions may be required. What is new? Despite general and pediatric-specific challenges to recruitment in RCTs, a paucity of evidence exists on effective recruitment strategies or assessment tools to reliably enhance recruitment. We developed a recruitment intervention for use in RCTs that enables clinical researchers to enhance recruitment. C1 [Bhatnagar, Sonika; Hoberman, Alejandro; Kearney, Diana H.; Shaikh, Nader] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Moxey-Mims, Marva M.] NIDDK, NIH, Bethesda, MD USA. [Chesney, Russell W.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Carpenter, Myra A.; Gravens-Mueller, Lisa; Ivanova, Anastasia] Univ N Carolina, Chapel Hill, NC USA. [Greenfield, Saul P.] Women & Childrens Hosp Buffalo, Buffalo, NY USA. [Keren, Ron] Univ Penn, Philadelphia, PA 19104 USA. [Mattoo, Tej K.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Mathews, Ranjiv] Johns Hopkins Sch Med, Baltimore, MD USA. RP Bhatnagar, S (reprint author), UPMC, Childrens Hosp Pittsburgh, Div Gen Acad Pediat, CHOB, 4401 Penn Ave,3 Floor, Pittsburgh, PA 15224 USA. EM sonika.bhatnagar@chp.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063]; Children's Hospital of Philadelphia Clinical and Translational Science Award from the National Center for Research Resources at the National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000003] FX The authors thank the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) participants, their families, and the participating clinicians, investigators, and staff for making this research possible. The RIVUR trial was supported by cooperative agreements U01 DK074059 (Carpenter), U01 DK074053 (Hoberman), U01 DK074082 (Mathews), U01 DK074064 (Keren), U01 DK074062 (Mattoo), and U01 DK074063 (Greenfield) from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services. The trial was also supported by the Children's Hospital of Philadelphia Clinical and Translational Science Award (UL1TR000003) from the National Center for Research Resources, now at the National Center for Advancing Translational Sciences, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. The RIVUR Web site is located at http://www.cscc.unc.edu/rivur/. NR 14 TC 4 Z9 4 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 EI 1938-2707 J9 CLIN PEDIATR JI Clin. Pediatr. PD FEB PY 2014 VL 53 IS 2 BP 151 EP 157 DI 10.1177/0009922813506961 PG 7 WC Pediatrics SC Pediatrics GA AJ8MZ UT WOS:000337960700008 PM 24151147 ER PT J AU Schmitz, R Ceribelli, M Pittaluga, S Wright, G Staudt, LM AF Schmitz, Roland Ceribelli, Michele Pittaluga, Stefania Wright, George Staudt, Louis M. TI Oncogenic Mechanisms in Burkitt Lymphoma SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID EPSTEIN-BARR-VIRUS; B-CELL LYMPHOMAS; C-MYC; GERMINAL CENTER; BET BROMODOMAINS; AFRICAN CHILDREN; TRANSGENIC MICE; IMMUNE-SYSTEM; CYCLIN D3; EXPRESSION AB Burkitt lymphoma is a germinal center B-cell-derived cancer that was instrumental in the identification of MYC as an important human oncogene more than three decades ago. Recently, new genomics technologies have uncovered several additional oncogenic mechanisms that cooperate with MYC to create this highly aggressive cancer. The transcription factor TCF-3 is central to Burkitt lymphoma pathogenesis. TCF-3 is rendered constitutively active in Burkitt lymphoma by two related mechanisms: (1) somatic mutations that inactivate its negative regulator ID3, and (2) somatic mutations in TCF-3 that block the ability of ID3 to bind and interfere with its activity as a transcription factor. TCF-3 is also a master regulator of normal germinal center B-cell differentiation. Within the germinal center, TCF-3 up-regulates genes that are characteristically expressed in the rapidly dividing centroblasts, the putative cell of origin for Burkitt lymphoma, while repressing genes expressed in the less proliferative centrocytes. TCF-3 promotes antigen-independent (tonic) B-cell-receptor signaling in Burkitt lymphoma by transactivating immunoglobulin heavy-and light-chain genes while repressing PTPN6, which encodes the phosphatase SHP-1, a negative regulator of B-cell- receptor signaling. Tonic B-cell-receptor signaling sustains Burkitt lymphoma survival by engaging the PI3 kinase pathway. In addition, TCF-3 promotes cell-cycle progression by transactivating CCND3, encoding a D-type cyclin that regulates the G(1)-S phase transition. Additionally, CCND3 accumulates oncogenic mutations that stabilize cyclin D3 protein expression and drive proliferation. These new insights into Burkitt lymphoma pathogenesis suggest new therapeutic strategies, which are sorely needed in developing regions of the world where this cancer is endemic. C1 [Schmitz, Roland; Ceribelli, Michele; Staudt, Louis M.] NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wright, George] NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe) FX We thank Moez Dawood for helpful discussion. R.S. is supported by the Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe). NR 61 TC 21 Z9 23 U1 1 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD FEB PY 2014 VL 4 IS 2 AR a014282 DI 10.1101/cshperspect.a014282 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AJ9HI UT WOS:000338018500003 ER PT J AU Kim, SH Xiao, S Paldurai, A Collins, PL Samal, SK AF Kim, Shin-Hee Xiao, Sa Paldurai, Anandan Collins, Peter L. Samal, Siba K. TI Role of C596 in the C-terminal extension of the haemagglutinin-neuraminidase protein in replication and pathogenicity of a highly virulent Indonesian strain of Newcastle disease virus SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MEMBRANE GLYCOPROTEIN PRECURSORS; PROTEOLYTIC CLEAVAGE; FUSION PROTEIN; ACTIVATION; SITE AB We modified the haemagglutinin neuraminidase (HN) glycoprotein of the virulent Newcastle disease virus (NDV) strain Banjarmasin/010/10 (Ban/010) by adding C-terminal extensions similar to those found in certain avirulent NDV strains. Extension of the 571 aa wt Ban/010 HN protein to 577 and 616 aa by removal of one or two translational stop codons moderately reduced HN function and viral pathogenicity in 1-day-old and 3-week-old chickens. Substantially greater reductions were achieved by altering the 616 aa form by introducing a R596C mutation or by replacing the C-terminal extension with that of avirulent strain Ulster, which naturally contains the amino acid 596C. These results showed that extension of the C terminus of HN reduces NDV pathogenicity, and that this effect is substantially increased by the presence of 596C. These results indicate that this attenuating mechanism in avirulent strains such as Ulster can be applied directly to a highly virulent strain recently in circulation. C1 [Kim, Shin-Hee; Xiao, Sa; Paldurai, Anandan; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [N01A060009]; NIAID, NIH, Intramural Research Program FX We thank Daniel Rockemann, Girmay Gebreluul, Yonas Araya, Andrea Ferrero-Perez and our laboratory members for excellent technical assistance; and Dr Bernard Moss [National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)] for providing the vaccinia T7 recombinant virus and the pTM1 plasmid. This research was supported by NIAID contract N01A060009 (85% support) and the NIAID, NIH, Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services, nor does mention of trade names, commercial practices or organizations imply endorsement by the US Government. NR 16 TC 3 Z9 3 U1 1 U2 6 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 2014 VL 95 BP 331 EP 336 DI 10.1099/vir.0.055285-0 PN 2 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA AK1LU UT WOS:000338177400009 PM 24197534 ER PT J AU Ludi, AB Horton, DL Li, Y Mahapatra, M King, DP Knowles, NJ Russell, CA Paton, DJ Wood, JLN Smith, DJ Hammond, JM AF Ludi, A. B. Horton, D. L. Li, Y. Mahapatra, M. King, D. P. Knowles, N. J. Russell, C. A. Paton, D. J. Wood, J. L. N. Smith, D. J. Hammond, J. M. TI Antigenic variation of foot-and-mouth disease virus serotype A SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID GENETIC EVOLUTION; MOLECULAR CHARACTERIZATION; MAXIMUM-LIKELIHOOD; RECEPTOR; EPIDEMIOLOGY; ANTIBODIES; EUROPE; SITES AB The current measures to control foot-and-mouth disease (FMD) include vaccination, movement control and slaughter of infected or susceptible animals. One of the difficulties in controlling FMD by vaccination arises due to the substantial diversity found among the seven serotypes of FMD virus (FMDV) and the strains within these serotypes. Therefore, vaccination using a single vaccine strain may not fully cross-protect against all strains within that serotype, and therefore selection of appropriate vaccines requires serological comparison of the field virus and potential vaccine viruses using relationship coefficients (r(1) values). Limitations of this approach are that antigenic relationships among field viruses are not addressed, as comparisons are only with potential vaccine virus. Furthermore, inherent variation among vaccine sera may impair reproducibility of one-way relationship scores. Here, we used antigenic cartography to quantify and visualize the antigenic relationships among FMD serotype A viruses, aiming to improve the understanding of FMDV antigenic evolution and the scope and reliability of vaccine matching. Our results suggest that predicting antigenic difference using genetic sequence alone or by geographical location is not currently reliable. We found co-circulating lineages in one region that were genetically similar but antigenically distinct. Nevertheless, by comparing antigenic distances measured from the antigenic maps with the full capsid (P1) sequence, we identified a specific amino acid substitution associated with an antigenic mismatch among field viruses and a commonly used prototype vaccine strain, A(22)/IRO124/64. C1 [Ludi, A. B.; Li, Y.; Mahapatra, M.; King, D. P.; Knowles, N. J.; Paton, D. J.; Hammond, J. M.] Pirbright Inst, Pirbright GU24 0NF, Surrey, England. [Ludi, A. B.; Horton, D. L.; Russell, C. A.; Wood, J. L. N.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge CB3 0ES, England. [Ludi, A. B.; Horton, D. L.; Smith, D. J.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Horton, D. L.] Anim Hlth & Vet Labs Agcy, Addlestone KT15 3NB, Surrey, England. [Russell, C. A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, D. J.] Erasmus MC, Dept Virol, NL-3000 CA Rotterdam, Netherlands. [Russell, C. A.; Smith, D. J.] Univ Cambridge, WHO Collaborating Ctr Modelling Evolut & Control, Cambridge CB2 3EJ, England. RP Ludi, AB (reprint author), ARS, Foreign Anim Dis Res Unit, USDA, Plum Isl Anim Dis Ctr, Greenport, NY 11944 USA. EM Anna.Ludi@ars.usda.gov; drliy@yahoo.com RI Horton, Daniel/D-9909-2011; APHA, Staff publications/E-6082-2010; Wood, James/A-1626-2008; Institute, Pirbright/K-4476-2014; OI Horton, Daniel/0000-0002-9126-2756; Wood, James/0000-0002-0258-3188; King, Donald/0000-0002-6959-2708; Russell, Colin/0000-0002-2113-162X FU Cambridge Infectious Diseases Consortium of the Veterinary Training and Research Initiative (Defra grant) [VT0105]; Alborada Trust; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center; EU [228292, 223498]; Defra UK [SE2939]; NIH Director's Pioneer Award [DP1-0D000490-0]; ANTIGONE [278976]; University Research Fellowship from the Royal Society FX Thanks are due to Bob Statham and the WRL/EURL FMD team for their advice and expertise on the VNT and r1 values. A. B. L. was supported by a fellowship from the Cambridge Infectious Diseases Consortium of the Veterinary Training and Research Initiative (Defra grant VT0105). J. L. N. W. is supported by the Alborada Trust and the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center. D. L. H. is partially supported by the Cambridge Infectious Diseases Consortium Veterinary Training and Research Initiative (Defra grant VT0105) and EU FP7 Research Infrastructure Grant 'European Virus Archive (EVA)' (grant 228292). N. J. K. was partially supported by a Defra UK grant (SE2939). D. J. S. and C. A. R. acknowledge the support of EU FP7 grants EMPERIE (223498). C. A. R. acknowledges the support of the NIH Director's Pioneer Award DP1-0D000490-0 and D.J. S., C. A. R. and J. L. N. W. are also supported by ANTIGONE (278976). C. A. R. was supported by a University Research Fellowship from the Royal Society. NR 46 TC 6 Z9 6 U1 0 U2 10 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 2014 VL 95 BP 384 EP 392 DI 10.1099/vir.0.057521-0 PN 2 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA AK1LU UT WOS:000338177400014 PM 24187014 ER PT J AU Scialla, JJ Xie, HL Rahman, M Anderson, AH Isakova, T Ojo, A Zhang, XM Nessel, L Hamano, T Grunwald, JE Raj, DS Yang, W He, J Lash, JP Go, AS Kusek, JW Feldman, H Wolf, M AF Scialla, Julia J. Xie, Huiliang Rahman, Mahboob Anderson, Amanda Hyre Isakova, Tamara Ojo, Akinlolu Zhang, Xiaoming Nessel, Lisa Hamano, Takayuki Grunwald, Juan E. Raj, Dominic S. Yang, Wei He, Jiang Lash, James P. Go, Alan S. Kusek, John W. Feldman, Harold Wolf, Myles CA Chronic Renal Insufficiency Cohort TI Fibroblast Growth Factor-23 and Cardiovascular Events in CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; GLOMERULAR-FILTRATION-RATE; HIGHLY SENSITIVE ASSAY; CORONARY-HEART-DISEASE; GENERAL-POPULATION; CARDIAC TROPONIN; ATHEROSCLEROSIS RISK; PARATHYROID-HORMONE; RENAL-DISEASE AB An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44 +/- 15 ml/min per 1.73m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4. C1 [Scialla, Julia J.; Xie, Huiliang; Isakova, Tamara; Wolf, Myles] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Rahman, Mahboob] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Anderson, Amanda Hyre; Zhang, Xiaoming; Nessel, Lisa; Hamano, Takayuki; Grunwald, Juan E.; Yang, Wei; Feldman, Harold] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ojo, Akinlolu] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Raj, Dominic S.] George Washington Univ, Washington, DC USA. [He, Jiang] Tulane Univ, New Orleans, LA 70118 USA. [Lash, James P.] Univ Illinois, Chicago, IL USA. [Go, Alan S.] Kaiser Permanente Div Res, Oakland, CA USA. [Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Wolf, M (reprint author), 633 N St Clair St, Chicago, IL 60611 USA. EM myles.wolf@northwestern.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania CTRC CTSA [UL1 RR-024134]; Johns Hopkins University [UL1 RR-025005]; University of Maryland GCRC [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) [UL1TR000439]; NIH roadmap for Medical Research [UL1RR024986]; University of Illinois at Chicago [CTSAUL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser NIH/NCRR UCSF-CTSI [UL1 RR-024131]; NIH [K23DK095949, K01DK092353, R01DK073665, HL268200900040C, R01HL107241, R01DK076116, R01DK081374, R01DK094796, K24DK093723, U54TR000255]; Michigan Institute for Clinical and Health Research [UL1RR024986] FX Funding for the CRIC study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the University of Pennsylvania CTRC CTSA UL1 RR-024134, Johns Hopkins University UL1 RR-025005, 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 National Institutes of Health (NIH) and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1RR024986, University of Illinois at Chicago CTSAUL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser NIH/NCRR UCSF-CTSI UL1 RR-024131. J.J.S. was supported by grant K23DK095949; A.H.A. by K01DK092353; D.S.R. by R01DK073665, HL268200900040C, and R01HL107241; and M.W. by R01DK076116, R01DK081374, R01DK094796, K24DK093723, and U54TR000255, all from the NIH. NR 47 TC 84 Z9 91 U1 5 U2 9 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB 1 PY 2014 VL 25 IS 2 BP 349 EP 360 DI 10.1681/ASN.2013050465 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AJ8QM UT WOS:000337971700017 PM 24158986 ER PT J AU Shirota, H Klinman, DM AF Shirota, Hidekazu Klinman, Dennis M. TI Recent progress concerning CpG DNA and its use as a vaccine adjuvant SO EXPERT REVIEW OF VACCINES LA English DT Review DE allergy; cancer; CpG oligonucleotide; infection; Toll-like receptor; vaccine adjuvant ID PLASMACYTOID DENDRITIC CELLS; B SURFACE-ANTIGEN; TOLL-LIKE RECEPTORS; DOUBLE-STRANDED-RNA; MUCOSAL IMMUNE-RESPONSES; NON-HODGKIN-LYMPHOMA; IN-SITU VACCINATION; BLOOD-STAGE VACCINE; RANDOMIZED PHASE-II; BACTERIAL-DNA AB CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides designed to specifically agonize Toll-like receptor 9. Here, we review recent progress in understanding the mechanism of action of CpG ODN and provide an overview of human clinical trial results using CpG ODN to improve the vaccines for cancer, allergy and infectious disease. C1 [Shirota, Hidekazu] Tohoku Univ, Dept Clin Oncol, Sendai, Miyagi 980, Japan. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, Bldg 567 Rm 205 NCI Frederick, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX DM Klinman and members of his laboratory are inventors/co-inventors on a number of patents pertaining to CpG ODN. All rights to these patents have been assigned to the Federal Government. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 163 TC 22 Z9 23 U1 2 U2 42 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD FEB PY 2014 VL 13 IS 2 BP 299 EP 312 DI 10.1586/14760584.2014.863715 PG 14 WC Immunology SC Immunology GA AJ8BB UT WOS:000337926200013 PM 24308579 ER PT J AU Simon, SL Linet, MS AF Simon, Steven L. Linet, Martha S. TI RADIATION-EXPOSED POPULATIONS: WHO, WHY, AND HOW TO STUDY SO HEALTH PHYSICS LA English DT Article DE epidemiology; exposure, occupational; medical radiation; National Council on Radiation Protection and Measurements ID ATOMIC-BOMB SURVIVORS; CHILDHOOD LEUKEMIA INCIDENCE; NUCLEAR-WEAPONS TESTS; LUNG-CANCER INCIDENCE; IONIZING-RADIATION; CHERNOBYL ACCIDENT; DOSE ESTIMATION; THYROID-CANCER; BREAST-CANCER; INDOOR RADON AB Everyone is exposed to natural and manmade ionizing radiation that can originate from sources in the environment and in medical and occupational settings. There is notable variation, however, among individuals and across populations in the types of sources of radiation and in the frequency, level, and duration of exposure. Adverse health effects associated with radiation exposure have been known for decades, and ionizing radiation exposure has been linkedwith a broad range of different types of cancer and benign neoplasms as well as birth defects, reproductive effects, and diseases of the circulatory, hematologic, and neurologic systems. Our present understanding of radiation-related health risks derives primarily from multidisciplinary health risk (epidemiologic) studies that provide the key information on radiation-associated health outcomes, quantify radiation-related disease risks, and enhance understanding of mechanisms of radiation-related disease pathogenesis. Such information is central to quantifying risks in relation to benefits; addressing public concerns, including societal and clinical needs in relation to radiation exposure; and providing the database needed for establishing recommendations for radiation protection. Because of the importance of determining risks compared to benefits for all situations where exposure to ionizing radiation might result, it is useful for planning new health risks studies to categorize exposed populations according to the sources and types of radiation. This paper describes a wide range of populations exposed to radiation and the motivation and key methodological criteria that drive the rationale and priority of studying such populations. Also, discussed are alternative methods for evaluating radiation-related health risks in these populations, with a major focus on epidemiologic approaches. This paper concludes with a short summary of major highlights from radiation epidemiologic research and important unanswered questions. C1 [Simon, Steven L.; Linet, Martha S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Simon, SL (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 75 TC 3 Z9 3 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 182 EP 195 DI 10.1097/HP.0000000000000006 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2SO UT WOS:000337512400007 PM 24378492 ER PT J AU Travis, LB Ng, AK Allan, JM Pui, CH Kennedy, AR Xu, XG Purdy, JA Applegate, K Yahalom, J Constine, LS Gilbert, ES Boice, JD AF Travis, Lois B. Ng, Andrea K. Allan, James M. Pui, Ching-Hon Kennedy, Ann R. Xu, X. George Purdy, James A. Applegate, Kimberly Yahalom, Joachim Constine, Louis S. Gilbert, Ethel S. Boice, John D., Jr. TI SECOND MALIGNANT NEOPLASMS AND CARDIOVASCULAR DISEASE FOLLOWING RADIOTHERAPY SO HEALTH PHYSICS LA English DT Article DE cancer; health effects; medical radiation; National Council on Radiation Protection and Measurements ID RADIATION-THERAPY; TESTICULAR CANCER; BREAST-CANCER; HODGKINS-DISEASE; RISK; CHEMOTHERAPY; CARCINOMA; SURVIVORS; ROLES; SUSCEPTIBILITY AB Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies. C1 [Travis, Lois B.; Constine, Louis S.] Univ Rochester, Med Ctr, Rubin Ctr Canc Survivorship, Rochester, NY 14642 USA. [Travis, Lois B.; Constine, Louis S.] Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Ng, Andrea K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Allan, James M.] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pui, Ching-Hon] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Pui, Ching-Hon] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Kennedy, Ann R.] Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Xu, X. George] Rensselaer Polytech Inst, Nucl Engn & Engn Phys Program, Troy, NY USA. [Purdy, James A.] Univ Calif Davis, Dept Radiat Oncol, Davis, CA 95616 USA. [Applegate, Kimberly] Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. [Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Gilbert, Ethel S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Boice, John D., Jr.] Natl Council Radiat Protect & Measurements, Bethesda, MD USA. [Boice, John D., Jr.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Travis, LB (reprint author), Univ Rochester, Med Ctr, Rubin Ctr Canc Survivorship, 265 Crittenden Blvd,CU 420318, Rochester, NY 14642 USA. EM Lois_Travis@URMC.Rochester.edu FU National Institutes of Health [CA21765]; American Lebanese Syrian Associated Charities; University of Rochester Medical Center FX Supported in part by grant CA21765 from the National Institutes of Health, the American Lebanese Syrian Associated Charities (Ching-Hon Pui), and the University of Rochester Medical Center (Lois B. Travis). NR 26 TC 9 Z9 10 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 229 EP 246 DI 10.1097/HP.0000000000000013 PG 18 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 AJ2SO UT WOS:000337512400013 PM 24378498 ER PT J AU Bouville, A Kryuchkov, V AF Bouville, Andre Kryuchkov, Victor TI INCREASED OCCUPATIONAL RADIATION DOSES: NUCLEAR FUEL CYCLE SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; accidents, nuclear; Chernobyl; occupational safety ID CHERNOBYL CLEANUP WORKERS; UKRAINIAN-AMERICAN; THYROID-CANCER; DOSIMETRY; RISK; LIQUIDATORS; ACCIDENT; RECONSTRUCTION; DISORDERS; LEUKEMIA AB The increased occupational doses resulting from the Chernobyl nuclear reactor accident that occurred in Ukraine in April 1986, the reactor accident of Fukushima that took place in Japan in March 2011, and the early operations of the Mayak Production Association in Russia in the 1940s and 1950s are presented and discussed. For comparison purposes, the occupational doses due to the other two major reactor accidents (Windscale in the United Kingdomin 1957 and Three Mile Island in the United States in 1979) and to the main plutonium-producing facility in the United States (Hanford Works) are also covered but in less detail. Both for the Chernobyl nuclear reactor accident and the routine operations at Mayak, the considerable efforts made to reconstruct individual doses from external irradiation to a large number of workers revealed that the recorded doses had been overestimated by a factor of about two. C1 [Bouville, Andre] NCI, Rockville, MD 20850 USA. [Kryuchkov, Victor] Fed Med Biol Agcy, Burnasyan Fed Med Biophys Ctr, Moscow 123182, Russia. RP Bouville, A (reprint author), 9609 Med Dr,Room 7E590,MSC 9778, Rockville, MD 20850 USA. EM andre.bouville@nih.gov NR 44 TC 3 Z9 3 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 259 EP 271 DI 10.1097/HP.0000000000000066 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2SO UT WOS:000337512400016 PM 24378501 ER PT J AU Hatch, M AF Hatch, Maureen TI NUCLEAR REACTOR ACCIDENTS: EXPOSURES AND HEALTH EFFECTS AMONG MEMBERS OF THE PUBLIC SO HEALTH PHYSICS LA English DT Editorial Material ID THYROID-CANCER; MILE-ISLAND; I-131; FUKUSHIMA; MORTALITY; DISEASES; PLANT C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hatch, M (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM hatchm@mail.nih.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 307 EP 308 DI 10.1097/HP.0000000000000014 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2SO UT WOS:000337512400022 PM 24378507 ER PT J AU Pai, VM Rodgers, M Conroy, R Luo, J Zhou, RX Seto, B AF Pai, Vinay M. Rodgers, Mary Conroy, Richard Luo, James Zhou, Ruixia Seto, Belinda TI Workshop on using natural language processing applications for enhancing clinical decision making: an executive summary SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID RADIOLOGY REPORTS; SUPPORT SYSTEMS; INFORMATION; KNOWLEDGE AB In April 2012, the National Institutes of Health organized a two-day workshop entitled 'Natural Language Processing: State of the Art, Future Directions and Applications for Enhancing Clinical Decision-Making' (NLP-CDS). This report is a summary of the discussions during the second day of the workshop. Collectively, the workshop presenters and participants emphasized the need for unstructured clinical notes to be included in the decision making workflow and the need for individualized longitudinal data tracking. The workshop also discussed the need to: (1) combine evidence-based literature and patient records with machine-learning and prediction models; (2) provide trusted and reproducible clinical advice; (3) prioritize evidence and test results; and (4) engage healthcare professionals, caregivers, and patients. The overall consensus of the NLP-CDS workshop was that there are promising opportunities for NLP and CDS to deliver cognitive support for healthcare professionals, caregivers, and patients. C1 [Pai, Vinay M.; Rodgers, Mary; Conroy, Richard; Luo, James; Zhou, Ruixia; Seto, Belinda] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Rodgers, Mary] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Pai, VM (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, 6707 Democracy Blvd,Ste 200, Bethesda, MD 20892 USA. EM paiv@mail.nih.gov RI Conroy, Richard/D-1979-2009 OI Conroy, Richard/0000-0002-8896-6090 FU National Institutes of Health FX National Institutes of Health. NR 28 TC 3 Z9 3 U1 0 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD FEB PY 2014 VL 21 IS E1 BP E2 EP E5 DI 10.1136/amiajnl-2013-001896 PG 4 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4UM UT WOS:000337672800002 PM 23921193 ER PT J AU Alao, H Liang, TJ AF Alao, Hawwa Liang, T. Jake TI Alternative interferons and immunomodulators in the treatment of hepatitis C SO LIVER INTERNATIONAL LA English DT Review DE antiviral drug development; innate immunity; interferon enhancer; toll-like receptors ID VIRUS-INFECTION; CLINICAL-TRIAL; ALBINTERFERON ALPHA-2B; CONSENSUS INTERFERON; RANDOMIZED-TRIAL; INNATE IMMUNITY; DOUBLE-BLIND; GENOTYPE 1; PHASE 1B; RIBAVIRIN AB Interferon- (IFN-) has been the mainstay of therapy for hepatitis C and is currently being combined with other drugs to improve the response rate. Newer therapeutic regimens are being developed to spare the use of IFN because of the important side effects associated with IFN-based therapy. However, there may still be a need for the use of IFN in certain populations. In addition, agents that mimic the actions of IFN but with fewer side effects may still be of major value. This review focuses on the development of alternative and new forms of IFNs and other immunomodulatory agents that may supplant IFN- in combination therapy for hepatitis C. C1 [Alao, Hawwa; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10-9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM jakel@bdlg10.niddk.nih.gov FU NIH FX NIH Funding. NR 42 TC 2 Z9 2 U1 0 U2 2 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 FEB PY 2014 VL 34 SU 1 SI SI BP 133 EP 138 DI 10.1111/liv.12402 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ2WA UT WOS:000337524000021 PM 24373090 ER PT J AU Leifer, ES Brawner, CA Fleg, JL Kraus, WE Whellan, DJ Pina, IL Keteyian, SJ AF Leifer, Eric S. Brawner, Clinton A. Fleg, Jerome L. Kraus, William E. Whellan, David J. Pina, Ileana L. Keteyian, Steven J. TI Are There Negative Responders to Exercise Training among Heart Failure Patients? SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE AEROBIC CAPACITY; TRAINING PROGRAM; RESPONSE VARIABILITY; NEGATIVE THRESHOLD ID TRIAL INVESTIGATING OUTCOMES; HERITAGE FAMILY; HF-ACTION; REPRODUCIBILITY; UPDATE; HEALTH AB Purpose: Aerobic exercise training has been used in patients with stable heart failure (HF) to reduce the risk of clinical events. However, due to patient heterogeneity, some patients may experience a decrease in functional capacity due to such training. The purpose of this study was to estimate the proportion of HF patients participating in a training program who had negative responses to such therapy and to compare them with a concurrent control group. Methods: Baseline and 3-month peak (V) over dotO(2) measurements were obtained on 1870 HF subjects who were randomized to receive either an exercise training program or a control program of usual care without exercise training. The exercise program consisted of supervised walking or stationary cycling 3 d.wk(-1) for 12 wk as well as a 2-d.wk(-1) home exercise program after completing 18 supervised sessions. A negative response was defined as a baseline-to-3-month decrease in peak (V) over dotO(2) of at least 5 mL.kg(-1).min(-1), which was two times the SD of the control group's change in peak (V) over dotO(2). Results: The mean T SD change in peak (V) over dotO(2) in the exercise group and control group was 0.8 +/- 2.5 mL.kg(-1).min(-1) and 0.2 +/- 2.5 mL.kg(-1).min(-1), respectively (P < 0.001). The percentage of negative responders in the exercise and control groups was 0.9% and 2.3% (P = 0.02). Conclusions: The low negative response rate in the exercise group combined with the slightly higher rate in the control group and equal variability in the exercise and control groups suggests that few if any subjects had training-related negative peak (V) over dotO(2) responses. These findings support current exercise recommendations for HF patients. C1 [Leifer, Eric S.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Brawner, Clinton A.; Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Med, Bethesda, MD 20892 USA. [Kraus, William E.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Philadelphia, PA 19107 USA. [Pina, Ileana L.] Albert Einstein Coll Med, Div Cardiol, Bronx, NY 10467 USA. RP Keteyian, SJ (reprint author), Henry Ford Hosp, 6525 Second Ave, Detroit, MI 48202 USA. EM sketeyi1@hfhs.org OI Brawner, Clinton A./0000-0002-1705-6620 FU National Heart, Lung, and Blood Institute FX The HF-ACTION trial was supported by grants from the National Heart, Lung, and Blood Institute. The authors thank the HF-ACTION participants and investigators who gave their time and effort to completion of the study. The authors also thank Drs. Nancy Geller, Michael Lauer, and James Troendle for their critical review of the manuscript. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 14 TC 3 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2014 VL 46 IS 2 BP 219 EP 224 DI 10.1249/MSS.0b013e3182a44164 PG 6 WC Sport Sciences SC Sport Sciences GA AJ4ZB UT WOS:000337688000002 PM 23860416 ER PT J AU Gibbs, BB Reis, JP Schelbert, EB Craft, LL Sidney, S Lima, J Lewis, CE AF Gibbs, Bethany Barone Reis, Jared P. Schelbert, Erik B. Craft, Lynette L. Sidney, Steve Lima, Joao Lewis, Cora E. TI Sedentary Screen Time and Left Ventricular Structure and Function: The CARDIA Study SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE LEFT VENTRICULAR MASS; SEDENTARY TIME; RACE DIFFERENCES; ECHOCARDIOGRAPHY ID RELATIVE WALL THICKNESS; WHITE ADULT MEN; PHYSICAL-ACTIVITY; CARDIOVASCULAR EVENTS; RISK-FACTORS; LIFE-STYLE; BED REST; MASS; OBESITY; HYPERTROPHY AB Introduction: Sedentary screen time (watching TV or using a computer) predicts cardiovascular outcomes independently from moderate and vigorous physical activity and could affect left ventricular structure and function through the adverse consequences of sedentary behavior. Purpose: This study aimed to determine whether sedentary screen time is associated with measures of left ventricular structure and function. Methods: The Coronary Artery Risk Development in Young Adults Study measured screen time by questionnaire and left ventricular structure and function by echocardiography in 2854 black and white participants, age 43-55 yr, in 2010-2011. Generalized linear models evaluated cross-sectional trends for echocardiography measures across higher categories of screen time and adjusting for demographics, smoking, alcohol, and physical activity. Further models adjusted for potential intermediate factors (blood pressure, antihypertensive medication use, diabetes, and body mass index). Results: The relationship between screen time and left ventricular mass (LVM) differed in blacks versus whites. Among whites, higher screen time was associated with larger LVM (P < 0.001), after adjustment for height, demographics, and lifestyle variables. Associations between screen time and LVM persisted when adjusting for blood pressure, antihypertensive medication use, and diabetes (P = 0.008) but not with additional adjustment for body mass index (P = 0.503). Similar relationships were observed for screen time with LVM indexed to height(2.7), relative wall thickness, and mass-to-volume ratio. Screen time was not associated with left ventricular structure among blacks or left ventricular function in either race group. Conclusions: Sedentary screen time is associated with greater LVM in white adults, and this relationship was largely explained by higher overall adiposity. The lack of association in blacks supports a potential qualitative difference in the cardiovascular consequences of sedentary screen-based behavior. C1 [Gibbs, Bethany Barone; Schelbert, Erik B.] Univ Pittsburgh, Pittsburgh, PA 15203 USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Craft, Lynette L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sidney, Steve] Kaiser Permanente Div Res, Oakland, CA USA. [Lima, Joao] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. RP Gibbs, BB (reprint author), Univ Pittsburgh, Phys Act & Weight Management Res Ctr, 2100 Wharton St,Suite 600, Pittsburgh, PA 15203 USA. EM bbarone@pitt.edu FU Coordinating Center, University of Alabama at Birmingham [N01-HC-95095]; Field Center, University of Alabama [N01-HC-48047]; Field Center and Diet Reading Center, University of Minnesota [N01-HC-48048]; Northwestern University Field Center [N01-HC-48049]; Kaiser Foundation Research Institute from the National Heart, Lung, and Blood Institute [N01-HC-48050]; National Heart, Lung, and Blood Institute [R01-HL-086792] FX This study was supported by the Coordinating Center, University of Alabama at Birmingham (grant no. N01-HC-95095); the Field Center, University of Alabama (grant no. N01-HC-48047); the Field Center and Diet Reading Center, University of Minnesota (grant no. N01-HC-48048); the Northwestern University Field Center (grant no. N01-HC-48049); and the Kaiser Foundation Research Institute (grant no. N01-HC-48050) from the National Heart, Lung, and Blood Institute. The CARDIA ECG Ancillary Study was supported by the National Heart, Lung, and Blood Institute (grant no. R01-HL-086792). NR 40 TC 9 Z9 9 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2014 VL 46 IS 2 BP 276 EP 283 DI 10.1249/MSS.0b013e3182a4df33 PG 8 WC Sport Sciences SC Sport Sciences GA AJ4ZB UT WOS:000337688000009 PM 23863618 ER PT J AU Melanson, E Keadle, SK Donnelly, JE Braun, B King, NA AF Melanson, Edward Keadle, Sarah Kozy Donnelly, Joseph E. Braun, Barry King, Neal A. TI Substitution and Compensation Erode the Energy Deficit from Exercise Interventions Response SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Letter ID PHYSICAL-ACTIVITY; MEN; WEIGHT; WOMEN; TIME C1 [Melanson, Edward] Univ Colorado, Aurora, CO 80045 USA. [Keadle, Sarah Kozy] NCI, Bethesda, MD 20892 USA. [Donnelly, Joseph E.] Univ Kansas, Lawrence, KS 66045 USA. [Braun, Barry] Univ Massachusetts, Amherst, MA 01003 USA. [King, Neal A.] Queensland Univ Technol, Brisbane, Qld 4001, Australia. RP Melanson, E (reprint author), Univ Colorado, Anschutz Med Campus, Aurora, CO 80045 USA. FU NCATS NIH HHS [UL1 TR001082]; NCRR NIH HHS [UL1 RR025780]; NHLBI NIH HHS [RC1 HL099557]; NIDDK NIH HHS [R01 DK077088] NR 7 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2014 VL 46 IS 2 BP 424 EP 424 DI 10.1249/MSS.0000000000000165 PG 1 WC Sport Sciences SC Sport Sciences GA AJ4ZB UT WOS:000337688000027 PM 24435074 ER PT J AU Buse, E Haeger, JD Svensson-Arvelund, J Markert, UR Faas, MM Ernerudh, J Dixon, D Cline, JM Pfarrer, C AF Buse, Eberhard Haeeger, Jan-Dirk Svensson-Arvelund, Judit Markert, Udo R. Faas, Marijke M. Ernerudh, Jan Dixon, Darlene Cline, J. Mark Pfarrer, Christiane TI The Placenta in Toxicology. Part I: Animal Models in Toxicology: Placental Morphology and Tolerance Molecules in the Cynomolgus Monkey (Macaca fascicularis) SO TOXICOLOGIC PATHOLOGY LA English DT Review DE cynomolgus monkey; animal models; placental morphology; HLA; FAS-ligand; IDO; annexin II ID INDOLEAMINE 2,3-DIOXYGENASE; HLA-G; TRYPTOPHAN CATABOLISM; ANNEXIN II; EXTRAVILLOUS TROPHOBLAST; IMMUNE PRIVILEGE; CORROSION CAST; UP-REGULATION; FAS LIGAND; T-CELLS AB The immune system represents a key defense mechanism against potential pathogens and adverse non-self materials. During pregnancy, the placenta is the point of contact between the maternal organism and non-self proteins of the fetal allograft and hence undoubtedly fulfils immune functions. In the placenta bacteria, foreign (non-self) proteins and proteins that might be introduced in toxicological studies or by medication are barred from reaching the progeny, and the maternal immune system is primed for acceptance of non-maternal fetal protein. Both immunologic protection of the fetus and acceptance of the fetus by the mother require effective mechanisms to prevent an immunologic fetomaternal conflict and to keep both organisms in balance. This is why the placenta requires toxicological consideration in view of its immune organ function. The following articles deal with placenta immune-, control-, and tolerance mechanisms in view of both fetal and maternal aspects. Furthermore, models for experimental access to placental immune function are addressed and the pathological evaluation is elucidated. "The Placenta as an Immune Organ and Its Relevance in Toxicological Studies'' was subject of a continuing education course at the 2012 Society of Toxicologic Pathology meeting held in Boston, MA. C1 [Buse, Eberhard] Covance Labs GmbH, D-48163 Munster, Germany. [Haeeger, Jan-Dirk; Pfarrer, Christiane] Univ Vet Med, Dept Anat, Hannover, Germany. [Svensson-Arvelund, Judit; Ernerudh, Jan] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. [Markert, Udo R.] Univ Hosp, Dept Obstet, Placenta Lab, Jena, Germany. [Faas, Marijke M.] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Div Med Biol, NL-9700 AB Groningen, Netherlands. [Dixon, Darlene] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. [Cline, J. Mark] Wake Forest Sch Med, Dept Pathol, Comparat Med Sect, Winston Salem, NC USA. RP Buse, E (reprint author), Covance Labs GmbH, Kesselfeld 29, D-48163 Munster, Germany. EM e.h.buse@googlemail.com RI Haeger, Jan-Dirk/B-6893-2016; OI Svensson-Arvelund, Judit/0000-0002-6260-0808 NR 82 TC 2 Z9 2 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2014 VL 42 IS 2 BP 314 EP 326 DI 10.1177/0192623313482208 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ4ES UT WOS:000337625300003 PM 23548606 ER PT J AU Svensson-Arvelund, J Ernerudh, J Buse, E Cline, JM Haeger, JD Dixon, D Markert, UR Pfarrer, C De Vos, P Faas, MM AF Svensson-Arvelund, Judit Ernerudh, Jan Buse, Eberhard Cline, J. Mark Haeger, Jan-Dirk Dixon, Darlene Markert, Udo R. Pfarrer, Christiane De Vos, Paul Faas, Marijke M. TI The Placenta in Toxicology. Part II: Systemic and Local Immune Adaptations in Pregnancy SO TOXICOLOGIC PATHOLOGY LA English DT Article DE pregnancy; immune regulation; tolerance; leukocytes; decidua; placenta ID NATURAL-KILLER-CELLS; REGULATORY T-CELLS; MATERNAL-FETAL INTERFACE; DECIDUAL NK CELLS; ADENOSINE DIPHOSPHATASE ACTIVITY; HUMAN CHORIONIC-GONADOTROPIN; LYMPHOID DENDRITIC CELLS; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; LOW-DOSE ENDOTOXIN AB During pregnancy, the maternal immune system is challenged by the semiallogeneic fetus, which must be tolerated without compromising fetal or maternal health. This review updates the systemic and local immune changes taking place during human pregnancy, including some examples in rodents. Systemic changes are induced by contact of maternal blood with placental factors and include enhanced innate immunity with increased activation of granulocytes and nonclassical monocytes. Although a bias toward T helper (Th2) and regulatory T cell (Treg) immunity has been associated with healthy pregnancy, the relationship between different circulating Th cell subsets is not straightforward. Instead, these adaptations appear most evidently at the fetal-maternal interface, where for instance Tregs are enriched and promote fetal tolerance. Also innate immune cells, that is, natural killer cells and macrophages, are enriched, constituting the majority of decidual leukocytes. These cells not only contribute to immune regulation but also aid in establishing the placenta by promoting trophoblast recruitment and angiogenesis. Thus, proper interaction between leukocytes and placental trophoblasts is necessary for normal placentation and immune adaptation. Consequently, spontaneous maladaptation or interference of the immune system with toxic substances may be important contributing factors for the development of pregnancy complications such as preeclampsia, preterm labor, and recurrent miscarriages. C1 [Svensson-Arvelund, Judit; Ernerudh, Jan] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. [Buse, Eberhard] Covance Labs, Munster, Germany. [Cline, J. Mark] Wake Forest Sch Med, Comparat Med Sect, Dept Pathol, Winston Salem, NC USA. [Haeger, Jan-Dirk; Pfarrer, Christiane] Univ Vet Med, Dept Anat, Hannover, Germany. [Dixon, Darlene] NIEHS, NTP, NTP Lab, Res Triangle Pk, NC 27709 USA. [Markert, Udo R.] Univ Hosp, Dept Obstet, Placenta Lab, Jena, Germany. [De Vos, Paul; Faas, Marijke M.] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Div Med Biol, NL-9713 AV Groningen, Netherlands. [De Vos, Paul; Faas, Marijke M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. RP Svensson-Arvelund, J (reprint author), Linkoping Univ, AIR, Dept Clin & Expt Med, Fac Hlth Sci, Patologihuset Plan 10, S-58185 Linkoping, Sweden. EM judit.svensson@liu.se RI Haeger, Jan-Dirk/B-6893-2016; OI Svensson-Arvelund, Judit/0000-0002-6260-0808 NR 162 TC 17 Z9 17 U1 2 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2014 VL 42 IS 2 BP 327 EP 338 DI 10.1177/0192623313482205 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ4ES UT WOS:000337625300004 PM 23531796 ER PT J AU Cline, JM Dixon, D Ernerudh, J Faas, MM Gohner, C Hager, JD Markert, UR Pfarrer, C Svensson-Arvelund, J Buse, E AF Cline, J. Mark Dixon, Darlene Ernerudh, Jan Faas, Marijke M. Goehner, Claudia Haeger, Jan-Dirk Markert, Udo R. Pfarrer, Christiane Svensson-Arvelund, Judit Buse, Eberhard TI The Placenta in Toxicology. Part III: Pathologic Assessment of the Placenta SO TOXICOLOGIC PATHOLOGY LA English DT Article DE macaca; mus; rodent pathology; primate pathology; placenta; toxicology ID RAT PLACENTA; FETAL; PREGNANCY; MICE; EXPRESSION; MORPHOLOGY; GESTATION; MACAQUE; LESIONS; WEIGHT AB This short review is derived from the peer-reviewed literature and the experience and case materials of the authors. Brief illustrated summaries are presented on the gross and histologic normal anatomy of rodent and macaque placentas, including typical organ weights, with comments on differences from the human placenta. Common incidental findings, background lesions, and induced toxic lesions are addressed, and a recommended strategy for pathologic evaluation of placentas is provided. C1 [Cline, J. Mark] Wake Forest Sch Med, Comparat Med Sect, Dept Pathol, Winston Salem, NC 27157 USA. [Dixon, Darlene] NIEHS, NTP, NTP Lab, Res Triangle Pk, NC 27709 USA. [Ernerudh, Jan; Svensson-Arvelund, Judit] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden. [Faas, Marijke M.] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Div Med Biol, Groningen, Netherlands. [Goehner, Claudia; Markert, Udo R.] Univ Hosp Jena, Dept Obstet, Placenta Lab, Jena, Germany. [Haeger, Jan-Dirk; Pfarrer, Christiane] Univ Vet Med Hannover, Dept Anat, Hannover, Germany. [Buse, Eberhard] Covance Labs GmbH, Munster, Germany. RP Cline, JM (reprint author), Wake Forest Sch Med, Comparat Med Sect, Dept Pathol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jmcline@wakehealth.edu RI Haeger, Jan-Dirk/B-6893-2016; OI Svensson-Arvelund, Judit/0000-0002-6260-0808; Gohner, Claudia/0000-0001-9309-914X NR 28 TC 0 Z9 0 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2014 VL 42 IS 2 BP 339 EP 344 DI 10.1177/0192623313482207 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ4ES UT WOS:000337625300005 PM 23531795 ER PT J AU Gohner, C Svensson-Arvelund, J Pfarrer, C Hager, JD Faas, M Ernerudh, J Cline, JM Dixon, D Buse, E Markert, UR AF Goehner, Claudia Svensson-Arvelund, Judit Pfarrer, Christiane Haeger, Jan-Dirk Faas, Marijke Ernerudh, Jan Cline, J. Mark Dixon, Darlene Buse, Eberhard Markert, Udo R. TI The Placenta in Toxicology. Part IV: Battery of Toxicological Test Systems Based on Human Placenta SO TOXICOLOGIC PATHOLOGY LA English DT Article DE trophoblast; placenta; placenta perfusion; placenta explant; choriocarcinoma; human toxicology ID HUMAN CHORIOCARCINOMA CELLS; HUMAN TROPHOBLAST; BISPHENOL-A; IN-VIVO; EXPRESSION; PERFUSION; JEG-3; ACCUMULATION; METABOLISM; TRANSPORT AB This review summarizes the potential and also some limitations of using human placentas, or placental cells and structures for toxicology testing. The placenta contains a wide spectrum of cell types and tissues, such as trophoblast cells, immune cells, fibroblasts, stem cells, endothelial cells, vessels, glands, membranes, and many others. It may be expected that in many cases the relevance of results obtained from human placenta will be higher than those from animal models due to species specificity of metabolism and placental structure. For practical and economical reasons, we propose to apply a battery of sequential experiments for analysis of potential toxicants. This should start with using cell lines, followed by testing placenta tissue explants and isolated placenta cells, and finally by application of single and dual side ex vivo placenta perfusion. With each of these steps, the relative workload increases while the number of feasible repeats decreases. Simultaneously, the predictive power enhances by increasing similarity with in vivo human conditions. Toxic effects may be detected by performing proliferation, vitality and cell death assays, analysis of protein and hormone expression, immunohistochemistry or testing functionality of signaling pathways, gene expression, transport mechanisms, and so on. When toxic effects appear at any step, the subsequent assays may be cancelled. Such a system may be useful to reduce costs and increase specificity in testing questionable toxicants. Nonetheless, it requires further standardization and end point definitions for better comparability of results from different toxicants and to estimate the respective in vivo translatability and predictive value. C1 [Goehner, Claudia; Markert, Udo R.] Univ Hosp, Dept Obstet, Placenta Lab, Jena, Germany. [Svensson-Arvelund, Judit; Ernerudh, Jan] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. [Pfarrer, Christiane; Haeger, Jan-Dirk] Univ Vet Med Hannover, Dept Anat, Hannover, Germany. [Faas, Marijke] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Div Med Biol, Groningen, Netherlands. [Cline, J. Mark] Wake Forest Sch Med, Comparat Med Sect, Dept Pathol, Winston Salem, NC USA. [Dixon, Darlene] NIEHS, NTP, NTP Lab, Res Triangle Pk, NC 27709 USA. [Buse, Eberhard] Covance Labs, Munster, Germany. RP Markert, UR (reprint author), Univ Jena, Ernst Abbe Pl 8, D-07743 Jena, Germany. EM udo.markert@med.uni-jena.de RI Haeger, Jan-Dirk/B-6893-2016; OI Svensson-Arvelund, Judit/0000-0002-6260-0808; Gohner, Claudia/0000-0001-9309-914X FU German Ministry of Research (BMBF) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CG is supported by a research grant from the German Ministry of Research (BMBF). NR 59 TC 2 Z9 2 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2014 VL 42 IS 2 BP 345 EP 351 DI 10.1177/0192623313482206 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ4ES UT WOS:000337625300006 PM 23548605 ER PT J AU Cesta, MF Malarkey, DE Herbert, RA Brix, A Hamlin, MH Singletary, E Sills, RC Bucher, JR Birnbaum, LS AF Cesta, Mark F. Malarkey, David E. Herbert, Ronald A. Brix, Amy Hamlin, Melvin H., II Singletary, Emily Sills, Robert C. Bucher, John R. Birnbaum, Linda S. TI The National Toxicology Program Web-based Nonneoplastic Lesion Atlas: A Global Toxicology and Pathology Resource SO TOXICOLOGIC PATHOLOGY LA English DT Article DE National Toxicology Program; NTP; atlas; nonneoplastic lesion; toxicologic pathology ID EXPOSURE AB Toxicologists and pathologists worldwide will benefit from a new, website-based, and completely searchable Nonneoplastic Lesion Atlas just released by the U. S. National Toxicology Program (NTP). The atlas is a much-needed resource with thousands of high-quality, zoomable images and diagnostic guidelines for each rodent lesion. Liver, gallbladder, nervous system, bone marrow, lower urinary tract and skin lesion images, and diagnostic strategies are available now. More organ and biological systems will be added with a total of 22 chapters planned for the completed project. The atlas will be used by the NTP and its many pathology partners to standardize lesion diagnosis, terminology, and the way lesions are recorded. The goal is to improve our understanding of nonneoplastic lesions and the consistency and accuracy of their diagnosis between pathologists and laboratories. The atlas is also a useful training tool for pathology residents and can be used to bolster any organization's own lesion databases. Researchers have free access to this online resource at http://ntp.niehs.nih.gov/nnl. C1 [Cesta, Mark F.; Malarkey, David E.; Herbert, Ronald A.; Sills, Robert C.; Bucher, John R.; Birnbaum, Linda S.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Brix, Amy; Hamlin, Melvin H., II; Singletary, Emily] Expt Pathol Labs Inc, Durham, NC 27713 USA. RP Cesta, MF (reprint author), NIEHS, Cellular & Mol Pathol Branch, POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. EM cesta@niehs.nih.gov FU Division of the National Toxicology Program. of the NIH, National Institute of Environmental Health Sciences (NIEHS) 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 Division of the National Toxicology Program. of the NIH, National Institute of Environmental Health Sciences (NIEHS). NR 9 TC 4 Z9 4 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2014 VL 42 IS 2 BP 458 EP 460 DI 10.1177/0192623313517304 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ4ES UT WOS:000337625300015 PM 24488020 ER PT J AU Ruiz, A Heilmann, S Becker, T Hernandez, I Wagner, H Thelen, M Mauleon, A Rosende-Roca, M Bellenguez, C Bis, JC Harold, D Gerrish, A Sims, R Sotolongo-Grau, O Espinosa, A Alegret, M Arrieta, JL Lacour, A Leber, M Becker, J Lafuente, A Ruiz, S Vargas, L Rodriguez, O Ortega, G Dominguez, MA Mayeux, R Haines, JL Pericak-Vance, MA Farrer, LA Schellenberg, GD Chouraki, V Launer, LJ van Duijn, C Seshadri, S Antunez, C Breteler, MM Serrano-Rios, M Jessen, F Tarraga, L Nothen, MM Maier, W Boada, M Ramirez, A AF Ruiz, A. Heilmann, S. Becker, T. Hernandez, I. Wagner, H. Thelen, M. Mauleon, A. Rosende-Roca, M. Bellenguez, C. Bis, J. C. Harold, D. Gerrish, A. Sims, R. Sotolongo-Grau, O. Espinosa, A. Alegret, M. Arrieta, J. L. Lacour, A. Leber, M. Becker, J. Lafuente, A. Ruiz, S. Vargas, L. Rodriguez, O. Ortega, G. Dominguez, M-A Mayeux, R. Haines, J. L. Pericak-Vance, M. A. Farrer, L. A. Schellenberg, G. D. Chouraki, V. Launer, L. J. van Duijn, C. Seshadri, S. Antunez, C. Breteler, M. M. Serrano-Rios, M. Jessen, F. Tarraga, L. Noethen, M. M. Maier, W. Boada, M. Ramirez, A. CA IGAP TI Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE dementia risk; DNA; GWAS; molecular epidemiology; SNP; thyroid receptor ID WIDE ASSOCIATION; COMMON VARIANTS; POPULATION; CD2AP; EPHA1; CD33; APOE; CLU; AD AB To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundacio ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P = 0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio = 1.31; confidence interval 95% (1.19-1.44); P = 9.74 x 10(-9)). C1 [Ruiz, A.; Hernandez, I.; Mauleon, A.; Rosende-Roca, M.; Sotolongo-Grau, O.; Espinosa, A.; Alegret, M.; Lafuente, A.; Ruiz, S.; Vargas, L.; Rodriguez, O.; Ortega, G.; Dominguez, M-A; Tarraga, L.; Boada, M.] Inst Catala Neurociencies Aplicades, Memory Clin, Fundacio ACE, Barcelona, Spain. [Heilmann, S.; Noethen, M. M.; Ramirez, A.] Univ Bonn, Inst Human Genet, D-53105 Bonn, Germany. [Heilmann, S.; Noethen, M. M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-53105 Bonn, Germany. [Becker, T.; Lacour, A.; Leber, M.; Breteler, M. M.; Jessen, F.; Maier, W.] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Becker, T.] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-53105 Bonn, Germany. [Wagner, H.; Thelen, M.; Becker, J.; Jessen, F.; Maier, W.; Ramirez, A.] Univ Bonn, Dept Psychiat & Psychotherapy, D-53105 Bonn, Germany. [Bellenguez, C.] INSERM, U744, F-59045 Lille, France. [Bellenguez, C.] Univ Lille 2, Lille, France. [Bellenguez, C.] Inst Pasteur, F-59019 Lille, France. [Bis, J. C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Harold, D.; Gerrish, A.; Sims, R.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Arrieta, J. L.] Univ Hosp La Paz Cantoblanco, Memory Unit, Madrid, Spain. [Mayeux, R.] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA. [Mayeux, R.] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA. [Haines, J. L.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Haines, J. L.] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN 37235 USA. [Pericak-Vance, M. A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Pericak-Vance, M. A.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Med Biomed Genet, Boston, MA USA. [Farrer, L. A.] Boston Univ, Dept Ophthalmol, Sch Publ Hlth, Boston, MA USA. [Farrer, L. A.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, L. A.; Chouraki, V.; Seshadri, S.; Noethen, M. M.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Schellenberg, G. D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Launer, L. J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [van Duijn, C.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [van Duijn, C.] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands. [van Duijn, C.] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands. [van Duijn, C.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [van Duijn, C.] Ctr Med Syst Biol, Leiden, Netherlands. [Antunez, C.] Univ Hosp Virgen de la Arrixaca, Dementia Unit, Murcia, Spain. [Serrano-Rios, M.] Hosp Clin San Carlos, CIBERDEM Spain, Madrid, Spain. [Boada, M.] Univ Autonoma Barcelona VHIR UAB, Hosp Univ Vall dHebron, Inst Recerca, Barcelona, Spain. RP Ramirez, A (reprint author), Univ Bonn, Dept Psychiat & Psychotherapy, Sigmund Freud Str 25, D-53105 Bonn, Germany. EM alfredo.ramirez@ukb.uni-bonn.de RI Breteler, Monique /J-5058-2014; OI Sotolongo-Grau, Oscar/0000-0002-9679-0670; Farrer, Lindsay/0000-0001-5533-4225; Seshadri, Sudha/0000-0001-6135-2622; Chouraki, Vincent/0000-0002-4698-1794; Harold, Denise/0000-0001-5195-0143; Lacour, Andre/0000-0003-2692-2583; Nothen, Markus/0000-0002-8770-2464 FU Fundacio ACE research programs; CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERNED are Instituto de Salud Carlos III ISCIII Projects FX We thank all patients and controls for their participation in this project. We thank all of the investigators from the International Genomics of Alzheimer Project (IGAP) consortium for their close collaboration and intellectual input, and for sharing their pre-publication data in order to permit rapid completion of this research work. The IGAP comprises four major Alzheimer's disease research groups: the Alzheimer Disease Genetics Consortium (ADGC); the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE); the European Initiative for Alzheimer Disease (EADI); and the Genetic and Environmental Risk in Alzheimer's Disease (GERAD). We are indebted to Trinitat Port-Carbo and her family for their support of the Fundacio ACE research programs. Fundacio ACE collaborates with the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The Diabetes Research Laboratory, Biomedical Research Foundation at University Hospital Clnico San Carlos received support from CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM). CIBERDEM and CIBERNED are Instituto de Salud Carlos III ISCIII Projects. Agustin Ruiz is supported by grant PI13/02434 (Accion Estrategica en Salud. Instituto de Salud Carlos III (ISCIII). Ministerio de Economia y Competitividad, Spain). Tim Becker and Markus M Nothen are members of the DFG-funded Excellence Cluster ImmunoSensation. This study was funded in part by the National institute of Health (NIH) project AG033193 to CHARGE. This publication was funded in part by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). NR 19 TC 23 Z9 23 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD FEB PY 2014 VL 4 AR e358 DI 10.1038/tp.2014.2 PG 4 WC Psychiatry SC Psychiatry GA AJ2RP UT WOS:000337508200003 PM 24495969 ER PT J AU McDermott, MM Liu, KA Ferrucci, L Tian, L Guralnik, J Kopp, P Van Horn, L Liao, YH Green, D Kibbe, M Sufit, R Zhao, LH Criqui, MH AF McDermott, Mary M. Liu, Kiang Ferrucci, Luigi Tian, Lu Guralnik, Jack Kopp, Peter Van Horn, Linda Liao, Yihua Green, David Kibbe, Melina Sufit, Robert Zhao, Lihui Criqui, Michael H. TI Vitamin D status, functional decline, and mortality in peripheral artery disease SO VASCULAR MEDICINE LA English DT Article DE exercise; intermittent claudication; peripheral arterial disease; peripheral vascular diseases; walking ID ANKLE BRACHIAL INDEX; SERUM 25-HYDROXYVITAMIN D; LOWER-EXTREMITY ISCHEMIA; 1,25-DIHYDROXYVITAMIN-D3 RECEPTORS; PHYSICAL-ACTIVITY; BLOOD-PRESSURE; OLDER-ADULTS; MUSCLE; RISK; ASSOCIATION AB Associations of vitamin D levels with prospectively measured functional decline and mortality in people with lower extremity peripheral artery disease (PAD) are unknown. We determined whether lower baseline vitamin D levels are associated with a faster decline in functional performance and higher mortality among people with and without PAD. A total of 658 participants (395 with PAD) underwent baseline measurement of 25-hydroxyvitamin D (DiaSorin radioimmunoassay), a 6-minute walk test, 4-meter walking velocity and the Short Physical Performance Battery (SPPB), and were followed annually for up to 4 years. Analyses were adjusted for age, sex, race, body mass index, comorbidities, the ankle-brachial index, and other confounders. Among participants with PAD, lower baseline vitamin D levels were associated with a faster decline in the 6-minute walk (vitamin D < 30 nmol/L: -70.0 feet/year; vitamin D 30 to < 50 nmol/L: -72.3 feet/year; vitamin D 50 to < 75 nmol/L: -35.5 feet/year; vitamin D 75 to < 120 nmol/L: -35.9 feet/year; p trend=0.012). PAD participants with vitamin D < 30 nmol/L had a faster decline in the SPPB and 6-minute walk compared to those with levels of 50 to < 75 (p=0.034 and p=0.04, respectively). Among participants without PAD, lower vitamin D was associated with a faster decline in the fast 4-meter walking velocity (p trend=0.003). There were no significant associations of baseline vitamin D levels with all-cause or cardiovascular disease mortality in PAD or non-PAD participants. In conclusion, among individuals with and without PAD, low vitamin D status was associated with a faster decline in some measures of functional performance but was not related to mortality. C1 [McDermott, Mary M.; Liu, Kiang; Kopp, Peter; Van Horn, Linda; Liao, Yihua; Green, David; Kibbe, Melina; Sufit, Robert; Zhao, Lihui] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Tian, Lu] Stanford Univ, Palo Alto, CA 94304 USA. [Guralnik, Jack] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, 750 Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute; Office of Dietary Supplements, National Institutes of Health (Bethesda, MD, USA) [R01-HL096849]; National Institute on Aging (Bethesda, MD, USA) FX Funded by the National Heart, Lung, and Blood Institute and by the Office of Dietary Supplements, National Institutes of Health (R01-HL096849) (Bethesda, MD, USA). Supported by the National Institute on Aging (Bethesda, MD, USA). NR 30 TC 5 Z9 5 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD FEB PY 2014 VL 19 IS 1 BP 18 EP 26 DI 10.1177/1358863X13518364 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ3PO UT WOS:000337579400003 PM 24442622 ER PT J AU Smith, JA Colbert, RA AF Smith, Judith A. Colbert, Robert A. TI The Interleukin-23/Interleukin-17 Axis in Spondyloarthritis Pathogenesis Th17 and Beyond SO ARTHRITIS & RHEUMATOLOGY LA English DT Review ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; HLA-B27 TRANSGENIC RATS; PLACEBO-CONTROLLED TRIAL; T-HELPER-CELLS; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; SOCIETY CLASSIFICATION CRITERIA; PRONE HLA-B27-TRANSGENIC RATS; INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION C1 [Smith, Judith A.] Univ Wisconsin, Madison, WI 53706 USA. [Colbert, Robert A.] NIAMSD, Bethesda, MD 20892 USA. RP Colbert, RA (reprint author), NIAMSD, Pediat Translat Res Branch, NIH, CRC, Bldg 10,Room 1-5142,10 Ctr Dr,MSC 1102, Bethesda, MD 20892 USA. EM colbertr@mail.nih.gov FU Rheumatology Research Foundation; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [Z01-AR-041184] FX Dr. Smith's work was supported by the Rheumatology Research Foundation (Disease Targeted Research pilot grant and Disease Targeted Innovative Research grant). Dr. Colbert's work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program grant Z01-AR-041184). NR 132 TC 30 Z9 34 U1 2 U2 10 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 FEB PY 2014 VL 66 IS 2 BP 231 EP 241 DI 10.1002/art.38291 PG 11 WC Rheumatology SC Rheumatology GA AJ0PQ UT WOS:000337357900001 PM 24504793 ER PT J AU Terrier, B Nagata, S Ise, T Rosenzwajg, M Pastan, I Klatzmann, D Saadoun, D Cacoub, P AF Terrier, Benjamin Nagata, Satoshi Ise, Tomoko Rosenzwajg, Michelle Pastan, Ira Klatzmann, David Saadoun, David Cacoub, Patrice TI CD21(-/low) Marginal Zone B Cells Highly Express Fc Receptor-like 5 Protein and Are Killed by Anti-Fc Receptor-like 5 Immunotoxins in Hepatitis C Virus-Associated Mixed Cryoglobulinemia Vasculitis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; HCV-INFECTED PATIENTS; II CRYOGLOBULINEMIA; RECOMBINANT IMMUNOTOXIN; VILLOUS LYMPHOCYTES; MULTIPLE-MYELOMA; SPLENIC LYMPHOMA; MALIGNANT-CELLS; MOLECULES; EXPANSION AB Objective. Hepatitis C virus (HCV) is associated with B cell lymphoproliferative disorders, including mixed cryoglobulinemia (MC) vasculitis and B cell non-Hodgkin's lymphoma. The expansion of clonal and autoreactive rheumatoid factor-bearing CD21(-/low) marginal zone (MZ) B cells was demonstrated in patients with HCV-associated MC vasculitis. Fc receptor-like (FCRL) proteins comprise a family of immunoregulatory proteins preferentially expressed on B lineage cells. The goal of this study was to investigate the expression of FCRL proteins 1-5 on B cells from patients with HCV-associated MC vasculitis. Methods. Expression of FCRL proteins 1-5 was assessed by flow cytometry on B cells from 15 HCV-infected patients with type II MC (7 of whom had B cell non-Hodgkin's lymphoma), 20 HCV-infected patients without MC, and 20 healthy donors. To evaluate FCRL-5 as an immunotherapy target in HCV-associated MC vasculitis, 2 anti-FCRL-5 recombinant immunotoxins were produced using anti-FCRL-5 monoclonal antibodies and Pseudomonas exotoxin. Results. Expression of FCRLs 2, 3, and 5 was markedly increased while expression of FCRL-1 was decreased on clonal CD21(-/low) MZ B cells, as compared with other B cell subsets, from HCV-infected patients and healthy donors. However, there was no difference in the pattern of FCRL expression between HCV-MC patients with lymphoma and those without lymphoma. The anti-FCRL-5 immunotoxins showed specific cytotoxicity against FCRL-5-expressing clonal CD21(-/low) MZ B cells isolated from HCV-infected patients as well as FCRL-5-transfected cell lines. No cytotoxicity against T cells or conventional B cells was observed. Conclusion. These findings suggest that FCRL-5-targeting therapies could be a specific treatment for HCV-associated MC vasculitis and other FCRL-5-positive autoimmune B cell disorders. C1 [Terrier, Benjamin; Saadoun, David; Cacoub, Patrice] Grp Hosp Pitie Salpetriere, CNRS, UMR 7211, INSERM,U959, F-75634 Paris, France. [Terrier, Benjamin; Saadoun, David; Cacoub, Patrice] Univ Paris 06, Paris, France. [Nagata, Satoshi; Ise, Tomoko] Univ S Dakota, Canc Biol Res Ctr, Sanford Res, Sioux Falls, SD USA. [Rosenzwajg, Michelle; Klatzmann, David] INSERM, U959, CNRS, UMR 7211, Paris, France. [Rosenzwajg, Michelle; Klatzmann, David] Grp Hosp Pitie Salpetriere, F-75634 Paris, France. [Pastan, Ira] NCI, NIH, Bethesda, MD 20892 USA. RP Terrier, B (reprint author), Hop La Pitie Salpetriere, CNRS UPMC, UMR 7211, Dept Internal Med,INSERM,U959, 47-83 Blvd Hop, F-75013 Paris, France. EM benj.terrier@gmail.com FU Fondation pour la Recherche Medicale; Agence Nationale pour la Recherche sur le Sida et les Hepatites; Societe Nationale Francaise de Medecine Interne; Leukemia Research Foundation; CLL Global Research Foundation; NIH [1P20-RR-024219-01A2]; NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX Dr. Terrier's work was supported by the Fondation pour la Recherche Medicale, the Agence Nationale pour la Recherche sur le Sida et les Hepatites, and the Societe Nationale Francaise de Medecine Interne. Dr. Nagata's work was supported by the Leukemia Research Foundation, the CLL Global Research Foundation, and the NIH (grant 1P20-RR-024219-01A2). Dr. Pastan's work was supported by the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 43 TC 3 Z9 3 U1 1 U2 6 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 FEB PY 2014 VL 66 IS 2 BP 433 EP 443 DI 10.1002/art.38222 PG 11 WC Rheumatology SC Rheumatology GA AJ0PQ UT WOS:000337357900026 PM 24504816 ER PT J AU McGuire, PJ Tarasenko, TN Wang, T Levy, E Zerfas, PM Moran, T Lee, HS Bequette, BJ Diaz, GA AF McGuire, Peter J. Tarasenko, Tatiana N. Wang, Tony Levy, Ezra Zerfas, Patricia M. Moran, Thomas Lee, Hye Seung Bequette, Brian J. Diaz, George A. TI Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency SO DISEASE MODELS & MECHANISMS LA English DT Article DE Urea cycle disorder; Hyperammonemia; Infection; Influenza ID UREA CYCLE DISORDERS; SPF-ASH MICE; PHOSPHATE SYNTHETASE; AMMONIA METABOLISM; OTC(SPF-ASH) MICE; ADAPTIVE IMMUNITY; OTC DEFICIENCY; LIVER; VIRUS; ADULT AB The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism. C1 [McGuire, Peter J.; Tarasenko, Tatiana N.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wang, Tony; Levy, Ezra; Diaz, George A.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Zerfas, Patricia M.] NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. [Moran, Thomas] Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. [Lee, Hye Seung] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. [Bequette, Brian J.] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU National Institutes of Health; Children's Health Research Center at Mount Sinai School of Medicine [K12 HD052890] FX This work was supported by the intramural program at the National Institutes of Health (P.J.M.) and the Children's Health Research Center (K12 HD052890) at Mount Sinai School of Medicine (P.J.M.). NR 30 TC 5 Z9 5 U1 0 U2 2 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 FEB PY 2014 VL 7 IS 2 BP 205 EP 213 DI 10.1242/dmm.013003 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AJ4CY UT WOS:000337619300007 PM 24271778 ER PT J AU Fero, K Bergeron, SA Horstick, EJ Codore, H Li, GH Ono, F Dowling, JJ Burgess, HA AF Fero, Kandice Bergeron, Sadie A. Horstick, Eric J. Codore, Hiba Li, Grace H. Ono, Fumihito Dowling, James J. Burgess, Harold A. TI Impaired embryonic motility in dusp27 mutants reveals a developmental defect in myofibril structure SO DISEASE MODELS & MECHANISMS LA English DT Article DE Zebrafish; dusp27; Motility; Myofibrillogenesis; Muscle ID DUAL-SPECIFICITY PHOSPHATASES; ZEBRAFISH EMBRYO; GENE-EXPRESSION; ACETYLCHOLINE-RECEPTORS; REGULATED GENES; IDENTIFICATION; MUTAGENESIS; PROTEIN; BEHAVIORS; INHIBITOR AB An essential step in muscle fiber maturation is the assembly of highly ordered myofibrils that are required for contraction. Much remains unknown about the molecular mechanisms governing the formation of the contractile apparatus. We identified an early embryonic motility mutant in zebrafish caused by integration of a transgene into the pseudophosphatase dual specificity phosphatase 27 (dusp27) gene. dusp27 mutants exhibit near complete paralysis at embryonic and larval stages, producing extremely low levels of spontaneous coiling movements and a greatly diminished touch response. Loss of dusp27 does not prevent somitogenesis but results in severe disorganization of the contractile apparatus in muscle fibers. Sarcomeric structures in mutants are almost entirely absent and only rare triads are observed. These findings are the first to implicate a functional role of dusp27 as a gene required for myofiber maturation and provide an animal model for analyzing the mechanisms governing myofibril assembly. C1 [Fero, Kandice; Bergeron, Sadie A.; Horstick, Eric J.; Codore, Hiba; Li, Grace H.; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. [Dowling, James J.] Univ Michigan, Dept Pediat, Med Ctr, Ann Arbor, MI 48109 USA. [Horstick, Eric J.; Dowling, James J.] Univ Michigan, Dept Neurol, Med Ctr, Ann Arbor, MI 48109 USA. [Dowling, James J.] Univ Michigan, Dept Neurosci, Med Ctr, Ann Arbor, MI 48109 USA. [Ono, Fumihito] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, Rockville, MD 20852 USA. [Dowling, James J.] Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. [Dowling, James J.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Dowling, James J.] Univ Toronto, Dept Paediat, Toronto, ON M5G 1X8, Canada. [Dowling, James J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1X8, Canada. RP Burgess, HA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. EM burgessha@mail.nih.gov RI Burgess, Harold/B-8474-2015; OI Burgess, Harold/0000-0003-1966-7801; Bergeron, Sadie/0000-0002-1238-8730 FU NICHD; NIAAA; National Institutes of Health [1K08AR054835, T32 NS007222] FX This work was supported by the Intramural Research Programs of the NICHD (H.A.B.) and of the NIAAA (F.O.), and National Institutes of Health grants 1K08AR054835 (J.J.D.) and T32 NS007222 ( E.J.H.). NR 62 TC 1 Z9 1 U1 0 U2 2 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 FEB PY 2014 VL 7 IS 2 BP 289 EP 298 DI 10.1242/dmm.013235 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AJ4CY UT WOS:000337619300016 PM 24203884 ER PT J AU Glasgow, RE Strycker, LA King, DK Toobert, DJ AF Glasgow, Russell E. Strycker, Lisa A. King, Diane K. Toobert, Deborah J. TI Understanding Who Benefits at Each Step in an Internet-Based Diabetes Self-Management Program: Application of a Recursive Partitioning Approach SO MEDICAL DECISION MAKING LA English DT Article DE diabetes self-management; interactive media; computer; prediction; health literacy; numeracy; Latino ID HEALTH-CARE SETTINGS; PHYSICAL-ACTIVITY; SUPPORT PROGRAM; OLDER-ADULTS; OUTCOMES; INTERVENTIONS; TRIAL; SCALE; RISK; RECRUITMENT AB Background. Efforts to predict success in chronic disease management programs have been generally unsuccessful. Objective. To identify patient subgroups associated with success at each of 6 steps in a diabetes self-management (DSM) program. Design. Using data from a randomized trial, recursive partitioning with signal detection analysis was used to identify subgroups associated with 6 sequential steps of program success: agreement to participate, completion of baseline, initial website engagement, 4-month behavior change, later engagement, and longer-term maintenance. Setting. The study was conducted in 5 primary care clinics within Kaiser Permanente Colorado. Patients. Different numbers of patients participated in each step, including 2076, 544, 270, 219, 127, and 89. All measures available were used to address success at each step. Intervention. Participants were randomized to receive either enhanced usual care or 1 of 2 Internet-based DSM programs: 1) self-administered, computer-assisted self-management and 2) the self-administered program with the addition of enhanced social support. Measurements. Two sets of potential predictor variables and 6 dichotomous outcomes were created. Results. Signal detection analysis differentiated successful and unsuccessful subgroups at all but the final step. Different patient subgroups were associated with success at these different steps. Demographic factors (education, ethnicity, income) were associated with initial participation but not with later steps, and the converse was true of health behavior variables. Limitations. Analyses were limited to one setting, and the sample sizes for some of the steps were modest. Conclusions. Signal detection and recursive partitioning methods may be useful for identifying subgroups that are more or less successful at different steps of intervention and may aid in understanding variability in outcomes. C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Strycker, Lisa A.; Toobert, Deborah J.] Oregon Res Inst, Eugene, OR 97403 USA. [King, Diane K.] Univ Alaska Anchorage, Anchorage, AK USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 6144, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [DK35524] FX Received 20 August 2012 from Implementation Science, Division of Cancer Control and Population Science, National Cancer Institute, Rockville, Maryland (REG); Oregon Research Institute, Eugene, Oregon (LAS, DJT); and University of Alaska, Anchorage, Alaska (DKK). This study was supported by grant DK35524 from the National Institute of Diabetes and Digestive and Kidney Diseases. Revision accepted for publication 22 June 2013. NR 50 TC 4 Z9 4 U1 3 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD FEB PY 2014 VL 34 IS 2 BP 180 EP 191 DI 10.1177/0272989X13498156 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AI8QH UT WOS:000337185600006 PM 23913917 ER PT J AU Byington, CL Higgins, S Kaskel, FJ Purucker, M Davis, JM Smoyer, WE AF Byington, Carrie L. Higgins, Sarah Kaskel, Fredrick J. Purucker, Mary Davis, Jonathan M. Smoyer, William E. TI The CTSA Mentored Career Development Program: Supporting the Careers of Child Health Investigators SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE Clinical and Translational Science Award; education; child health; KL2 program; K12 program; Institutional Career Development Award ID TRANSLATIONAL SCIENCE; SCIENTISTS AB Training translational scientists is a priority of the Clinical and Translational Science Award (CTSA) consortium. Objectives: 1) Describe the landscape of CTSA Mentored Research Career Development Awards (CDA) and 2) evaluate participation and outcomes of child health investigators in these programs. Design: Survey of the CTSA Child Health Oversight Committee (CC-CHOC) and review of nonresponders' CTSA Websites. Results: Thirty-two of 53 CC-CHOC members (60%) responded and all nonresponder Websites were reviewed. Institutions supported 1,166 CDA positions from 2006 to 2011, with 134 awarded to child health investigators (11.5%). Respondents reported a mean of 29.8 KL2 positions (95% CI 17.5-42.2) during their award period, with a mean of 2.8 (95% CI 1.8-3.8) awarded to child health investigators. The proportion of child health awardees varied from 0% to 50% across institutions. We identified 45 subsequent National Institutes of Health (NIH) awards to the 134 child health investigators (34%). Conclusions: The CTSA program contributes substantially to training the next generation of translational investigators. One-third of child health investigators obtained subsequent NIH awards in the short follow-up period demonstrating success of the CTSA CDA programs. Child health investigators are represented variably across the consortium. Pediatric institutions can partner with the CTSA program to further support training child health investigators. C1 [Byington, Carrie L.] Univ Utah, Hlth Sci Ctr, Utah Ctr Clin & Translat Sci, Salt Lake City, UT 84112 USA. [Byington, Carrie L.] Univ Utah, Hlth Sci Ctr, Dept Pediat, Salt Lake City, UT USA. [Higgins, Sarah; Smoyer, William E.] Ohio State Univ, Ctr Clin & Translat Res, Nationwide Childrens Hosp, Ctr Clin & Translat Sci,Res Inst, Columbus, OH 43210 USA. [Kaskel, Fredrick J.] Albert Einstein Coll Med, Einstein Montefiore Inst Clin & Translat Res, New York, NY USA. [Kaskel, Fredrick J.] Albert Einstein Coll Med, Dept Pediat, New York, NY USA. [Purucker, Mary] NIH, Clin & Translat Sci Awards Program, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Boston, MA USA. [Davis, Jonathan M.] Tufts Med Ctr, Floating Hosp Children, Tufts Clin Translat Sci Inst, Boston, MA USA. RP Byington, CL (reprint author), Univ Utah, Hlth Sci Ctr, Utah Ctr Clin & Translat Sci, Salt Lake City, UT 84112 USA. EM Carrie.byington@hsc.utah.edu OI Byington, Carrie/0000-0002-7350-9495 FU National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000105]; NIH [UL1TR000090-15, 3UL1RR025750-0255, UL1 RR025752]; University of Utah, NIH [8UL1TR000105]; Ohio State University, NIH [UL1TR000090]; Albert Einstein College of Medicine [3UL1RR025750]; Tufts Medical Center, NIH [UL1 RR025752] FX This work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 8UL1TR000105 (formerly UL1RR025764) and NIH awards UL1TR000090-15, 3UL1RR025750-0255, and UL1 RR025752. The authors acknowledge CTSA support to their institutions through the following grants: University of Utah, NIH 8UL1TR000105; The Ohio State University, NIH UL1TR000090; Albert Einstein College of Medicine, 3UL1RR025750; and Tufts Medical Center, NIH UL1 RR025752. The CTSA Consortium Publications Committee approved the manuscript on February 19, 2013. NR 11 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD FEB PY 2014 VL 7 IS 1 BP 44 EP 47 DI 10.1111/cts.12122 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA9VE UT WOS:000331440300013 PM 24528899 ER PT J AU De Groot, AS Moise, L Liu, R Gutierrez, AH Terry, F Koita, OA Ross, TM Martin, W AF De Groot, Anne S. Moise, Lenny Liu, Rui Gutierrez, Andres H. Terry, Frances Koita, Ousmane A. Ross, Ted M. Martin, William TI Cross-conservation of T-cell epitopes Now even more relevant to (H7N9) influenza vaccine design SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Editorial Material DE H7N9; H1N1; avian-origin; influenza; genome; recombinant protein; hemagglutinin; cell-mediated immunity; T-cell epitope; T cell; CD4+T cell; T helper ID VIRUS-LIKE PARTICLE; SEASONAL INFLUENZA; A VIRUS; HUMAN INFECTION; ORIGIN; MICE; RESPONSES; A(H7N9); FERRETS; TRANSMISSION C1 [De Groot, Anne S.; Moise, Lenny; Liu, Rui; Gutierrez, Andres H.] Univ Rhode Isl, Inst Immunol & Informat, Providence, RI 02908 USA. [De Groot, Anne S.; Moise, Lenny; Terry, Frances; Martin, William] EpiVax Inc, Providence, RI USA. [Koita, Ousmane A.] Univ Bamako, Lab Appl Mol Biol, Bamako, Mali. [Koita, Ousmane A.] Univ Sci Tech & Technol Bamako, Inst Natl Malad Infect & Allerg, Ctr Rech & Format VIH Sida & Tuberculose, Project SEREFO NIAID, Bamako, Mali. [Ross, Ted M.] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. RP De Groot, AS (reprint author), Univ Rhode Isl, Inst Immunol & Informat, 825 Chalkstone Ave, Providence, RI 02908 USA. EM AnnieD@EpiVax.com RI De Groot, Anne/B-6221-2013 OI De Groot, Anne/0000-0001-5911-1459 NR 50 TC 15 Z9 15 U1 0 U2 8 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD FEB PY 2014 VL 10 IS 2 BP 256 EP 262 DI 10.4161/hv.28135 PG 7 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA AI1YV UT WOS:000336652500010 PM 24525618 ER PT J AU Woo, EJ Winiecki, SK Ou, AC AF Woo, Emily Jane Winiecki, Scott K. Ou, Alan C. TI Motor palsies of cranial nerves (excluding VII) after vaccination Reports to the US Vaccine Adverse Event Reporting System SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE vaccine; cranial nerve palsy; ptosis; disconjugate gaze; adverse event; postmarketing safety surveillance ID ATTENUATED INFLUENZA VACCINE; BELLS-PALSY; POSTMARKETING EVALUATION; UNITED-STATES; SAFETY; H1N1; VAERS; AGE AB We reviewed cranial nerve palsies, other than VII, that have been reported to the US Vaccine Adverse Event Reporting System (VAERS). We examined patterns for differences in vaccine types, seriousness, age, and clinical characteristics. We identified 68 reports of cranial nerve palsies, most commonly involving the oculomotor (III), trochlear (IV), and abducens (VI) nerves. Isolated cranial nerve palsies, as well as palsies occurring as part of a broader clinical entity, were reported. Forty reports (59%) were classified as serious, suggesting that a cranial nerve palsy may sometimes be the harbinger of a broader and more ominous clinical entity, such as a stroke or encephalomyelitis. There was no conspicuous clustering of live vs. inactivated vaccines. The patient age range spanned the spectrum from infants to the elderly. Independent data may help to clarify whether, when, and to what extent the rates of cranial nerve palsies following particular vaccines may exceed background levels. C1 [Woo, Emily Jane; Winiecki, Scott K.] US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Ou, Alan C.] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Woo, EJ (reprint author), US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. EM jane.woo@fda.hhs.gov OI Winiecki, Scott/0000-0003-4912-4621 NR 23 TC 2 Z9 2 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD FEB PY 2014 VL 10 IS 2 BP 301 EP 305 DI 10.4161/hv.27032 PG 5 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA AI1YV UT WOS:000336652500014 PM 24231288 ER PT J AU Takeshita, J Mohler, ER Krishnamoorthy, P Moore, J Rogers, WT Zhang, LF Gelfand, JM Mehta, NN AF Takeshita, Junko Mohler, Emile R., III Krishnamoorthy, Parasuram Moore, Jonni Rogers, Wade T. Zhang, Lifeng Gelfand, Joel M. Mehta, Nehal N. TI Endothelial Cell-, Platelet-, and Monocyte/Macrophage-Derived Microparticles are Elevated in Psoriasis Beyond Cardiometabolic Risk Factors SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; inflammation; microparticles endothelium; platelets; psoriasis; risk factor ID HUMAN ATHEROSCLEROTIC PLAQUES; CIRCULATING MICROPARTICLES; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; INFLAMMATION; DISEASES; PECAM-1 AB Background-Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes. Methods and Results-Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V, CD3, CD31, CD41a, CD64, CD105, and CD144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet-free plasma was separated from whole blood by one-step centrifugation for microparticle analysis. Microparticles were fluorescently labeled and characterized by flow cytometry. Higher concentrations of CD105 (5.5/mu L versus 2.5/mu L, P<0.001), CD31 (31/mu L versus 18/mu L, P=0.002), CD41a (50/mu L versus 22/mu L, P<0.001), and CD64 (5.0/mu L versus 4.1/mu L, P=0.02) singly positive microparticles corresponding to endothelial cell-, platelet-, and monocyte/macrophage-derived microparticles, respectively, were found in psoriasis patients compared with controls. These differences persisted after adjustment for traditional cardiometabolic risk factors including body mass index. Conclusions-Increased microparticle concentrations, independent of cardiometabolic risk factors, in patients with psoriasis suggest that the presence of increased endothelial cell, platelet, and monocyte/macrophage activation with cell turnover may contribute to the heightened atherogenesis associated with psoriasis. C1 [Mohler, Emile R., III] Univ Penn, Perelman Sch Med, Sect Vasc Med, Philadelphia, PA 19104 USA. [Mohler, Emile R., III; Zhang, Lifeng; Mehta, Nehal N.] Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Dis, Philadelphia, PA 19104 USA. [Takeshita, Junko; Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Moore, Jonni; Rogers, Wade T.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Krishnamoorthy, Parasuram] Englewood Hosp & Med Ctr, Englewood, NJ USA. [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, Bethesda, MD USA. RP Mehta, NN (reprint author), NHLBI, Sect Inflammat & Cardiometab Dis, Bldg 10, Bethesda, MD USA. EM nehal.mehta@nih.gov OI Krishnamoorthy, Parasuram/0000-0002-4560-7346 FU Intramural Research Program at the NIH [T32 GM 075766-6]; National Psoriasis Foundation Fellowship Award; Dermatology Foundation Career Development Award; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24-AR064310]; National Heart Lung and Blood Institute [R01-HL111293] FX This work was partly funded by a grant from the Intramural Research Program at the NIH (Mehta), Training Grant T32 GM 075766-6 (Takeshita), a National Psoriasis Foundation Fellowship Award (Takeshita), a Dermatology Foundation Career Development Award (Takeshita), a K24-AR064310 grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Gelfand), and a R01-HL111293 grant from the National Heart Lung and Blood Institute. NR 33 TC 14 Z9 15 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000507 DI 10.1161/JAHA.113.000507 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500046 PM 24584739 ER PT J AU Jelovsek, JE Chagin, K Brubaker, L Rogers, RG Richter, HE Arya, L Barber, MD Shepherd, JP Nolen, TL Norton, P Sung, V Menefee, S Siddiqui, N Meikle, SF Kattan, MW AF Jelovsek, J. Eric Chagin, Kevin Brubaker, Linda Rogers, Rebecca G. Richter, Holly E. Arya, Lily Barber, Matthew D. Shepherd, Jonathan P. Nolen, Tracy L. Norton, Peggy Sung, Vivian Menefee, Shawn Siddiqui, Nazema Meikle, Susan F. Kattan, Michael W. CA Pelvic Floor Disorders Network TI A Model for Predicting the Risk of De Novo Stress Urinary Incontinence in Women Undergoing Pelvic Organ Prolapse Surgery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID REDUCTION EFFORTS CARE; FREE VAGINAL TAPE; ABDOMINAL SACROCOLPOPEXY; NOMOGRAM; REPAIR; VALIDATION; TRIAL; RECURRENCE; COLPOPEXY; DESIGN AB OBJECTIVE: To construct and validate a prediction model for estimating the risk of de novo stress urinary incontinence (SUI) after vaginal pelvic organ prolapse (POP) surgery and compare it with predictions using preoperative urinary stress testing and expert surgeons' predictions. MATERIALS AND METHODS: Using the data set (n=457) from the Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial, a model using 12 clinical preoperative predictors of de novo SUI was constructed. De novo SUI was determined by Pelvic Floor Distress Inventory responses through 12 months postoperatively. After fitting the multivariable logistic regression model using the best predictors, the model was internally validated with 1,000 bootstrap samples to obtain bias-corrected accuracy using a concordance index. The model's predictions were also externally validated by comparing findings against actual outcomes using Colpopexy and Urinary Reduction Efforts trial patients (n=316). The final model's performance was compared with experts using a test data set of 32 randomly chosen Outcomes Following Vaginal Prolapse Repair and Midurethral Sling trial patients through comparison of the model's area under the curve against: 1) 22 experts' predictions; and 2) preoperative prolapse reduction stress testing. RESULTS: A model containing seven predictors discriminated between de novo SUI status (concordance index 0.73, 95% confidence interval [CI] 0.65-0.80) in Outcomes Following Vaginal Prolapse Repair and Midurethral Sling participants and outperformed expert clinicians (area under the curve 0.72 compared with 0.62, P<.001) and preoperative urinary stress testing (area under the curve 0.72 compared with 0.54, P<.001). The concordance index for Colpopexy and Urinary Reduction Efforts trial participants was 0.62 (95% CI 0.56-0.69). CONCLUSION: This individualized prediction model for de novo SUI after vaginal POP surgery is valid and outperforms preoperative stress testing, prediction by experts, and preoperative reduction cough stress testing. An online calculator is provided for clinical use. C1 Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44195 USA. [Jelovsek, J. Eric] Cleveland Clin, Cleveland, OH 44195 USA. Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol & Urol, Chicago, IL 60611 USA. Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. Univ New Mexico, Hlth Sci Ctr, Dept Surg, Albuquerque, NM 87131 USA. Univ Alabama Birmingham, Dept Obstet, Birmingham, AL USA. Univ Alabama Birmingham, Dept Gynecol, Birmingham, AL USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Utah, Salt Lake City, UT USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Kaiser Permanente, San Diego, CA USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Pittsburgh, Med Ctr, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. RTI Int, Res Triangle Pk, NC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Jelovsek, JE (reprint author), Cleveland Clin, 9500 Euclid Ave A81, Cleveland, OH 44195 USA. EM jelovsj@ccf.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [2U01HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241, U10 HD069013, U10 HD069025, U10 HD069010, U01 HD069031]; National Institutes of Health Office of Research on Women's Health FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (2U01HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD54136, 1U10 HD54214, 1U10 HD54215, 1U10 HD54241, U10 HD069013, U10 HD069025, U10 HD069010, U10 HD069010, and U01 HD069031) and the National Institutes of Health Office of Research on Women's Health. NR 20 TC 13 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2014 VL 123 IS 2 BP 279 EP 287 DI 10.1097/AOG.0000000000000094 PN 1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AI4AY UT WOS:000336808800009 PM 24402598 ER PT J AU Pinar, H Goldenberg, RL Koch, MA Heim-Hall, J Hawkins, HK Shehata, B Abramowsky, C Parker, CB Dudley, DJ Silver, RM Stoll, B Carpenter, M Saade, G Moore, J Conway, D Varner, MW Hogue, CJR Coustan, DR Sbrana, E Thorsten, V Willinger, M Reddy, UM AF Pinar, Halit Goldenberg, Robert L. Koch, Matthew A. Heim-Hall, Josefine Hawkins, Hal K. Shehata, Bahig Abramowsky, Carlos Parker, Corette B. Dudley, Donald J. Silver, Robert M. Stoll, Barbara Carpenter, Marshall Saade, George Moore, Janet Conway, Deborah Varner, Michael W. Hogue, Carol J. R. Coustan, Donald R. Sbrana, Elena Thorsten, Vanessa Willinger, Marian Reddy, Uma M. TI Placental Findings in Singleton Stillbirths SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PERINATAL AUTOPSY; RISK-FACTORS; POSTMORTEM EXAMINATION; FETAL; CLASSIFICATION; INFECTION; DEATH; OUTCOMES; BIRTH; RATES AB OBJECTIVE: To compare placental lesions for stillbirth cases and live birth controls in a population-based study. METHODS: Pathologic examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. RESULTS: Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate were present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births. Among stillbirths, inflammation and retroplacental hematoma were more common in placentas from early deliveries, whereas thrombotic lesions were more common in later gestation. Inflammatory lesions were especially common in early live births. CONCLUSIONS: Placental lesions were highly associated with stillbirth compared with live births. All lesions associated with stillbirth were found in live births but often with variations by gestational age at delivery. Knowledge of lesion prevalence within gestational age groups in both stillbirths and live birth controls contributes to an understanding of the association between placental abnormality and stillbirth. C1 Brown Univ, Warren Alpert Med Sch, Providence, RI 02905 USA. Columbia Univ, Sch Med, New York, NY USA. RTI Int, Durham, NC USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Tufts Univ, Med Ctr, Boston, MA 02111 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Pinar, H (reprint author), Brown Univ, Women & Infants Hosp, Div Perinatal Pathol, Warren Alpert Med Sch, 101 Dudley St, Providence, RI 02905 USA. EM hpinar@brown.edu RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD45925, HD45944, HD45952, HD45953, HD45954] FX Supported by grants (HD45925, HD45944, HD45952, HD45953, HD45954, and HD45925) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 29 TC 38 Z9 39 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2014 VL 123 IS 2 BP 325 EP 336 DI 10.1097/AOG.0000000000000100 PN 1 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AI4AY UT WOS:000336808800015 PM 24402599 ER PT J AU Kawabata, S Chiang, CT Tsurutani, J Shiga, H Arwood, ML Komiya, T Gills, JJ Memmott, RM Dennis, PA AF Kawabata, Shigeru Chiang, Chun-Te Tsurutani, Junji Shiga, Hideaki Arwood, Matthew L. Komiya, Takefumi Gills, Joell J. Memmott, Regan M. Dennis, Phillip A. TI Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer SO ONCOTARGET LA English DT Article DE Rapamycin; Pemetrexed; Drug synergy; mTOR; Thymidylate Synthase; Lung Cancer ID PHARMACOLOGICAL INHIBITION; CHEMOTHERAPY; CYTOTOXICITY; EXPRESSION; SENSITIVITY; COMBINATION; ACTIVATION; RESISTANCE; KINASE; NSCLC AB Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed. C1 [Kawabata, Shigeru; Arwood, Matthew L.; Gills, Joell J.; Memmott, Regan M.; Dennis, Phillip A.] Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. [Chiang, Chun-Te; Tsurutani, Junji; Shiga, Hideaki; Komiya, Takefumi] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dennis, PA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. EM pdennis@jhmi.edu OI Shiga, Hideaki/0000-0001-7218-154X FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute; Open Access Promotion Fund of the Johns Hopkins University Libraries FX This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. 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 organization imply endorsement by the United States Government. Publication of this article was funded in part by the Open Access Promotion Fund of the Johns Hopkins University Libraries. NR 30 TC 8 Z9 8 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB PY 2014 VL 5 IS 4 BP 1062 EP 1070 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AI6EA UT WOS:000336962300019 PM 24658085 ER PT J AU Casady, M Faia, L Nazemzadeh, M Nussenblatt, R Chan, CC Sen, HN AF Casady, Megan Faia, Lisa Nazemzadeh, Maryam Nussenblatt, Robert Chan, Chi-Chao Sen, H. Nida TI FUNDUS AUTOFLUORESCENCE PATTERNS IN PRIMARY INTRAOCULAR LYMPHOMA SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE cytokines; diagnosis; fundus autofluorescence; primary intraocular lymphoma; primary vitreoretinal lymphoma; uveitis ID COLLABORATIVE GROUP-REPORT AB Purpose: To evaluate fundus autofluorescence (FAF) patterns in patients with primary intraocular (vitreoretinal) lymphoma. Methods: Records of all patients with primary intraocular lymphoma who underwent FAF imaging at the National Eye Institute were reviewed. Fundus autofluorescence patterns were evaluated with respect to clinical disease status and the findings on fluorescein angiography and spectral-domain optical coherence tomography. Results: There were 18 eyes (10 patients) with primary intraocular lymphoma that underwent FAF imaging. Abnormal autofluorescence in the form of granular hyperautofluorescence and hypoautofluorescence was seen in 11 eyes (61%), and blockage by mass lesion was seen in 2 eyes (11%). All eyes with granular pattern on FAF had active primary intraocular lymphoma at the time of imaging, but there were 5 eyes with unremarkable FAF, which were found to have active lymphoma. The most common pattern on fluorescein angiography was hypofluorescent round spots with a "leopard spot" appearance (43%). These hypofluorescent spots on fluorescein angiography correlated with hyperautofluorescent spots on FAF in 5 eyes (36%) (inversion of FAF). Nodular hyperreflective spots at the level of retinal pigment epithelium on optical coherence tomography were noted in 43% of eyes. The hyperautofluorescent spots on FAF correlated with nodular hyperreflective spots on optical coherence tomography in 6 eyes (43%). Conclusion: Granularity on FAF was associated with active lymphoma in majority of the cases. An inversion of FAF (hyperautofluorescent spots on FAF corresponding to hypofluorescent spots on fluorescein angiography) was observed in less than half of the eyes. C1 [Casady, Megan; Faia, Lisa; Nazemzadeh, Maryam; Nussenblatt, Robert; Chan, Chi-Chao; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Faia, Lisa] Associated Retinal Consultants PC, Royal Oak, MI USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 21 TC 10 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2014 VL 34 IS 2 BP 366 EP 372 PG 7 WC Ophthalmology SC Ophthalmology GA AI6DF UT WOS:000336959400021 PM 23958842 ER PT J AU Dohle, W Leese, MP Jourdan, FL Major, MR Bai, RL Hamel, E Ferrandis, E Kasprzyk, PG Fiore, A Newman, SP Purohit, A Potter, BVL AF Dohle, Wolfgang Leese, Mathew P. Jourdan, Fabrice L. Major, Meriel R. Bai, Ruoli Hamel, Ernest Ferrandis, Eric Kasprzyk, Philip G. Fiore, Ann Newman, Simon P. Purohit, Atul Potter, Barry V. L. TI Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1-Substituted Tetrahydroisoquinolines SO CHEMMEDCHEM LA English DT Article DE colchicine; microtubules; steric repulsion; tetrahydroisoquinolines; tubulin ID MULTITARGETED ANTITUMOR AGENTS; BREAST-CANCER CELLS; IN-VITRO; ANTICANCER ACTIVITY; ANTIMITOTIC AGENTS; TUBULIN; VIVO; INHIBITION; ANALOGS; DERIVATIVES AB The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (+/-)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6b), for example, was found to be similar to 10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy- 1,2,3,4-tetrahydroisoquinoline (4b) against DU-145 prostate cancer cells (GI(50) values: 220 nm and 2.1 mm, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study. C1 [Dohle, Wolfgang; Leese, Mathew P.; Jourdan, Fabrice L.; Major, Meriel R.; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. [Bai, Ruoli; Hamel, Ernest] NCI, Frederick, MD 21702 USA. [Ferrandis, Eric] Inst Rech Henri Beaufour, F-91966 Les Ulis, France. [Kasprzyk, Philip G.; Fiore, Ann] IPSEN, Milford, MA 01757 USA. [Newman, Simon P.; Purohit, Atul] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London W12 0NN, England. RP Potter, BVL (reprint author), Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. EM B.V.L.Potter@bath.ac.uk FU Sterix Ltd. a member of the IPSEN Group FX This work was supported by Sterix Ltd., a member of the IPSEN Group. We thank Ms. Alison Smith (University of Bath) for technical support, and the NCI DTP program for providing in vitro screening resources. NR 32 TC 6 Z9 6 U1 0 U2 10 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD FEB PY 2014 VL 9 IS 2 BP 350 EP 370 DI 10.1002/cmdc.201300412 PG 21 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AI3GE UT WOS:000336748000012 PM 24436228 ER PT J AU Sioka, C Estrada-Veras, J Maric, I Gahl, WA Chen, CC AF Sioka, Chrissa Estrada-Veras, Juvianee Maric, Irinia Gahl, William A. Chen, Clara C. TI FDG PET Images in a Patient With Erdheim-Chester Disease SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE PET/CT; FDG; Erdheim-Chester disease; histiocytosis ID IMAGING FINDINGS; INVOLVEMENT C1 [Sioka, Chrissa; Chen, Clara C.] NHGRI, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Estrada-Veras, Juvianee; Gahl, William A.] NHGRI, Med Genet Branch, Off Clin Director, Bethesda, MD 20892 USA. [Maric, Irinia] NIH, Hematol Sect, Dept Lab Med, Bethesda, MD 20892 USA. RP Chen, CC (reprint author), Ctr Clin, Div Nucl Med, Dept Radiol & Imaging Sci, Bldg 10,RM 1C-459,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM cchen1@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 8 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2014 VL 39 IS 2 BP 170 EP 177 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI3DB UT WOS:000336738100027 PM 23640213 ER PT J AU Pearson, MR Derlega, VJ Henson, JM Holmes, KY Ferrer, RA Harrison, SB AF Pearson, Matthew R. Derlega, Valerian J. Henson, James M. Holmes, Karen Y. Ferrer, Rebecca A. Harrison, Scott B. TI Role of Neuroticism and Coping Strategies in Psychological Reactions to a Racist Incident Among African American University Students SO JOURNAL OF BLACK PSYCHOLOGY LA English DT Article DE discrimination; personality; coping; structural equation model; racism ID PERCEIVED DISCRIMINATION; COLLEGE-STUDENTS; STRESS PROCESS; MENTAL-HEALTH; PERSONALITY; RACE; COMMUNITY; SYMPTOMS; WOMEN; MODEL AB A total of 562 African American university students provided data on individual differences in neuroticism; coping with a recent experience being the target of prejudice, racism, and/or discrimination; and psychological reactions to the incident. Higher negative affect, lower positive affect, more intrusive thoughts about the incident, and lack of forgiveness for the perpetrator were used to index distress in response to the racist incident. Using factor analyses, we determined the factor structure of the Brief COPE in our sample. Using structural equation modeling, we then examined neuroticism and each coping factor as unique predictors of reactions to the race-related incident. We documented that there were direct and indirect associations (via the selection of coping strategies) between neuroticism and the outcome measures. Neuroticism also moderated the association between particular coping strategies and reactions to the racist incident. There was also evidence for direct associations between various coping strategies and the outcome measures. The research, though preliminary, suggests the importance of neuroticism and coping strategies in understanding psychological reactions to being the target of racism. C1 [Pearson, Matthew R.; Derlega, Valerian J.; Henson, James M.; Harrison, Scott B.] Old Dominion Univ, Norfolk, VA USA. [Holmes, Karen Y.] Norfolk State Univ, Norfolk, VA USA. [Ferrer, Rebecca A.] NCI, Rockville, MD USA. RP Pearson, MR (reprint author), Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87111 USA. EM mateo.pearson@gmail.com NR 43 TC 1 Z9 1 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0095-7984 EI 1552-4558 J9 J BLACK PSYCHOL JI J. Black Psychol. PD FEB PY 2014 VL 40 IS 1 BP 81 EP 111 DI 10.1177/0095798412471682 PG 31 WC Psychology, Multidisciplinary SC Psychology GA AI0AO UT WOS:000336508500005 ER PT J AU Lozito, TP Jackson, WM Nesti, LJ Tuan, RS AF Lozito, Thomas P. Jackson, Wesley M. Nesti, Leon J. Tuan, Rocky S. TI Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs SO MATRIX BIOLOGY LA English DT Article DE Mesenchymal stem cells (MSCs); Matrix metalloprotease (MMP); Tissue inhibitors of metalloprotease (TIMP) ID HUMAN BONE-MARROW; MATRIX METALLOPROTEINASES; TISSUE-INHIBITOR; PROGENITOR CELLS; STROMAL CELLS; SKIN CARCINOGENESIS; GELATINASE-A; DENTAL-PULP; DIFFERENTIATION; ACTIVATION AB Mesenchymal stem cells (MSCs) are attractive candidates for inclusion in cell-based therapies by virtue of their abilities to home to wound sites. However, in-depth characterization of the specific effects of MSCs on their microenvironments is needed to realize their full therapeutic potentials. Furthermore, since MSCs of varying properties can be isolated from a diverse spectrum of tissues, a strategic and rational approach in MSC sourcing for a particular application has yet to be achieved. For example, MSCs that activate their proteolytic environments may promote tissue remodeling, while those from different tissue sources may inhibit proteases and promote tissue stabilization. This study attempts to address these issues by analyzing MSCs isolated from three adult tissue sources in terms of their effects on their proteolytic microenvironments. Human bone marrow, adipose, and traumatized muscle derived MSCs were compared in their soluble and cellular-associated MMP components and activity. For all types of MSCs, MMP activity associated with the cell surface, but activity levels and MMP profiles differed with tissue source. All MSC types bound exogenous active MMPs at their surfaces. MSCs were also able to activate exogenous proMMP-2 and proMMP-13. This is in marked contrast to the MSC soluble compartment, which strongly inhibited MMPs via endogenous TIMPs. The exact TIMP used to inhibit the exogenous MMP differed with MSC type. Thus, MSCs saturate their environment with both MMPs and TIMPs. Since they bind and activate MMPs at their surfaces, the net result is a very controlled pericellular localization of MMP activities by MSCs. (C) 2013 Elsevier B.V. All rights reserved. C1 [Lozito, Thomas P.; Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15261 USA. [Jackson, Wesley M.; Nesti, Leon J.] NIAMSD, Orthopaed Res Grp, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Nesti, Leon J.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Nesti, Leon J.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. RP Tuan, RS (reprint author), Ctr Cellular & Mol Engn, Dept Orthopaed Surg, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU Department of Defense [W81XWH-10-1-0850]; Military Amputee Research Program at WRAMC [PO5-A011]; Commonwealth of Pennsylvania Department of Health FX This project was supported by grants from the Department of Defense (W81XWH-10-1-0850), the Military Amputee Research Program at WRAMC (PO5-A011), and the Commonwealth of Pennsylvania Dept Anent of Health. NR 53 TC 17 Z9 17 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD FEB PY 2014 VL 34 BP 132 EP 143 DI 10.1016/j.matbio.2013.10.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AH9PD UT WOS:000336473400014 PM 24140982 ER PT J AU Thurm, A Manwaring, SS Luckenbaugh, DA Lord, C Swedo, SE AF Thurm, Audrey Manwaring, Stacy S. Luckenbaugh, David A. Lord, Catherine Swedo, Susan E. TI Patterns of skill attainment and loss in young children with autism SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID SPECTRUM DISORDERS; DEVELOPMENTAL REGRESSION; LANGUAGE REGRESSION; HOME VIDEOTAPES; ONSET PATTERNS; AGE; INFANTS; COMMUNICATION; BRAIN; RECOGNITION AB The purpose of this study was to extend the literature on the ontogeny of autism spectrum disorder (ASD) by examining early attainment and loss of specific sociocommunicative skills in children with autism (AUT; n = 125), pervasive developmental disorder not otherwise specified (PDD-NOS; n = 42), nonspectrum developmental delays (n = 46), and typical development (n = 31). The ages of skill attainment and loss were obtained from a caregiver interview. The findings indicated that children with AUT, PDD-NOS, and developmental delays diverged from typically developing children in attainment of sociocommunicative skills early in the first year of life. Loss of at least one skill was reported in a majority of children with AUT and PDD-NOS. Significant delays in attainment of skills were also reported in children who lost skills. The wide variation in skill attainment and loss reported across children indicates that symptom onset and regression may be best represented continuously, with at least some early delay and loss present for a great majority of children with ASD. C1 [Thurm, Audrey; Luckenbaugh, David A.; Swedo, Susan E.] NIMH, Bethesda, MD 20892 USA. [Manwaring, Stacy S.] Univ Utah, Salt Lake City, UT 84112 USA. [Lord, Catherine] Cornell Univ, Ithaca, NY 14853 USA. RP Thurm, A (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM athurm@mail.nih.gov OI Manwaring, Stacy/0000-0002-0835-9398 FU Intramural NIH HHS [Z99 MH999999] NR 53 TC 2 Z9 3 U1 6 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FEB PY 2014 VL 26 IS 1 BP 203 EP 214 DI 10.1017/S0954579413000874 PG 12 WC Psychology, Developmental SC Psychology GA AD0UV UT WOS:000332950500014 PM 24274034 ER PT J AU Guyer, AE Benson, B Choate, VR Bar-Haim, Y Perez-Edgar, K Jarcho, JM Pine, DS Ernst, M Fox, NA Nelson, EE AF Guyer, Amanda E. Benson, Brenda Choate, Victoria R. Bar-Haim, Yair Perez-Edgar, Koraly Jarcho, Johanna M. Pine, Daniel S. Ernst, Monique Fox, Nathan A. Nelson, Eric E. TI Lasting associations between early-childhood temperament and late-adolescent reward-circuitry response to peer feedback SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID SOCIAL-ANXIETY-DISORDER; BEHAVIORAL-INHIBITION; HUMAN STRIATUM; CHILDREN; WITHDRAWAL; PSYCHOPATHOLOGY; SPEECH; PHOBIA; FACES; BRAIN AB Behavioral inhibition, a temperament identifiable in infancy, is associated with heightened withdrawal from social encounters. Prior studies raise particular interest in the striatum, which responds uniquely to monetary gains in behaviorally inhibited children followed into adolescence. Although behavioral manifestations of inhibition are expressed primarily in the social domain, it remains unclear whether observed striatal alterations to monetary incentives also extend to social contexts. In the current study, imaging data were acquired from 39 participants (17 males, 22 females; ages 16-18 years) characterized since infancy on measures of behavioral inhibition. A social evaluation task was used to assess neural response to anticipation and receipt of positive and negative feedback from novel peers, classified by participants as being of high or low interest. As with monetary rewards, striatal response patterns differed during both anticipation and receipt of social reward between behaviorally inhibited and noninhibited adolescents. The current results, when combined with prior findings, suggest that early-life temperament predicts altered striatal response in both social and nonsocial contexts and provide support for continuity between temperament measured in early childhood and neural response to social signals measured in late adolescence and early adulthood. C1 [Guyer, Amanda E.] Univ Calif Davis, Davis, CA 95618 USA. [Benson, Brenda; Jarcho, Johanna M.; Pine, Daniel S.; Ernst, Monique; Nelson, Eric E.] NIMH, Bethesda, MD 20892 USA. [Choate, Victoria R.] Univ Massachusetts, Boston, MA 02125 USA. [Bar-Haim, Yair] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Perez-Edgar, Koraly] Penn State Univ, University Pk, PA 16802 USA. [Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. RP Guyer, AE (reprint author), Univ Calif Davis, Dept Human Ecol, Ctr Mind & Brain, 267 Cousteau Pl, Davis, CA 95618 USA. EM aeguyer@ucdavis.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563; Jarcho, Johanna/0000-0001-9075-6968; Nelson, Eric/0000-0002-3376-2453 FU NIMH NIH HHS [MH080076, MH074454, R00 MH080076, R01 MH074454, R01 MH094633, U01 MH074454] NR 81 TC 20 Z9 20 U1 3 U2 21 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 EI 1469-2198 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD FEB PY 2014 VL 26 IS 1 BP 229 EP 243 DI 10.1017/S0954579413000941 PG 15 WC Psychology, Developmental SC Psychology GA AD0UV UT WOS:000332950500016 PM 24444176 ER PT J AU Williams, KE Anderton, DL Lee, MP Pentecost, BT Arcaro, KF AF Williams, Kristin E. Anderton, Douglas L. Lee, Maxwell P. Pentecost, Brian T. Arcaro, Kathleen F. TI High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines SO EPIGENETICS LA English DT Article DE Tamoxifen Resistance; Breast Cancer; Estrogen Receptor; HumanMethylation450 BeadChip; methylation; ZNF350; MAGED1 ID GENE-EXPRESSION; 5-AZA-2'-DEOXYCYTIDINE; CARCINOMAS; MECHANISMS; INDUCTION; INVASION; VARIANT AB Roughly two-thirds of all breast cancers are ER-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ER-positive TMX2-11 had 4000 hypermethylated sites and ER-negative TMX2-28 had over 33000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2?deoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome. C1 [Williams, Kristin E.; Arcaro, Kathleen F.] Univ Massachusetts, Dept Vet & Anim Sci, Mol & Cellular Biol Grad Program, Amherst, MA 01003 USA. [Anderton, Douglas L.] Univ S Carolina, Dept Sociol, Columbia, SC 29208 USA. [Lee, Maxwell P.] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Pentecost, Brian T.] Wadsworth Ctr, Albany, NY USA. RP Arcaro, KF (reprint author), Univ Massachusetts, Dept Vet & Anim Sci, Mol & Cellular Biol Grad Program, Amherst, MA 01003 USA. EM karcaro@vasci.umass.edu FU Department of Defense CDMRP Breast Cancer Pre-doctoral grant; Avon Foundation for Women; Rays of Hope Foundation FX The authors would like to thank Dr John Gierthy for his generous gift of TMX2-11 and TMX2-28. Williams KE was funded by the Department of Defense CDMRP Breast Cancer Pre-doctoral grant. This research was supported by grants from the Avon Foundation for Women and the Rays of Hope Foundation to KFA. NR 27 TC 7 Z9 7 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD FEB 1 PY 2014 VL 9 IS 2 BP 297 EP 307 DI 10.4161/epi.27111 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AB6EK UT WOS:000331880200014 PM 24225485 ER PT J AU Wu, MC Joubert, BR Kuan, PF Haberg, SE Nystad, W Peddada, SD London, SJ AF Wu, Michael C. Joubert, Bonnie R. Kuan, Pei-fen Haberg, Siri E. Nystad, Wenche Peddada, Shyamal D. London, Stephanie J. TI A systematic assessment of normalization approaches for the Infinium 450K methylation platform SO EPIGENETICS LA English DT Article DE association testing; cotinine exposure; genome wide methylation profiling; normalization; reproducibility ID DNA METHYLATION; QUANTILE NORMALIZATION; PREGNANCY; NEWBORNS; SMOKING; CANCER AB The Illumina Infinium HumanMethylation450 BeadChip has emerged as one of the most popular platforms for genome wide profiling of DNA methylation. While the technology is wide-spread, systematic technical biases are believed to be present in the data. For example, this array incorporates two different chemical assays, i.e., Type I and Type II probes, which exhibit different technical characteristics and potentially complicate the computational and statistical analysis. Several normalization methods have been introduced recently to adjust for possible biases. However, there is considerable debate within the field on which normalization procedure should be used and indeed whether normalization is even necessary. Yet despite the importance of the question, there has been little comprehensive comparison of normalization methods. We sought to systematically compare several popular normalization approaches using the Norwegian Mother and Child Cohort Study (MoBa) methylation data set and the technical replicates analyzed with it as a case study. We assessed both the reproducibility between technical replicates following normalization and the effect of normalization on association analysis. Results indicate that the raw data are already highly reproducible, some normalization approaches can slightly improve reproducibility, but other normalization approaches may introduce more variability into the data. Results also suggest that differences in association analysis after applying different normalizations are not large when the signal is strong, but when the signal is more modest, different normalizations can yield very different numbers of findings that meet a weaker statistical significance threshold. Overall, our work provides useful, objective assessment of the effectiveness of key normalization methods. C1 [Wu, Michael C.; Kuan, Pei-fen] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA. [Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Joubert, Bonnie R.; Peddada, Shyamal D.; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Haberg, Siri E.; Nystad, Wenche] Norwegian Inst Publ Hlth, Oslo, Norway. RP Wu, MC (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA. EM mcwu@fhcrc.org; London2@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290; Wu, Michael C./0000-0002-3357-6570 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019]; NIH [P30ES010126, R01HD058008]; Norwegian Ministry of Health; Ministry of Education and Research, NIH/NIEHS [NO-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and NIH grants P30ES010126 and R01HD058008. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no NO-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). NR 24 TC 24 Z9 24 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD FEB 1 PY 2014 VL 9 IS 2 BP 318 EP 329 DI 10.4161/epi.27119 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AB6EK UT WOS:000331880200016 PM 24241353 ER PT J AU West, RR Hsu, AP Holland, SM Cuellar-Rodriguez, J Hickstein, DD AF West, Robert R. Hsu, Amy P. Holland, Steven M. Cuellar-Rodriguez, Jennifer Hickstein, Dennis D. TI Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation SO HAEMATOLOGICA LA English DT Article ID CHRONIC MYELOMONOCYTIC LEUKEMIA; FAMILIAL MYELODYSPLASTIC SYNDROME; PROGNOSTIC MODEL; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; MONOMAC SYNDROME; SRSF2 MUTATIONS; PROSTATE-CANCER; POOR-PROGNOSIS; GENE-MUTATIONS AB Inherited or sporadic heterozygous mutations in the transcription factor GATA2 lead to a clinical syndrome characterized by non-tuberculous mycobacterial and other opportunistic infections, a severe deficiency in monocytes, B cells and natural killer cells, and progression from a hypocellular myelodysplastic syndrome to myeloid leukemias. To identify acquired somatic mutations associated with myeloid transformation in patients with GATA2 mutations, we sequenced the region of the ASXL1 gene previously associated with transformation from myelodysplasia to myeloid leukemia. Somatic, heterozygous ASXL1 mutations were identified in 14/48 (29%) of patients with GATA2 deficiency, including four out of five patients who developed a proliferative chronic myelomonocytic leukemia. Although patients with GATA2 mutations had a similarly high incidence of myeloid transformation when compared to previously described patients with ASXL1 mutations, GATA2 deficiency patients with acquired ASXL1 mutation were considerably younger, almost exclusively female, and had a high incidence of transformation to a proliferative chronic myelomonocytic leukemia. These patients may benefit from allogeneic hematopoietic stem cell transplantation before the development of acute myeloid leukemia or chronic myelomonocytic leukemia. C1 [West, Robert R.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hsu, Amy P.; Holland, Steven M.; Cuellar-Rodriguez, Jennifer] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP West, RR (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM westrob@mail.nih.gov FU National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases; Mark Hatfield Clinical Research Center FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and the Mark Hatfield Clinical Research Center. NR 43 TC 23 Z9 23 U1 0 U2 5 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2014 VL 99 IS 2 BP 276 EP 281 DI 10.3324/haematol.2013.090217 PG 6 WC Hematology SC Hematology GA AH6PU UT WOS:000336253900019 PM 24077845 ER PT J AU Kristinsson, SY Gridley, G Hoover, RN Check, D Landgren, O AF Kristinsson, Sigurdur Y. Gridley, Gloria Hoover, Robert N. Check, David Landgren, Ola TI Long-term risks after splenectomy among 8,149 cancer-free American veterans: a cohort study with up to 27 years follow-up SO HAEMATOLOGICA LA English DT Article ID POSTSPLENECTOMY INFECTION; ANTIBODY-RESPONSE; PREVENTION; MORTALITY; SPLEEN; ADULTS; POLYSACCHARIDE; THROMBOSIS; CHILDHOOD; CLEARANCE AB Although preservation of the spleen following abdominal trauma and spleen-preserving surgical procedures have become gold standards, about 22,000 splenectomies are still conducted annually in the USA. Infections, mostly by encapsulated organisms, are the most well-known complications following splenectomy. Recently, thrombosis and cancer have become recognized as potential adverse outcomes post-splenectomy. Among more than 4 million hospitalized USA veterans, we assessed incidence and mortality due to infections, thromboembolism, and cancer including 8,149 cancer-free veterans who underwent splenectomy with a follow-up of up to 27 years. Relative risk estimates and 95% confidence intervals were calculated using time-dependent Poisson regression methods for cohort data. Splenectomized patients had an increased risk of being hospitalized for pneumonia, meningitis, and septicemia (rate ratios = 1.9-3.4); deep venous thrombosis and pulmonary embolism (rate ratios = 2.2); certain solid tumors: buccal, esophagus, liver, colon, pancreas, lung, and prostate (rate ratios = 1.3-1.9); and hematologic malignancies: non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and any leukemia (rate ratios = 1.8-6.0). They also had an increased risk of death due to pneumonia and septicemia (rate ratios = 1.6-3.0); pulmonary embolism and coronary artery disease (rate ratios = 1.4-4.5); any cancer: liver, pancreas, and lung cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and any leukemia (rate ratios = 1.3-4.7). Many of the observed risks were increased more than 10 years after splenectomy. Our results underscore the importance of vaccination, surveillance, and thromboprophylaxis after splenectomy. C1 [Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kristinsson, Sigurdur Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. [Gridley, Gloria; Hoover, Robert N.; Check, David; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Univ Iceland, Fac Med, Reykjavik, Iceland. EM sigyngvi@hi.is RI Kristinsson, Sigurdur /M-2910-2015; Check, David/J-7184-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476; Check, David/0000-0003-3887-0493 FU National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA FX This work was funded by the Intramural Research Program of the National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA. NR 47 TC 45 Z9 46 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2014 VL 99 IS 2 BP 392 EP 398 DI 10.3324/haematol.2013.092460 PG 7 WC Hematology SC Hematology GA AH6PU UT WOS:000336253900035 PM 24056815 ER EF