FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Leinonen, M Soderberg, K Olivecrona, H Raboisson, MA Sibley, C Brewer, C Plass, N King, K Zalewski, C Kim, J Stone, D Chapelle, D Goldbach-Mansky, R AF Leinonen, M. Soderberg, K. Olivecrona, H. Raboisson, M. Alden Sibley, C. Brewer, C. Plass, N. King, K. Zalewski, C. Kim, J. Stone, D. Chapelle, D. Goldbach-Mansky, R. TI THE IL-1RA ANTAGONIST KINERET (R) (ANAKINRA) STABILIZES HEARING LOSS IN PATIENTS WITH SEVERE CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Leinonen, M.] 4Pharma AB, Stockholm, Sweden. [Soderberg, K.; Olivecrona, H.; Raboisson, M. Alden] Swedish Orphan Biovitrum, Stockholm, Sweden. [Sibley, C.; Plass, N.; Stone, D.; Chapelle, D.; Goldbach-Mansky, R.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Brewer, C.; King, K.; Zalewski, C.; Kim, J.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 730 EP 731 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587904259 ER PT J AU Kullenberg, T Lofqvist, M Olivecrona, H Plass, N Kost, B Sibley, C Goldbach-Mansky, R AF Kullenberg, T. Lofqvist, M. Olivecrona, H. Plass, N. Kost, B. Sibley, C. Goldbach-Mansky, R. TI SAFETY PROFILE OF THE IL-1 RECEPTOR ANTAGONIST KINERET (R) (ANAKINRA) IN A LONG-TERM OUTCOME STUDY IN PATIENTS WITH SEVERE CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract C1 [Kullenberg, T.; Lofqvist, M.; Olivecrona, H.] Swedish Orphan Biovitrum, Stockholm, Sweden. [Plass, N.; Kost, B.; Sibley, C.; Goldbach-Mansky, R.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUN PY 2013 VL 72 SU 3 BP 745 EP 746 PG 2 WC Rheumatology SC Rheumatology GA AB1XT UT WOS:000331587904304 ER PT J AU Melvin, CL Corbie-Smith, G Kumanyika, SK Pratt, CA Nelson, C Walker, ER Ammerman, A Ayala, GX Best, LG Cherrington, AL Economos, CD Green, LW Harman, J Hooker, SP Murray, DM Perri, MG Ricketts, TC AF Melvin, Cathy L. Corbie-Smith, Giselle Kumanyika, Shiriki K. Pratt, Charlotte A. Nelson, Cheryl Walker, Evelyn R. Ammerman, Alice Ayala, Guadalupe X. Best, Lyle G. Cherrington, Andrea L. Economos, Christina D. Green, Lawrence W. Harman, Jane Hooker, Steven P. Murray, David M. Perri, Michael G. Ricketts, Thomas C. CA Workshop Working Grp CVD TI Developing a Research Agenda for Cardiovascular Disease Prevention in High-Risk Rural Communities SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CORONARY-HEART-DISEASE; UNITED-STATES; PHYSICAL-ACTIVITY; PRIMARY-CARE; HEALTH-CARE; MORTALITY; CHILDREN; WEIGHT; POLICY; WOMEN AB The National Institutes of Health convened a workshop to engage researchers and practitioners in dialogue on research issues viewed as either unique or of particular relevance to rural areas, key content areas needed to inform policy and practice in rural settings, and ways rural contexts may influence study design, implementation, assessment of outcomes, and dissemination. Our purpose was to develop a research agenda to address the disproportionate burden of cardiovascular disease (CVD) and related risk factors among populations living in rural areas. Complementary presentations used theoretical and methodological principles to describe research and practice examples from rural settings. Participants created a comprehensive CVD research agenda that identified themes and challenges, and provided 21 recommendations to guide research, practice, and programs in rural areas. C1 [Melvin, Cathy L.] Med Univ S Carolina, Charleston, SC 29425 USA. [Corbie-Smith, Giselle; Ammerman, Alice; Ricketts, Thomas C.] Univ N Carolina, Chapel Hill, NC USA. [Kumanyika, Shiriki K.] Univ Penn, Philadelphia, PA 19104 USA. [Pratt, Charlotte A.; Nelson, Cheryl; Walker, Evelyn R.; Harman, Jane] NHLBI, NIH, Bethesda, MD 20892 USA. [Ayala, Guadalupe X.] San Diego State Univ, San Diego, CA 92182 USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Cherrington, Andrea L.] Univ Alabama Birmingham, Birmingham, AL USA. [Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Medford, MA 02155 USA. [Green, Lawrence W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hooker, Steven P.] Univ S Carolina, Columbia, SC 29208 USA. [Murray, David M.] Ohio State Univ, Columbus, OH 43210 USA. [Perri, Michael G.] Univ Florida, Gainesville, FL USA. RP Melvin, CL (reprint author), Med Univ S Carolina, MSC 955, Charleston, SC 29425 USA. EM melvinc@musc.edu OI Hooker, Steven/0000-0001-9969-6244 FU National Heart, Lung and Blood Institute; National Institute of Minority Health and Health Disparities; Centers for Disease Control and Prevention (CDC); Office of Rural Health Policy (OHRP), Health Resources and Services Administration (HRSA) FX The June 14-15, 2010, workshop, Developing a Research Agenda for Cardiovascular Disease Prevention in High-risk Rural Communities: Guiding Principles and Recommendations, was funded by the National Heart, Lung and Blood Institute and in collaboration with the National Institute of Minority Health and Health Disparities, the Centers for Disease Control and Prevention (CDC), and the Office of Rural Health Policy (OHRP), Health Resources and Services Administration (HRSA). NR 56 TC 10 Z9 10 U1 1 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2013 VL 103 IS 6 BP 1011 EP 1021 DI 10.2105/AJPH.2012.300984 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3FI UT WOS:000330977900030 PM 23597371 ER PT J AU Gaglio, B Shoup, JA Glasgow, RE AF Gaglio, Bridget Shoup, Jo Ann Glasgow, Russell E. TI The RE-AIM Framework: A Systematic Review of Use Over Time SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Review ID PUBLIC-HEALTH IMPACT; SELF-MANAGEMENT INTERVENTION; PHYSICAL-ACTIVITY; PREVENTION PROGRAM; TRANSLATION; WOMEN; MODEL; IMPLEMENTATION; DISSEMINATION; EVALUATE AB We provided a synthesis of use, summarized key issues in applying, and highlighted exemplary applications in the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. We articulated key RE-AIM criteria by reviewing the published literature from 1999 to 2010 in several databases to describe the application and reporting on various RE-AIM dimensions. After excluding nonempirical articles, case studies, and commentaries, 71 articles were identified. The most frequent publications were on physical activity, obesity, and disease management. Four articles reported solely on 1 dimension compared with 44 articles that reported on all 5 dimensions of the framework. RE-AIM was broadly applied, but several criteria were not reported consistently. C1 [Gaglio, Bridget] Kaiser Permanente Midatlantic States, Midatlantic Permanente Res Inst, Rockville, MD 20852 USA. [Shoup, Jo Ann] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci Disseminat & Imple, Rockville, MD USA. RP Gaglio, B (reprint author), Kaiser Permanente Midatlantic States, Midatlantic Permanente Res Inst West 3, Rockville, MD 20852 USA. EM bridget.gaglio@kp.org NR 33 TC 61 Z9 61 U1 11 U2 41 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUN PY 2013 VL 103 IS 6 BP E38 EP E46 DI 10.2105/AJPH.2013.301299 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3FI UT WOS:000330977900012 PM 23597377 ER PT J AU Rowland, JH Kent, EE Forsythe, LP Loge, JH Hjorth, L Glaser, A Mattioli, V Fossa, SD AF Rowland, Julia H. Kent, Erin E. Forsythe, Laura P. Loge, Jon Havard Hjorth, Lars Glaser, Adam Mattioli, Vittorio Fossa, Sophie D. TI Cancer Survivorship Research in Europe and the United States: Where Have We Been, Where Are We Going, and What Can We Learn From Each Other? SO CANCER LA English DT Article DE cancer; survivorship; research; Europe; United States ID QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; LONG-TERM SURVIVORS; HEALTH INTERVIEW SURVEY; BREAST-CANCER; CHILDHOOD-CANCER; TESTICULAR CANCER; PHYSICAL-ACTIVITY; INITIAL TREATMENT; CLINICAL-TRIALS AB The growing number of cancer survivors worldwide has led to of the emergence of diverse survivorship movements in the United States and Europe. Understanding the evolution of cancer survivorship within the context of different political and health care systems is important for identifying the future steps that need to be taken and collaborations needed to promote research among and enhance the care of those living after cancer. The authors first review the history of survivorship internationally and important related events in both the United States and Europe. Lessons learned from survivorship research are then broadly discussed, followed by examination of the infrastructure needed to sustain and advance this work, including platforms for research, assessment tools, and vehicles for the dissemination of findings. Future perspectives concern the identification of collaborative opportunities for investigators in Europe and the United States to accelerate the pace of survivorship science going forward. (C) 2013 American Cancer Society. C1 [Rowland, Julia H.; Kent, Erin E.; Forsythe, Laura P.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. [Kent, Erin E.; Forsythe, Laura P.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH,DHHS, Bethesda, MD 20892 USA. [Loge, Jon Havard; Fossa, Sophie D.] Oslo Univ Hosp, Norwegian Radium Hosp, Natl Resource Ctr Late Effects Canc Treatment, Oslo, Norway. [Loge, Jon Havard; Fossa, Sophie D.] Univ Oslo, Oslo, Norway. [Hjorth, Lars] Lund Univ, Dept Pediat, Skane Univ Hosp, Lund, Sweden. [Glaser, Adam] Leeds Teaching Hosp NHS Trust, Paediat & Adolescent Oncol Program, Leeds, W Yorkshire, England. [Glaser, Adam] Natl Canc Survivor Initiat, Dept Hlth, London, England. [Mattioli, Vittorio] Natl Canc Res Ctr, Dept Crit Area & Surg, Giovanni Paolo II Canc Inst, Bari, Italy. RP Rowland, JH (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM rowlandj@mail.nih.gov FU National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health; American Cancer Society's Behavioral Research Center FX This supplement was sponsored by the National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health-funded research project "Multidimensional assessment of long-term cancer survivors including discovery of genetic bases of susceptibility, depressive stage, prevention of affective disorders," and through intramural funding of the American Cancer Society's Behavioral Research Center. NR 74 TC 27 Z9 27 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 1 PY 2013 VL 119 SU 11 BP 2094 EP 2108 DI 10.1002/cncr.28060 PG 15 WC Oncology SC Oncology GA 303LJ UT WOS:000330675400005 PM 23695922 ER PT J AU Minton, O Berger, A Barsevick, A Cramp, F Goedendorp, M Mitchell, SA Stone, PC AF Minton, Ollie Berger, Ann Barsevick, Andrea Cramp, Fiona Goedendorp, Martine Mitchell, Sandra A. Stone, Patrick C. TI Cancer-Related Fatigue and Its Impact on Functioning SO CANCER LA English DT Article DE cancer-related fatigue; neoplasms; survivors; interventions ID PATIENT-REPORTED OUTCOMES; CLINICAL-TRIALS; PHYSICAL-ACTIVITY; SURVIVORS; RECOMMENDATIONS; REHABILITATION; INTERVENTIONS; METAANALYSIS; ONCOLOGY; COMMON AB This article presents the contrasting European and American perspectives on cancer-related fatigue (CRF) and its impact on functioning in cancer survivors. The content is presented in 3 sections: state of the art, intervention studies, and future areas of research, followed by a discussion. Gaps identified include a lack of understanding of the etiology, definition, and measurement of CRF. Models to guide the study of CRF, selection of biomarkers, and design of interventions are needed. There is overlap between Europe and the United States concerning the future directions for research and collaboration related to CRF. The authors suggest the need for international consensus regarding the defining features of CRF in cancer survivors to identify phenotypes, a harmonized measurement of CRF outcomes using instruments that have demonstrated measurement equivalence across languages and cultures, and interventions (including exercise, rehabilitation, and psychoeducational) that have been manualized to permit intervention fidelity across diverse contexts. Coordinated intercontinental efforts would increase understanding of the biological, psychological, and social mechanisms underlying CRF and assist in the design of future intervention studies as well as revisions to clinical guidelines. (C) 2013 American Cancer Society. C1 [Minton, Ollie; Stone, Patrick C.] St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 ORE, England. [Berger, Ann] Univ Nebraska, Coll Nursing, Omaha, NE 68198 USA. [Barsevick, Andrea] Thomas Jefferson Univ, Fox Chase Canc Ctr, Philadelphia, PA 19107 USA. [Cramp, Fiona] Univ W England, Fac Hlth & Life Sci, Bristol BS16 1QY, Avon, England. [Goedendorp, Martine] Radboud Univ Nijmegen, Med Ctr, Expert Ctr Chron Fatigue, NL-6525 ED Nijmegen, Netherlands. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Minton, O (reprint author), St Georges Univ London, Div Populat Hlth Sci & Educ, 6th Fl Hunter Wing,Cranmer Terrace, London SW17 ORE, England. EM ominton@sgul.ac.uk; aberger@unmc.edu OI Cramp, Fiona/0000-0001-8035-9758; Barsevick, Andrea/0000-0003-1829-6826; Stone, Patrick/0000-0002-5765-9047 FU National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health; American Cancer Society's Behavioral Research Center FX This supplement was sponsored by the National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health- funded research project "Multidimensional assessment of long-term cancer survivors including discovery of genetic bases of susceptibility, depressive stage, prevention of affective disorders," and through intramural funding of the American Cancer Society's Behavioral Research Center. NR 48 TC 33 Z9 36 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 1 PY 2013 VL 119 SU 11 BP 2124 EP 2130 DI 10.1002/cncr.28058 PG 7 WC Oncology SC Oncology GA 303LJ UT WOS:000330675400007 PM 23695924 ER PT J AU Alfano, CM Molfino, A Muscaritoli, M AF Alfano, Catherine M. Molfino, Alessio Muscaritoli, Maurizio TI Interventions to Promote Energy Balance and Cancer Survivorship SO CANCER LA English DT Article DE cancer; survivorship; research; Europe; United States; diet; exercise; obesity ID RANDOMIZED CONTROLLED-TRIAL; PHYSICAL-ACTIVITY TRIALS; QUALITY-OF-LIFE; BREAST-CANCER; RISK-FACTORS; EXERCISE INTERVENTIONS; COLORECTAL-CARCINOMA; SUPERVISED EXERCISE; MODERATE EXERCISE; WEIGHT-REDUCTION AB The growing population of cancer survivors worldwide and the growing epidemics of obesity and physical inactivity have brought increased attention to the role that interventions to promote exercise and a healthy body weight may play in mitigating the chronic and late effects of cancer. In this light, the authors describe the similarities and differences in research and clinical priorities related to energy balance interventions among post-treatment cancer survivors in Europe versus North America. Randomized controlled trials that targeted nutrition, exercise, and weight are reviewed to determine the affect on survivorship outcomes. Interventions focused on improving prognosis or survival are investigated along with the emerging literature on the interventions targeting pathways and mechanisms of prognosis or survival. Current North American and European guidelines for diet, exercise, and weight control among cancer survivors also are investigated along with the implications of the current state of this science for clinical care. Finally, the authors delineate future European and American priorities for research and care involving energy balance among survivors. It is hoped that this dialogue launches an international conversation that will lead to better research and care for all post-treatment cancer survivors. (C) 2013 American Cancer Society. C1 [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Molfino, Alessio; Muscaritoli, Maurizio] Univ Roma La Sapienza, Dept Clin Med, I-00185 Rome, Italy. RP Muscaritoli, M (reprint author), Univ Roma La Sapienza, Dept Clin Med, Viale Univ 37, I-00185 Rome, Italy. EM maurizio.muscaritoli@uniroma1.it FU National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health; American Cancer Society's Behavioral Research Center FX This supplement was sponsored by the National Cancer Research Centre Istituto Tumori "Giovanni Paolo II" Bari (Italy) through the Italian Ministry of Health-funded research project "Multidimensional assessment of long-term cancer survivors including discovery of genetic bases of susceptibility, depressive stage, prevention of affective disorders," and through intramural funding of the American Cancer Society's Behavioral Research Center. NR 65 TC 10 Z9 10 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 1 PY 2013 VL 119 SU 11 BP 2143 EP 2150 DI 10.1002/cncr.28062 PG 8 WC Oncology SC Oncology GA 303LJ UT WOS:000330675400009 PM 23695926 ER PT J AU Simeon-Dubach, D Zaayenga, A Henderson, MK AF Simeon-Dubach, Daniel Zaayenga, Andy Henderson, Marianne K. TI Disaster and Recovery: The Importance of Risk Assessment and Contingency Planning for Biobanks SO BIOPRESERVATION AND BIOBANKING LA English DT Editorial Material C1 [Simeon-Dubach, Daniel] Medserv Biobanking Consulting & Serv, Walchwil, Switzerland. [Zaayenga, Andy] Lab Automat Consulting, SmarterLab, Martinsville, NJ USA. [Henderson, Marianne K.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Henderson, MK (reprint author), NCI, Off Div Operat & Anal, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. EM hendersm@mail.nih.gov RI Simeon-Dubach, Daniel/J-8276-2016 NR 0 TC 2 Z9 2 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD JUN PY 2013 VL 11 IS 3 BP 133 EP 134 DI 10.1089/bio.2013.1131 PG 2 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA 300GT UT WOS:000330453100001 PM 24850087 ER PT J AU Grizzle, WE Moore, HM AF Grizzle, William E. Moore, Helen M. TI Mouse Model Findings and the Future of Human Tissue in Disease Research SO BIOPRESERVATION AND BIOBANKING LA English DT Editorial Material C1 [Grizzle, William E.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Moore, Helen M.] NCI, Bethesda, MD 20892 USA. RP Grizzle, WE (reprint author), Univ Alabama Birmingham, Div Anat Pathol, Dept Pathol, ZRB 408,1720 Second Ave South, Birmingham, AL 35294 USA. EM wgrizzle@uab.edu; moorehe@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD JUN PY 2013 VL 11 IS 3 BP 135 EP 136 DI 10.1089/bio.2013.1132 PG 2 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA 300GT UT WOS:000330453100002 PM 24850088 ER PT J AU Glasgow, RE AF Glasgow, Russell E. TI What Does It Mean to Be Pragmatic? Pragmatic Methods, Measures, and Models to Facilitate Research Translation SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE evaluation; implementation; measurement; pragmatic trial; research design; theory ID PRACTICAL CLINICAL-TRIALS; HEALTH BEHAVIOR; CARE; DESIGN; POLICY; DISSEMINATION; INTERVENTIONS; VALIDATION; DEPRESSION; SCIENCE AB Background. One of the reasons for the slow and uncertain translation of research into practice is likely due to the emphasis in science on explanatory models and efficacy designs rather than more pragmatic approaches. Methods. Following a brief definition of what constitutes a pragmatic approach, I provide examples of pragmatic methods, measures, and models and how they have been applied. Results. Descriptions are provided of pragmatic trials and related designs, practical measures including patient-reported items for the electronic health record, and the Evidence Integration Triangle and RE-AIM practical models, each of which can help increase the relevance of research to policy makers, practitioners, and patients/consumers. Conclusions. By focusing on the perspective of stakeholders and the context for application of scientific findings, pragmatic approaches can accelerate the integration of research, policy, and practice. Progress has been made, especially in pragmatic trials but even more opportunities remain. C1 [Glasgow, Russell E.] NCI, Rockville, MD 20852 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 1630 Execut Blvd, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov NR 55 TC 55 Z9 55 U1 2 U2 26 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD JUN PY 2013 VL 40 IS 3 BP 257 EP 265 DI 10.1177/1090198113486805 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 298AC UT WOS:000330295200001 PM 23709579 ER PT J AU Glasgow, RE Eckstein, ET ElZarrad, MK AF Glasgow, Russell E. Eckstein, Erin T. ElZarrad, M. Khair TI Implementation Science Perspectives and Opportunities for HIV/AIDS Research: Integrating Science, Practice, and Policy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE implementation Science; external validity; framework; dissemination; HIV/AIDS; evaluation ID EFFECTIVE BEHAVIORAL INTERVENTIONS; PARTICIPATORY RESEARCH; DISEASE PREVENTION; HEALTH-CARE; TRANSLATION; HIV; POPULATIONS; STRATEGIES; DIFFUSION; SETTINGS AB Background: Disparities in the incidence and mortality of HIV/AIDS persist, challenging researchers, practitioners, and communities to develop improved strategies to reach vulnerable and marginalized populations. Methods: The emerging field of Implementation Science, with its focus on context, external validity, and innovative design approaches, is well suited to respond to this challenge. We provide an overview of Implementation Science, including its frameworks, tools, and strategies, and how they can inform the response to HIV/AIDS. Results: We summarize pioneering Implementation Science frameworks, and then present examples using newer models, including RE-AIM (Reach, Effectiveness/Efficacy, Adoption, Implementation, Maintenance) and the Evidence Integration Triangle, a framework for combining research and practice using participatory and adaptive processes in a multilevel context. Conclusions: Although still developing, the international field of Implementation Science can offer helpful perspectives for facilitating the more rapid integration of HIV/AIDS research, practice, and policy. C1 [Glasgow, Russell E.; Eckstein, Erin T.; ElZarrad, M. Khair] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [ElZarrad, M. Khair] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 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 Agency for Healthcare Research and Quality; [R13 MH-081733-01A1] FX Supported by the Agency for Healthcare Research and Quality. Additional support for the supplement was provided by R13 MH-081733-01A1. NR 39 TC 19 Z9 19 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2013 VL 63 SU 1 BP S26 EP S31 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300IU UT WOS:000330458400005 PM 23673882 ER PT J AU Rausch, DM Grossman, CI Erbelding, EJ AF Rausch, Dianne M. Grossman, Cynthia I. Erbelding, Emily J. TI Integrating Behavioral and Biomedical Research in HIV Interventions: Challenges and Opportunities SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE integration; HIV prevention; HIV research; behavioral; biomedical ID PLANNED BEHAVIOR; SEXUAL-BEHAVIOR; PREEXPOSURE PROPHYLAXIS; ANTIRETROVIRAL THERAPY; PREVENTION; CARE; INFECTION; ADHERENCE; WOMEN; TRANSMISSION AB Recent clinical trials have demonstrated overwhelming success of biomedical tools to prevent the spread of HIV infection. However, the complex and somewhat disparate results of some of these trials have highlighted the need for effective integration of biomedical and behavioral sciences in the design and implementation of any future intervention trial. Integrating behavioral and biomedical sciences will require appropriate behavioral theories that can be used in the context of biomedical clinical trials and multidisciplinary teams working together from the earliest stages of trial design through to completion. It is also clear that integration of behavioral science will be necessary to implement prevention at the population level and reverse the HIV epidemic. C1 [Rausch, Dianne M.; Grossman, Cynthia I.] NIMH, Div AIDS Res, Rockville, MD 20852 USA. [Erbelding, Emily J.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Rausch, DM (reprint author), NIMH, Div AIDS Res, 6001 Execut Blvd,Room 6105, Rockville, MD 20852 USA. EM drausch@mail.nih.gov FU [R13 MH-081733-01A1] FX Support for the supplement was provided by R13 MH-081733-01A1. NR 43 TC 5 Z9 5 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2013 VL 63 SU 1 BP S6 EP S11 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300IU UT WOS:000330458400003 PM 23673890 ER PT J AU Zhou, SY Yang, TH Jacobson, KA Liang, BT AF Zhou, Siyuan Yang, Tiehong Jacobson, Kenneth A. Liang, Bruce T. TI The Therapeutic Effect of 2-Cyclohexylthio-AMP in Heart Failure SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE heart failure; P2X4 receptor; cardiac contractility; purines; ischemia ID CARDIAC P2X(4) RECEPTORS; CALSEQUESTRIN OVEREXPRESSION; VENTRICULAR MYOCYTES; ION-CHANNEL; ATP; CARDIOMYOPATHY; ACTIVATION; MECHANISM; RESCUE; MODEL AB Aim: The aim of this study was to investigate the therapeutic effect of 2-cyclohexylthio-adenosine 5 '-monophosphate (AMP) in mice with heart failure (HF). Methods: 2-Cyclohexylthio-AMP was dissolved in phosphate-buffered saline and infused in mice with ischemic HF after permanent left coronary [left anterior descending (LAD)] ligation and in calsequestrin (CSQ) mice with HF. Myocardial function ex vivo was determined in the working heart model. Cardiac function in vivo was assessed by echocardiography. Results: Injection of 2-cyclohexylthio-AMP induced a dose-dependent increase in +dP/dt, -dP/dt, and left ventricular developed pressure in normal wild-type mice and in CSQ mice with HF using the ex vivo working heart model. Spontaneous heart rate did not change after the injection of 2-cyclohexylthio-AMP. Compared with normal saline-treaded mice, chronic infusion of 2-cyclohexylthio-AMP in mice with ischemic HF after left coronary artery (LAD) ligation and in CSQ mice resulted in improved +dP/dt, -dP/dt, left ventricular developed pressure, and fractional shortening, restored the beta-adrenergic response and decreased heart weight/body weight ratios. Conclusions: 2-Cyclohexylthio-AMP improved the cardiac contractile performance and rescued mice from HF. This salutary action may result from the reduction of myocardial hypertrophy and the restoration of the beta-adrenergic response in both LAD ligation and CSQ mouse models of HF. The fact that this agent can increase contractile performance without heart rate increase should be desirable in HF therapy. C1 [Zhou, Siyuan; Yang, Tiehong; Liang, Bruce T.] Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, Farmington, CT 06030 USA. [Zhou, Siyuan; Yang, Tiehong] Fourth Mil Med Univ, Dept Pharmaceut, Sch Pharm, Xian 710032, Peoples R China. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, MC-3946,263 Farmington Ave, Farmington, CT 06030 USA. EM bliang@uchc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases; [RO1-HL48225] FX Supported in part by RO1-HL48225 to Bruce T. Liang. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 29 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 EI 1533-4023 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD JUN PY 2013 VL 61 IS 6 BP 553 EP 559 PG 7 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 298UP UT WOS:000330350300015 PM 23474842 ER PT J AU Gudmundsson, LS Scher, AI Sigurdsson, S Geerlings, MI Vidal, JS Eiriksdottir, G Garcia, MI Harris, TB Kjartansson, O Aspelund, T van Buchem, MA Gudnason, V Launer, LJ AF Gudmundsson, Larus S. Scher, Ann I. Sigurdsson, Sigurdur Geerlings, Mirjam I. Vidal, Jean-Sebastien Eiriksdottir, Gudny Garcia, Melissa I. Harris, Tamara B. Kjartansson, Olafur Aspelund, Thor van Buchem, Mark A. Gudnason, Vilmundur Launer, Lenore J. TI Migraine, depression, and brain volume The AGES-Reykjavik Study SO NEUROLOGY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; CARDIOVASCULAR-DISEASE; DSM-IV; RISK; METAANALYSIS; POPULATION; COMORBIDITY; HEADACHE; MINI; PREVALENCE AB Objective: To examine the joint association of migraine headache and major depressive disorder on brain volume in older persons without dementia. Methods: Participants (n = 4,296, 58% women) from the population-based Age, Gene/Environment Susceptibility-Reykjavik Study were assessed for migraine headache in 1967-1991 (age 51 years [range 33-65]) according to modified International Classification of Headache Disorders-II criteria. In 2002-2006 (age 76 years [range 66-96]), lifetime history of major depressive disorder (depression) was diagnosed according to DSM-IV criteria, and full-brain MRI was acquired, which was computer postprocessed into total brain volume (TBV) (gray matter [GM], white matter [WM], white matter hyperintensities) and CSF volume for each study subject. We compared brain tissue volumes by headache categories with or without depression using linear regression, adjusting for intracranial volume and other factors. Results: Compared with the reference group (no headache, no depression) TBV and WM and GM volumes were smaller in those with both migraine and depression (TBV -19.2 mL, 95% confidence interval [CI] -35.3, -3.1, p = 0.02; WM -12.8 mL, CI -21.3, -4.3, p = 0.003; GM -13.0 mL, CI -26.0, 0.1, p = 0.05) but not for those with migraine alone (TBV 0.4 mL, WM 0.2 mL, GM 0.6 mL) or depression alone (TBV -3.9 mL, WM -0.9 mL, GM -2.9 mL). Conclusions: Reporting both migraine and major depressive disorder was associated with smaller brain tissue volumes than having one or neither of these conditions. Migraineurs with depression may represent a distinct clinical phenotype with different long-term sequelae. Nonetheless, the number of subjects in the current study is relatively small and these findings need to be confirmed in future studies. C1 [Gudmundsson, Larus S.; Scher, Ann I.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Gudmundsson, Larus S.; Scher, Ann I.; Geerlings, Mirjam I.; Vidal, Jean-Sebastien; Garcia, Melissa I.; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Eiriksdottir, Gudny; Kjartansson, Olafur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Geerlings, Mirjam I.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Vidal, Jean-Sebastien] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. RP Gudmundsson, LS (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. EM larus.gudmundsson@usuhs.edu RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; Vidal, Jean-Sebastien/D-1941-2016 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Vidal, Jean-Sebastien/0000-0001-6770-0720 FU NIH [N01-AG-12100]; National Institute on Aging Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (the Icelandic Parliament) FX Supported by the NIH (N01-AG-12100), National Institute on Aging Intramural Research Program, Hjartavernd (Icelandic Heart Association), and Althingi (the Icelandic Parliament). NR 39 TC 9 Z9 10 U1 3 U2 9 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 JUN PY 2013 VL 80 IS 23 BP 2138 EP 2144 DI 10.1212/WNL.0b013e318295d69e PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 300MW UT WOS:000330469000014 PM 23700334 ER PT J AU Beydoun, MA Beydoun, HA Shroff, MR Kitner-Triolo, MH Zonderman, AB AF Beydoun, May A. Beydoun, Hind A. Shroff, Monal R. Kitner-Triolo, Melissa H. Zonderman, Alan B. TI Helicobacter pylori Seropositivity and Cognitive Performance Among US Adults: Evidence From a Large National Survey SO PSYCHOSOMATIC MEDICINE LA English DT Article DE Helicobacter pylori; seropositivity; cognitive function; adults; aging ID ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; UNITED-STATES; INFECTION; GASTRITIS; RISK; EPIDEMIOLOGY; ASSOCIATION; DEMENTIA; ATHEROSCLEROSIS AB Background: Helicobacter pylori seropositivity is a potential risk for poor cognition among US adults. Methods: Cross-sectional data from the National Health and Nutrition Examination Survey III, Phase 1 (1988Y1991), were used. Measures included age group-specific neuropsychological test batteries and two measures of H. pylori seropositivity (immunoglobulin G [IgG] and IgG CagA) (20-59 years old: n = 2090-2,248; 60-90 years old: n = 2123-2388). We explored sex-and race-specific associations. Results: Using multiple ordinary least square and zero-inflated Poisson regression models, we detected a poorer performance among those 60-90 years old with H. pylori IgG+ versus IgG- on a verbal memory test (story recall, correct items), overall (beta = -0.04 [0.01], p = .010). Non-Hispanic (NH) blacks and women (20-59 years old) performed worse on the serial digits learning total errors (SDL-TE) when H. pylori IgG+ (versus IgG-), another verbal memory test (beta = +0.94 [0.40; p = .029] and beta = +1.19 [0.44; p = .012], respectively; p<.10 for interaction by sex and race). More trials to completion on this test (SDL-TTC) were also required among H. pylori IgG+ overall (20-59 years old; beta = +0.30 [0.13], p = .033). Other race-specific associations without significant interaction by race were detected in the same direction of worse performance with seropositivity in all three major race groups and for both age categories, covering several domains of cognition. Conclusions: H. pylori seropositivity markers were associated with poor cognition among US adults. Longitudinal research is needed to extrapolote those findings to cognitive decline, incident dementia, and Alzheimer's disease. C1 [Beydoun, May A.; Kitner-Triolo, Melissa H.; Zonderman, Alan B.] NIA, NIH, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Shroff, Monal R.] Michigan Publ Hlth Inst, Okemos, MI USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging FX This research was fully supported by the Intramural Research Program of the National Institute on Aging. The authors report no conflicts of interest. NR 42 TC 17 Z9 19 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUN PY 2013 VL 75 IS 5 BP 486 EP 496 DI 10.1097/PSY.0b013e31829108c3 PG 11 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 300MO UT WOS:000330468200008 PM 23697465 ER PT J AU Sutin, AR Zonderman, AB Uda, M Deiana, B Taub, DD Longo, DL Ferrucci, L Schlessinger, D Cucca, F Terracciano, A AF Sutin, Angelina R. Zonderman, Alan B. Uda, Manuela Deiana, Barbara Taub, Dennis D. Longo, Dan L. Ferrucci, Luigi Schlessinger, David Cucca, Francesco Terracciano, Antonio TI Personality Traits and Leptin SO PSYCHOSOMATIC MEDICINE LA English DT Article DE leptin; personality traits; appetite; conscientiousness; neuroticism; obesity; impulsivity; self-discipline; inflammation; depression ID SERUM LEPTIN; BODY-MASS; DEPRESSION; OBESITY; OVERWEIGHT; STRESS; WEIGHT AB Objective: Personality traits related to high neuroticism and low conscientiousness are consistently associated with obesity. Hormones implicated in appetite and metabolism, such as leptin, may also be related to personality and may contribute to the association between these traits and obesity. The present research examined the association between leptin and Five Factor Model personality traits. Methods: A total of 5214 participants (58% women; mean [standard deviation] age = 44.42 [15.93] years; range, 18Y94 years) from the SardiNIA project completed the Revised NEO Personality Inventory, a comprehensive measure of personality traits, and their blood samples were assayed for leptin. Results: As expected, lower conscientiousness was associated with higher circulating levels of leptin (r = -0.05, p < .001), even after controlling for body mass index, waist circumference, or inflammatory markers (r = -0.05, p < .001). Neuroticism, in contrast, was unrelated to leptin (r = 0.01, p = .31). Conclusions: Individuals who are impulsive and lack discipline (low conscientiousness) may develop leptin resistance, which could be one factor that contributes to obesity, whereas the relation between a proneness to anxiety and depression (high neuroticism) and obesity may be mediated through other physiological and/or behavioral pathways. C1 [Sutin, Angelina R.; Terracciano, Antonio] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Sutin, Angelina R.; Zonderman, Alan B.; Taub, Dennis D.; Longo, Dan L.; Ferrucci, Luigi; Schlessinger, David; Terracciano, Antonio] NIA, NIH, DHHS, Baltimore, MD 21224 USA. [Uda, Manuela; Deiana, Barbara; Cucca, Francesco] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu RI terracciano, antonio/B-1884-2008; OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The authors report no conflicts of interest. NR 26 TC 9 Z9 9 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUN PY 2013 VL 75 IS 5 BP 505 EP 509 DI 10.1097/PSY.0b013e3182919ff4 PG 5 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 300MO UT WOS:000330468200010 PM 23697464 ER PT J AU Wolfe, LA Krasnewich, D AF Wolfe, Lynne A. Krasnewich, Donna TI CONGENITAL DISORDERS OF GLYCOSYLATION AND INTELLECTUAL DISABILITY SO DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS LA English DT Review DE metabolic disease; glycosylation; glycan; intellectual disability; microcephaly; macrocephaly; osteopenia ID EHLERS-DANLOS-SYNDROME; MENTAL-RETARDATION; GENETIC EVALUATION; CLINICAL SPECTRUM; MUTATIONS; DEFICIENCY; DEFECT; MANIFESTATIONS; BIOSYNTHESIS; TRANSPORTER AB The congenital disorders of glycosylation (CDG) are a rapidly growing group of inborn errors of metabolism that result from defects in the synthesis of glycans. Glycosylation is a major post-translational protein modification and an estimated 2% of the human genome encodes proteins for glycosylation. The molecular bases for the current 60 disorders, affecting approximately 800 individuals, have been identified, many in the last 5 years. CDG should be considered in any multi-system syndrome or single tissue disorder not explained by the identification of another disorder. The initial clinical presentation varies significantly among individuals, even between affected siblings. However, two thirds of the known CDGs are associated with intellectual disabilities and most affected individuals need support services throughout their lives. Additional disorders of glycosylation are likely to be characterized over time. (C) 2013 Wiley Periodicals, Inc. C1 [Wolfe, Lynne A.] NHGRI, Undiag Dis Program, Bethesda, MD 20892 USA. [Krasnewich, Donna] NIGMS, Bethesda, MD USA. RP Wolfe, LA (reprint author), NHGRI, Undiag Dis Program, 10 Ctr DR,MSC 1205,RM 3-2551, Bethesda, MD 20892 USA. EM Lynne.Wolfe@nih.gov FU National Human Genome Research Institute (NIH, Bethesda, Maryland) FX This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, Maryland). NR 81 TC 9 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1940-5510 EI 1940-5529 J9 DEV DISABIL RES REV JI Dev. Disabil. Res. Rev. PD JUN PY 2013 VL 17 IS 3-4 SI SI BP 211 EP 225 DI 10.1002/ddrr.1115 PG 15 WC Clinical Neurology; Neurosciences; Pediatrics; Psychiatry SC Neurosciences & Neurology; Pediatrics; Psychiatry GA 296HM UT WOS:000330175900004 PM 23798010 ER PT J AU Palm-Meinders, IH Arkink, EB Koppen, H Amlal, S Terwindt, GM Launer, LJ van Buchem, MA Ferrari, MD Kruit, MC AF Palm-Meinders, I. H. Arkink, E. B. Koppen, H. Amlal, S. Terwindt, G. M. Launer, L. J. van Buchem, M. A. Ferrari, M. D. Kruit, M. C. TI Structural Changes in Visual and Auditory Processing Brain Areas of Migraineurs from the General Population Using Voxel-Based Morphometry (VBM) SO CEPHALALGIA LA English DT Meeting Abstract CT International Headache Congress of the International-Headache-Society and American-Headache-Society CY JUN 27-30, 2013 CL Boston, MA SP Int Headache Soc, Amer Headache Soc C1 [Palm-Meinders, I. H.; Arkink, E. B.; Koppen, H.; Amlal, S.; Terwindt, G. M.; van Buchem, M. A.; Ferrari, M. D.; Kruit, M. C.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Koppen, H.] Haga Hosp, The Hague, Netherlands. [Launer, L. J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD JUN PY 2013 VL 33 IS S8 SU 8 BP 9 EP 9 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 287LS UT WOS:000329543900016 ER PT J AU Peterlin, BL Rosso, AL Williams, MA Rosenberg, JD Haythornthwaite, JA Merikangas, KR Gottesman, RF Bond, DS He, JP Zonderman, AB AF Peterlin, B. L. Rosso, A. L. Williams, M. A. Rosenberg, J. D. Haythornthwaite, J. A. Merikangas, K. R. Gottesman, R. F. Bond, D. S. He, J. -P. Zonderman, A. B. TI Episodic Migraine and Obesity: The Influence of Age, Sex, and Race SO CEPHALALGIA LA English DT Meeting Abstract CT International Headache Congress of the International-Headache-Society and American-Headache-Society CY JUN 27-30, 2013 CL Boston, MA SP Int Headache Soc, Amer Headache Soc C1 [Peterlin, B. L.; Rosenberg, J. D.; Gottesman, R. F.] Johns Hopkins Sch Med, Baltimore, MD USA. [Rosso, A. L.] Univ Pittsburgh, Pittsburgh, PA USA. [Williams, M. A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Haythornthwaite, J. A.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Merikangas, K. R.; He, J. -P.] NIMH, Hlth Serv, Bethesda, MD 20892 USA. [Merikangas, K. R.; He, J. -P.] NIMH, Human Serv, Bethesda, MD 20892 USA. [Bond, D. S.] Brown Alpert Med Sch, Providence, RI USA. [Zonderman, A. B.] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD JUN PY 2013 VL 33 IS S8 SU 8 BP 128 EP 128 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 287LS UT WOS:000329543900196 ER PT J AU Koppen, H Palm-Meinders, H Koutstaal, B Boele, HJ Koekoek, BK van der Geest, J Launer, LJ van Buchem, MA Terwindt, GM Ferrari, MD Kruit, MC de Zeeuw, CI AF Koppen, H. Palm-Meinders, H., I Koutstaal, B. Boele, H. -J. Koekoek, B. K. van der Geest, J. Launer, L. J. van Buchem, M. A. Terwindt, G. M. Ferrari, M. D. Kruit, M. C. de Zeeuw, C. I. TI Cerebellar Function in Migraine Patients and Its Relation with Cerebellar Ischemic Lesions SO CEPHALALGIA LA English DT Meeting Abstract CT International Headache Congress of the International-Headache-Society and American-Headache-Society CY JUN 27-30, 2013 CL Boston, MA SP Int Headache Soc, Amer Headache Soc C1 [Koppen, H.; Koutstaal, B.] Hagahospital The Hague, The Hague, Netherlands. [Palm-Meinders, H., I; van Buchem, M. A.; Terwindt, G. M.; Ferrari, M. D.; Kruit, M. C.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Boele, H. -J.; Koekoek, B. K.; van der Geest, J.; de Zeeuw, C. I.] Erasmus MC, Rotterdam, Netherlands. [Launer, L. J.] NIA, NIH, Bethesda, MD 20892 USA. RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD JUN PY 2013 VL 33 IS S8 SU 8 BP 228 EP 228 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 287LS UT WOS:000329543900358 ER PT J AU Lindeman, NI Cagle, PT Beasley, MB Chitale, DA Dacic, S Giaccone, G Jenkins, RB Kwiatkowski, DJ Saldivar, JS Squire, J Thunnissen, E Ladanyi, M AF Lindeman, Neal I. Cagle, Philip T. Beasley, Mary Beth Chitale, Dhananjay Arun Dacic, Sanja Giaccone, Giuseppe Jenkins, Robert Brian Kwiatkowski, David J. Saldivar, Juan-Sebastian Squire, Jeremy Thunnissen, Erik Ladanyi, Marc TI Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; FACTOR-RECEPTOR GENE; IN-SITU-HYBRIDIZATION; POLYMERASE-CHAIN-REACTION; MUTATION-SPECIFIC ANTIBODIES; RESOLUTION MELTING ANALYSIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; CHEMOTHERAPY-NAIVE PATIENTS; EML4-ALK FUSION GENE; SMART-AMPLIFICATION PROCESS AB Objective.-To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants.-Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence.-Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process.-Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions.-The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines. C1 [Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Cagle, Philip T.] Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Beasley, Mary Beth] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Chitale, Dhananjay Arun] Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA. [Dacic, Sanja] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Giaccone, Giuseppe] NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Jenkins, Robert Brian] Mayo Clin, Dept Lab Med & Pathol, Dept Lab Genet, Rochester, MN USA. [Saldivar, Juan-Sebastian] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Squire, Jeremy] Queens Univ, Kingston Gen Hosp, Dept Pathol & Mol Med, Kingston, ON, Canada. [Thunnissen, Erik] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Lindeman, NI (reprint author), Brigham & Womens Hosp, Shapiro 5020,75 Francis St, Boston, MA 02115 USA. EM nlindeman@partners.org RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU NCI NIH HHS [P01 CA129243] NR 318 TC 167 Z9 173 U1 0 U2 16 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 JUN PY 2013 VL 137 IS 6 BP 828 EP 860 DI 10.5858/arpa.2012-0720-OA PG 33 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 269QF UT WOS:000328256300016 PM 23551194 ER PT J AU Hayman, TJ Kramp, T Kahn, J Jamal, M Camphausen, K Tofilon, PJ AF Hayman, Thomas J. Kramp, Tamalee Kahn, Jenna Jamal, Muhammad Camphausen, Kevin Tofilon, Philip J. TI Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity SO TRANSLATIONAL ONCOLOGY LA English DT Article ID MAMMALIAN TARGET; TRANSLATION INITIATION; ANTITUMOR-ACTIVITY; CANCER; RAPAMYCIN; THERAPY; PATHWAY; GAMMA-H2AX; CARCINOMA; EIF4E AB The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR-containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on in vitro radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according gamma H2AX foci. PP242 exposure did not influence the initial level of gamma H2AX foci after irradiation but did significantly delay the dispersal of radiation-induced gamma H2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair. C1 [Hayman, Thomas J.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Hayman, Thomas J.; Kramp, Tamalee; Kahn, Jenna; Jamal, Muhammad; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Kahn, Jenna] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. RP Tofilon, PJ (reprint author), NCI, 10 Ctr Dr MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov FU National Cancer Institute [ZIA BC011373] FX Funding Source: National Cancer Institute (ZIA BC011373). NR 31 TC 5 Z9 5 U1 1 U2 2 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD JUN PY 2013 VL 6 IS 3 BP 355 EP 362 DI 10.1593/tlo.13163 PG 8 WC Oncology SC Oncology GA 270ZU UT WOS:000328360000016 PM 23730416 ER PT J AU Walton-Diaz, A Khan, S Bourboulia, D Trepel, JB Neckers, L Mollapour, M AF Walton-Diaz, Annerleim Khan, Sahar Bourboulia, Dimitra Trepel, Jane B. Neckers, Len Mollapour, Mehdi TI Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID SHOCK-PROTEIN 90; BREAST-CANCER MODELS; MOLECULAR CHAPERONE; SACCHAROMYCES-CEREVISIAE; ATPASE ACTIVITY; CRYSTAL-STRUCTURE; COCHAPERONE AHA1; MIDDLE DOMAIN; TYROSINE PHOSPHORYLATION; CONFORMATIONAL DYNAMICS AB Hsp90 is a molecular chaperone and important driver of stabilization and activation of several oncogenic proteins that are involved in the malignant transformation of tumor cells. Therefore, it is not surprising that Hsp90 has been reported to be a promising target for the treatment of several neoplasias, such as non-small-cell lung cancer and HER2-positive breast cancer. Hsp90 chaperone function depends on its ability to bind and hydrolyze ATP and Hsp90 inhibitors have been shown to compete with nucleotides for binding to Hsp90. Multiple factors, such as co-chaperones and post-translational modification, are involved in regulating Hsp90 ATPase activity. Here, the impact of post-translational modifications and co-chaperones on the efficacy of Hsp90 inhibitors are reviewed. C1 [Walton-Diaz, Annerleim; Khan, Sahar; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bourboulia, Dimitra; Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA. [Bourboulia, Dimitra; Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Trepel, Jane B.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mollapour, M (reprint author), SUNY Upstate Med Univ, Dept Biochem & Mol Biol, 750 East Adams St, Syracuse, NY 13210 USA. EM mollapourm@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the 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 139 TC 30 Z9 30 U1 2 U2 7 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 EI 1756-8927 J9 FUTURE MED CHEM JI Future Med. Chem. PD JUN PY 2013 VL 5 IS 9 BP 1059 EP 1071 DI 10.4155/fmc.13.88 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 257ZZ UT WOS:000327428300010 PM 23734688 ER PT J AU Chambers, DA Azrin, ST AF Chambers, David A. Azrin, Susan T. TI Partnership: A Fundamental Component of Dissemination and Implementation Research SO PSYCHIATRIC SERVICES LA English DT Article ID SCIENCE AB This columndescribes the essential role of partnerships in the conduct of dissemination and implementation (D&I) research. This research field, which develops knowledge to support the integration of health information and evidence-based practices, has thrived in recent years through research initiatives by federal agencies, states, foundations, and other funders. The authors describe three ongoing studies anchored in research partnerships to improve the implementation of effective practices within various service systems. Inherent in the challenge of introducing evidence-based practices in clinical and community settings is the participation of a wide range of stakeholders who may influence D&I efforts. Opportunities to enhance partnerships in D&I research are described, specifically in light of recent initiatives led by the National Institutes of Health. Partnerships remain a crucial component of successful D&I research. The future of the field depends on the ability to utilize partnerships to conduct more rigorous and robust research. C1 [Chambers, David A.; Azrin, Susan T.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Chambers, DA (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7144, Bethesda, MD 20892 USA. EM dchamber@mail.nih.gov NR 15 TC 17 Z9 17 U1 1 U2 6 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 JUN PY 2013 VL 64 IS 6 BP 509 EP 511 DI 10.1176/appi.ps.201300032 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 255XF UT WOS:000327272700003 PM 23728600 ER PT J AU Peng, J Liu, QY Rao, MS Zeng, XM AF Peng, Jun Liu, Qiuyue Rao, Mahendra S. Zeng, Xianmin TI Using Human Pluripotent Stem Cell-Derived Dopaminergic Neurons to Evaluate Candidate Parkinson's Disease Therapeutic Agents in MPP+ and Rotenone Models SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE stem cells; dopaminergic neurons; parkinsonism; neuroprotective ID NEUROTROPHIC FACTOR; DEFINED CONDITIONS; SUBSTANTIA-NIGRA; GDNF; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; DEGENERATION; APOPTOSIS; EXPOSURE; PATHWAY; CULTURE AB To begin to develop a high-throughput assay system to evaluate potential small-molecule therapy for Parkinson's disease (PD), we have performed a low-throughput assay with a small number of compounds using human pluripotent stem cell-derived dopaminergic neurons. We first evaluated the role of 44 compounds known to work in rodent systems in a 1-methyl-4-phenylpyridinium (MPP+) assay in a 96-well format using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay as a readout for neuroprotection. Glial cell-derived neurotrophic factor was used as a positive control because of its well-documented neuroprotective effect on dopaminergic neurons, and two concentrations of each drug were tested. Of 44 compounds screened, 16 showed a neuroprotective effect at one or both dosages tested. A dose-response curve of a subset of the 16 positives was established in the MPP+ model. In addition, we validated neuroprotective effects of these compounds in a rotenone-induced dopaminergic neuronal cell death, another established model for PD. Our human primary dopaminergic neuron-based assays provide a platform for rapid screening and/or validation of potential neuroprotective agents in PD treatment using patient-specific cells and show the importance of using human cells for such assays. C1 [Peng, Jun; Liu, Qiuyue; Zeng, Xianmin] Buck Inst Res Aging, Novato, CA 94945 USA. [Rao, Mahendra S.] NIH, Natl Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Zeng, XM (reprint author), Buck Inst Res Aging, Novato, CA 94945 USA. EM xzeng@buckinstitute.org FU California Institute for Regenerative Medicine [TR-01856, CL1-00501]; NIH CRM, a common fund initiative FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by California Institute for Regenerative Medicine Grants TR-01856 and CL1-00501 to X.Z. and the NIH CRM, a common fund initiative, to M. S. R. The authors thank Drs. Wei Zheng and Manju Swaroop and the compound management team at the National Center for Advancing Translational Sciences for proving the compounds. NR 23 TC 22 Z9 24 U1 0 U2 10 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 JUN PY 2013 VL 18 IS 5 BP 522 EP 533 DI 10.1177/1087057112474468 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 148ET UT WOS:000319226600002 PM 23364514 ER PT J AU Boreiri, M Samadi, F Etemadi, A Babaei, M Ahmadi, E Sharifi, AH Nikmanesh, A Houshiar, A Pouifarzi, F Yazdanbod, A Alimohammadian, M Sotoudeh, M AF Boreiri, Majid Samadi, Fatemeh Etemadi, Arash Babaei, Masoud Ahmadi, Emad Sharifi, Amir Houshang Nikmanesh, Arash Houshiar, Afshin Pouifarzi, Farhad Yazdanbod, Abbas Alimohammadian, Masoomeh Sotoudeh, Masoud TI Gastric Cancer Mortality in a High Incidence Area: Long-term follow-up of Helicobacter pylori-related Precancerous Lesions in the General Population SO ARCHIVES OF IRANIAN MEDICINE LA English DT Article DE Cohort study; gastric cancer; Helicobacter pylori; precancerous lesions; risk factors ID HIGH-RISK; CARDIA CANCER; IRAN; INFECTION; EPIDEMIOLOGY; ARDABIL; ADENOCARCINOMA; ERADICATION; PREVALENCE; REGISTRY AB Background: Due to a lack of clear criteria for recognizing subjects at risk of progression to gastric cancer (GC), this cohort study seeks to identify predictors of GC death in a high-risk population. Methods: During 2000-2001, 1011 randomly selected residents of Ardabil, Iran without a history of gastrointestinal diseases, underwent upper endoscopy with targeted biopsy sampling. Until 2013, cancer mortality data were obtained using cancer and death registry data and verbal autopsy reports. Cox regression was used to estimate hazard ratios (HR). Results: A total of 3.95% of the participants [mean age: 53.1 +/- 9.9 years, 49.8% males, and 88.2% Helicobacter pylori (H. pylori)-positive] died of GC. In the multivariate model, precancerous lesions at the beginning of follow-up were associated with increased GC mortality. The HR [95% confidence interval (CI)] was 7.4(1.6-33.8) for atrophic gastritis (AG) and 23.6 (5.5-102.3) for intestinal metaplasia (IM). Age over 50 (HR = 4.4; 1.3-14.2), family history of GC (HR = 6.8; 3.3-13.8), smoking (HR = 7.4; 3.2-17.3), and endoscopically confirmed gastric ulcer (GU, HR = 6.5; 2.5-16.4) were independently associated with GC mortality. The concomitant presence of a precancerous lesion increased the HR to 46.5 (10.8-198.6) for a family history of GC, 27.6 (6.5-116.4) for smoking, and 25.1 (6.3-105.3) for age >50 years. Conclusion: In this population with a high rate of H. pylori infection, age over 50 years, smoking, family history of GC, IM, AG, and in particular, an undiagnosed GU were significant independent risk factors for mortality due to GC. The assessment of a combination of these risk factors might identify individuals at risk of GC who could possibly benefit from regular surveillance. C1 [Boreiri, Majid; Samadi, Fatemeh; Etemadi, Arash; Ahmadi, Emad; Sharifi, Amir Houshang; Nikmanesh, Arash; Alimohammadian, Masoomeh; Sotoudeh, Masoud] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Samadi, Fatemeh; Babaei, Masoud; Houshiar, Afshin; Pouifarzi, Farhad; Yazdanbod, Abbas] Ardabil Univ Med Sci, Gastrointestinal Canc Res Ctr, Ardebil, Iran. [Etemadi, Arash] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Alimohammadian, Masoomeh] Univ Tehran Med Sci, Sch Publ Hlth, Tehran, Iran. RP Samadi, F (reprint author), Shariati Hosp, Digest Dis Res Ctr, Kargar E Shomali St, Tehran 14117, Iran. EM fatemsamadi@gmail.com RI Etemadi, Arash/C-1386-2016 OI Etemadi, Arash/0000-0002-3458-1072 FU Digestive Disease Research Center of Tehran University of Medical Sciences; National Cancer Institute at the National Institutes of Health, USA FX Financial support for this study was provided by a grant from the Digestive Disease Research Center of Tehran University of Medical Sciences. Also, intramural funds from the National Cancer Institute at the National Institutes of Health, USA contributed partly to this study. The funders were not involved in designing the study, collecting and analyzing the data, decision to publish, or preparing the manuscript. NR 36 TC 7 Z9 7 U1 0 U2 1 PU ACAD MEDICAL SCIENCES I R IRAN PI TEHRAN PA PO BOX 19395-5655, TEHRAN, 00000, IRAN SN 1029-2977 J9 ARCH IRAN MED JI Arch. Iran. Med. PD JUN PY 2013 VL 16 IS 6 BP 343 EP 347 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 243FX UT WOS:000326303400005 PM 23725067 ER PT J AU Garcia-Villada, L Drake, JW AF Garcia-Villada, Libertad Drake, John W. TI Experimental selection reveals a trade-off between fecundity and lifespan in the coliphage Q beta SO OPEN BIOLOGY LA English DT Article DE phage life-history evolution; phage fecundity; lifespan trade-off; phage evolutionary constraints; bacteriophage Q ss ID MOUTH-DISEASE VIRUS; CELL-CULTURE; LYSIS TIME; BACTERIOPHAGE; EVOLUTION; REPRODUCTION; COSTS; ADAPTATION; MUTATIONS; INFECTION AB Understanding virus evolution is key for improving ways to counteract virus-borne diseases. Results from comparative analyses have previously suggested a trade-off between fecundity and lifespan for viruses that infect the bacterium Escherichia coli (i.e. for coliphages), which, if confirmed, would define a particular constraint on the evolution of virus fecundity. Here, the occurrence of such a trade-off is investigated through a selection experiment using the coliphage Q ss. Selection was applied for increased fecundity in three independent wild-type Q ss populations, and the ability of the virions to remain viable outside the host was determined. The Q ss life-history traits involved in the evolution of fecundity and the genetic changes associated with this evolution were also investigated. The results reveal that short-term evolution of increased fecundity in Q ss was associated with decreased viability of phage virions. This trade-off apparently arose because fecundity increased at the expense of reducing the amount of resources (mainly time) invested per produced virion. Thus, the results also indicate that Q ss fecundity may be enhanced through increases in the rates of adsorption to the host and progeny production. Finally, genomic sequencing of the evolved populations pinpointed sequences likely to be involved in the evolution of Q ss fecundity. C1 [Garcia-Villada, Libertad; Drake, John W.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Garcia-Villada, L (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM garciavillal@niehs.nih.gov FU Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES065016] FX This research was supported by funds allocated to project number(s) Z01ES065016 of the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences. NR 43 TC 1 Z9 1 U1 0 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 2046-2441 J9 OPEN BIOL JI Open Biol PD JUN PY 2013 VL 3 IS 6 AR 130043 DI 10.1098/rsob.130043 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238UE UT WOS:000325975400005 PM 23760365 ER PT J AU Tajuddin, SM Amaral, AFS Fernandez, AF Rodriguez-Rodero, S Rodriguez, RM Moore, LE Tardon, A Carrato, A Garcia-Closas, M Silverman, DT Jackson, BP Garcia-Closas, R Cook, AL Cantor, KP Chanock, S Kogevinas, M Rothman, N Real, FX Fraga, MF Malats, N AF Tajuddin, Salman M. Amaral, Andre F. S. Fernandez, Agustin F. Rodriguez-Rodero, Sandra Maria Rodriguez, Ramon Moore, Lee E. Tardon, Adonina Carrato, Alfredo Garcia-Closas, Montserrat Silverman, Debra T. Jackson, Brian P. Garcia-Closas, Reina Cook, Ashley L. Cantor, Kenneth P. Chanock, Stephen Kogevinas, Manolis Rothman, Nathaniel Real, Francisco X. Fraga, Mario F. Malats, Nuria CA Spanish Bladder Canc EPICURO Study TI Genetic and Non-genetic Predictors of LINE-1 Methylation in Leukocyte DNA SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE DNA methylation; epigenetics; LINE-1; one-carbon metabolism gene variants; smoking; trace elements ID BLADDER-CANCER; EXPRESSION PROFILES; FOLATE STATUS; RISK; BLOOD; METABOLISM; MUTATIONS; ELEMENTS; LOCI; HYPOMETHYLATION AB BACKGROUND: Altered DNA methylation has been associated with various diseases. OBJECTIVE: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study. METHODS: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (beta s) by robust linear regression. RESULTS: Women had lower levels of LINE-1 methylation than men (beta = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (beta = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (beta = -3.6, p = 0.003). By contrast, iron (beta = 0.002, p = 0.009) and nickel (beta = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, beta = 0.3, p = 0.002), TCN2 (rs9606756-GG, beta = 1.9, p = 0.008; rs4820887-AA, beta = 4.0, p = 4.8 x 10(-7); rs9621049-TT, beta = 4.2, p = 4.7 x 10(-9)), AS3MT (rs7085104-GG, beta = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: beta = 0.5 and CC vs. TT: beta = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: beta = 0.3 and TT vs. CC; beta = -0.8, global p = 0.05) were associated with LINE-1 methylation. CONCLUSIONS: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants. C1 [Tajuddin, Salman M.; Amaral, Andre F. S.; Cook, Ashley L.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Fernandez, Agustin F.; Rodriguez-Rodero, Sandra; Maria Rodriguez, Ramon; Fraga, Mario F.] IUOPA, Canc Epigenet Lab, Oviedo, Spain. [Moore, Lee E.; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel] NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Carrato, Alfredo] Hosp Gen Univ Elche, Elche, Spain. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Jackson, Brian P.] Dartmouth Coll, Dept Earth Sci, Trace Element Anal Core, New Spring, MD USA. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Real, Francisco X.] Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid 28029, Spain. [Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Fraga, Mario F.] CSIC, CNB, Dept Immunol & Oncol, Madrid, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM nmalats@cnio.es RI Amaral, Andre/A-7662-2008; Hernandez-Llodra, S/H-6863-2014; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Fernandez, Agustin/N-7302-2014; Kogevinas, Manolis/C-3918-2017; OI Tajuddin, Salman M./0000-0002-7919-8528; Amaral, Andre/0000-0002-0369-9449; Rodriguez-Rodero, Sandra/0000-0001-8868-3667; Hernandez-Llodra, S/0000-0003-3963-3756; Puente, Diana/0000-0003-4725-537X; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Fernandez, Agustin/0000-0002-3792-4085; Soto, Jose Luis/0000-0003-0234-9188 FU Association for International Cancer Research (AICR) [09-0780]; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, MINECO, Spain [00/0745, PI051436, PI061614, PI09-02102, G03/174]; Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020-RTICC]; U.S. National Institutes of Health [RO1-CA089715]; Fundacion Cientifica de la AECC; Fundacio Marato TV3; Johns Hopkins University Vredenburg Scholarship FX This work was partially supported by the Association for International Cancer Research (AICR; grant 09-0780, and a doctoral scholarship awarded to S. M. T.); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, MINECO, Spain (grants 00/0745, PI051436, PI061614, PI09-02102, and G03/174); Red Tematica de Investigacion Cooperativa en Cancer (grant RD06/0020-RTICC); the U.S. National Institutes of Health (grant RO1-CA089715); a postdoctoral fellowship awarded to A.F.S.A. from the Fundacion Cientifica de la AECC; Fundacio Marato TV3; and The Johns Hopkins University Vredenburg Scholarship awarded to A.L.C. NR 48 TC 31 Z9 31 U1 1 U2 19 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2013 VL 121 IS 6 BP 650 EP 656 DI 10.1289/ehp.1206068 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VN UT WOS:000323709400012 PM 23552396 ER PT J AU Schug, TT Nadadur, SS Johnson, AF AF Schug, Thaddeus T. Nadadur, Srikanth S. Johnson, Anne F. TI Nano GO Consortium-A Team Science Approach to Assess Engineered Nanomaterials: Reliable Assays and Methods SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Schug, Thaddeus T.; Nadadur, Srikanth S.] Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Div Extramural Res & Training,Cellular Organs & S, Res Triangle Pk, NC USA. [Johnson, Anne F.] MDB Inc, Res Triangle Pk, NC USA. RP Schug, TT (reprint author), Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Div Extramural Res & Training,Cellular Organs & S, Res Triangle Pk, NC USA. EM nadadurs@niehs.nih.gov NR 7 TC 3 Z9 3 U1 1 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2013 VL 121 IS 6 BP A176 EP A177 DI 10.1289/ehp.1306866 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VN UT WOS:000323709400001 PM 23733101 ER PT J AU Coppock, JD Wieking, BG Molinolo, AA Gutkind, JS Miskimins, WK Lee, JH AF Coppock, Joseph D. Wieking, Bryant G. Molinolo, Alfredo A. Gutkind, J. Silvio Miskimins, W. Keith Lee, John H. TI Improved Clearance during Treatment of HPV-Positive Head and Neck Cancer through mTOR Inhibition SO NEOPLASIA LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; PAPILLOMAVIRUS-ASSOCIATED CANCERS; KINASE TYPE M2; MAMMALIAN TARGET; MOLECULAR TARGET; IMMUNE-RESPONSE; TUMOR-CELLS; LACTIC-ACID; RAPAMYCIN; AUTOPHAGY AB Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC. C1 [Coppock, Joseph D.; Wieking, Bryant G.; Miskimins, W. Keith; Lee, John H.] Sanford Res USD, Canc Biol Res Ctr, Sioux Falls, SD 57104 USA. [Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Lee, John H.] Sanford Hlth, Dept Otolaryngol Head & Neck Surg, Sioux Falls, SD USA. RP Lee, JH (reprint author), Sanford Res USD, 2301 60th St North, Sioux Falls, SD 57104 USA. EM john.lee@sanfordhealth.org FU Cancer CoBRE grant FX We thank Satoshi Nagata and Pradip De for insightful discussions and the Flow Cytometry, Molecular Pathology, and Tumor Biology Cores of Sanford Research funded by the Cancer CoBRE grant. NR 52 TC 16 Z9 16 U1 0 U2 5 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUN PY 2013 VL 15 IS 6 BP 620 EP + DI 10.1593/neo.13432 PG 13 WC Oncology SC Oncology GA 219DW UT WOS:000324486800005 PM 23730210 ER PT J AU Deng, CW Li, Y Liang, SM Cui, KR Salz, T Yang, H Tang, ZY Gallagher, PG Qiu, Y Roeder, R Zhao, KJ Bungert, J Huang, SM AF Deng, Changwang Li, Ying Liang, Shermi Cui, Kairong Salz, Tal Yang, Hui Tang, Zhanyun Gallagher, Patrick G. Qiu, Yi Roeder, Robert Zhao, Keji Bungert, Joerg Huang, Suming TI USF1 and hSET1A Mediated Epigenetic Modifications Regulate Lineage Differentiation and HoxB4 Transcription SO PLOS GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; METHYLTRANSFERASE COMPLEX; HEMATOPOIETIC-CELLS; SELF-RENEWAL; HAEMOGENIC ENDOTHELIUM; CHROMATIN SIGNATURES; H3K4 METHYLATION; BIVALENT DOMAINS; IN-VITRO; EXPRESSION AB The interplay between polycomb and trithorax complexes has been implicated in embryonic stem cell (ESC) self-renewal and differentiation. It has been shown recently that WRD5 and Dpy-30, specific components of the SET1/MLL protein complexes, play important roles during ESC self-renewal and differentiation of neural lineages. However, not much is known about how and where specific trithorax complexes are targeted to genes involved in self-renewal or lineage-specification. Here, we report that the recruitment of the hSET1A histone H3K4 methyltransferase (HMT) complex by transcription factor USF1 is required for mesoderm specification and lineage differentiation. In undifferentiated ESCs, USF1 maintains hematopoietic stem/progenitor cell (HS/PC) associated bivalent chromatin domains and differentiation potential. Furthermore, USF1 directed recruitment of the hSET1A complex to the HoxB4 promoter governs the transcriptional activation of HoxB4 gene and regulates the formation of early hematopoietic cell populations. Disruption of USF or hSET1A function by overexpression of a dominant-negative AUSF1 mutant or by RNA-interference-mediated knockdown, respectively, led to reduced expression of mesoderm markers and inhibition of lineage differentiation. We show that USF1 and hSET1A together regulate H3K4me3 modifications and transcription preinitiation complex assembly at the hematopoietic-associated HoxB4 gene during differentiation. Finally, ectopic expression of USF1 in ESCs promotes mesoderm differentiation and enforces the endothelial-to-hematopoietic transition by inducing hematopoietic-associated transcription factors, HoxB4 and TAL1. Taken together, our findings reveal that the guided-recruitment of the hSET1A histone methyltransferase complex and its H3K4 methyltransferase activity by transcription regulator USF1 safeguards hematopoietic transcription programs and enhances mesoderm/hematopoietic differentiation. C1 [Deng, Changwang; Li, Ying; Liang, Shermi; Salz, Tal; Bungert, Joerg; Huang, Suming] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Yang, Hui; Qiu, Yi] Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL USA. [Tang, Zhanyun; Roeder, Robert] Rockefeller Univ, Lab Biochem & Mol Biol, New York, NY 10021 USA. [Gallagher, Patrick G.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Bungert, Joerg] Univ Florida, Coll Med, Genet Inst, Gainesville, FL USA. RP Deng, CW (reprint author), Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. EM sumingh@ufl.edu FU ARRA Administrative supplement [HL091929, HL091929-01A1S1-]; NHLBI; NIH; [HL090589]; [DK52356]; [HL095674]; [CA129325]; [DK071900] FX This work was supported by HL091929, HL091929-01A1S1-the ARRA Administrative supplement, and HL090589 to SH; DK52356 to JB; HL095674 to YQ; CA129325 and DK071900 to RR. KZ is supported by the intramural Research Programs, NHLBI and NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 15 Z9 15 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2013 VL 9 IS 6 AR e1003524 DI 10.1371/journal.pgen.1003524 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 175HX UT WOS:000321222600012 PM 23754954 ER PT J AU Fu, HQ Maunakea, AK Martin, MM Huang, L Zhang, Y Ryan, M Kim, R Lin, CM Zhao, K Aladjem, MI AF Fu, Haiqing Maunakea, Alika K. Martin, Melvenia M. Huang, Liang Zhang, Ya Ryan, Michael Kim, RyangGuk Lin, Chii Meil Zhao, Keji Aladjem, Mirit I. TI Methylation of Histone H3 on Lysine 79 Associates with a Group of Replication Origins and Helps Limit DNA Replication Once per Cell Cycle SO PLOS GENETICS LA English DT Article ID BETA-GLOBIN LOCUS; CHROMATIN STRUCTURE; DYNAMIC REGULATION; H3K79 METHYLATION; INITIATION; METHYLTRANSFERASE; DOMAIN; REGION; SITES; DOT1 AB Mammalian DNA replication starts at distinct chromosomal sites in a tissue-specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication at particular genomic locations. Here we report that a distinct fraction of replication initiation sites in the human genome are associated with a high frequency of dimethylation of histone H3 lysine K79 (H3K79Me2). H3K79Me2-containing chromatin exhibited the highest genome-wide enrichment for replication initiation events observed for any chromatin modification examined thus far (23.39% of H3K79Me2 peaks were detected in regions adjacent to replication initiation events). The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 dimethylation exhibited wider distribution on chromatin during S-phase, but only regions with H3K79 methylation in G1 and G2 were enriched in replication initiation events. H3K79 was dimethylated in a region containing a functional replicator (a DNA sequence capable of initiating DNA replication), but the methylation was not evident in a mutant replicator that could not initiate replication. Depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication although most cells could continue to proliferate and replicate DNA in the absence of methylated H3K79. Thus, prevention of H3K79 methylation might affect regulatory processes that modulate the order and timing of DNA replication. These data are consistent with the hypothesis that dimethylated H3K79 associates with some replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability. C1 [Fu, Haiqing; Martin, Melvenia M.; Huang, Liang; Zhang, Ya; Lin, Chii Meil; Aladjem, Mirit I.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Maunakea, Alika K.; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Ryan, Michael; Kim, RyangGuk] InSilico Solut, Fairfax, VA USA. RP Fu, HQ (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov RI Huang, Liang/B-2831-2013 OI Huang, Liang/0000-0003-1663-7025 FU CCR, National Cancer Institute, National Institutes of Health FX This work was funded by the intramural program of the CCR, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 38 Z9 38 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2013 VL 9 IS 6 AR e1003542 DI 10.1371/journal.pgen.1003542 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 175HX UT WOS:000321222600022 PM 23754963 ER PT J AU Nirala, NK Rahman, M Walls, SM Singh, A Zhu, LJ Bamba, T Fukusaki, E Srideshikan, SM Harris, GL Ip, YT Bodmer, R Acharya, UR AF Nirala, Niraj K. Rahman, Motiur Walls, Stanley M. Singh, Alka Zhu, Lihua Julie Bamba, Takeshi Fukusaki, Eiichiro Srideshikan, Sargur M. Harris, Greg L. Ip, Y. Tony Bodmer, Rolf Acharya, Usha R. TI Survival Response to Increased Ceramide Involves Metabolic Adaptation through Novel Regulators of Glycolysis and Lipolysis SO PLOS GENETICS LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; DIET-INDUCED OBESITY; INSULIN-RESISTANCE; FAT-BODY; ENERGY-METABOLISM; STEM-CELLS; KINASE-B; DROSOPHILA; EXPRESSION; HOMEOSTASIS AB The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic C1 [Nirala, Niraj K.; Rahman, Motiur; Singh, Alka; Zhu, Lihua Julie; Acharya, Usha R.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Nirala, Niraj K.; Rahman, Motiur; Singh, Alka; Zhu, Lihua Julie; Ip, Y. Tony; Acharya, Usha R.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Walls, Stanley M.; Harris, Greg L.] San Diego State Univ, Cell & Mol Biol Program, San Diego, CA 92182 USA. [Zhu, Lihua Julie] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA USA. [Bamba, Takeshi; Fukusaki, Eiichiro] Osaka Univ, Dept Biotechnol, Grad Sch Engn, Osaka, Japan. [Srideshikan, Sargur M.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. [Bodmer, Rolf] Sanford Burnham Med Res Inst, Dev & Aging Program, La Jolla, CA USA. RP Nirala, NK (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. EM usha.acharya@umassmed.edu FU NIH [RO1EY016469, DK83450]; ARCS Foundation FX This research is supported by NIH grant (RO1EY016469) to URA. YTI is supported by NIH grant (DK83450) and is a member of the UMass DERC (DK32520). SMW is a Rees-Stealy Research Foundation Fellow, an ARCS Foundation supported Scholar and American Heart Association Predoctoral Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 4 Z9 4 U1 3 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2013 VL 9 IS 6 AR e1003556 DI 10.1371/journal.pgen.1003556 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 175HX UT WOS:000321222600033 PM 23818862 ER PT J AU Randall, JC Winkler, TW Kutalik, Z Berndt, SI Jackson, AU Monda, KL Kilpelainen, TO Esko, T Magi, R Li, SX Workalemahu, T Feitosa, MF Croteau-Chonka, DC Day, FR Fall, T Ferreira, T Gustafsson, S Locke, AE Mathieson, I Scherag, A Vedantam, S Wood, AR Liang, LM Steinthorsdottir, V Thorleifsson, G Dermitzakis, ET Dimas, AS Karpe, F Min, JL Nicholson, G Clegg, DJ Person, T Krohn, JP Bauer, S Buechler, C Eisinger, K Bonnefond, A Froguel, P Hottenga, JJ Prokopenko, I Waite, LL Harris, TB Smith, AV Shuldiner, AR McArdle, WL Caulfield, MJ Munroe, PB Gronberg, H Chen, YDI Li, G Beckmann, JS Johnson, T Thorsteinsdottir, U Teder-Laving, M Khaw, KT Wareham, NJ Zhao, JH Amin, N Oostra, BA Kraja, AT Province, MA Cupples, LA Heard-Costa, NL Kaprio, J Ripatti, S Surakka, I Collins, FS Saramies, J Tuomilehto, J Jula, A Salomaa, V Erdmann, J Hengstenberg, C Loley, C Schunkert, H Lamina, C Wichmann, HE Albrecht, E Gieger, C Hicks, AA Johansson, A Pramstaller, PP Kathiresan, S Speliotes, EK Penninx, B Hartikainen, AL Jarvelin, MR Gyllensten, U Boomsma, DI Campbell, H Wilson, JF Chanock, SJ Farrall, M Goel, A Medina-Gomez, C Rivadeneira, F Estrada, K Uitterlinden, AG Hofman, A Zillikens, MC den Heijer, M Kiemeney, LA Maschio, A Hall, P Tyrer, J Teumer, A Volzke, H Kovacs, P Tonjes, A Mangino, M Spector, TD Hayward, C Rudan, I Hall, AS Samani, NJ Attwood, AP Sambrook, JG Hung, J Palmer, LJ Lokki, ML Sinisalo, J Boucher, G Huikuri, H Lorentzon, M Ohlsson, C Eklund, N Eriksson, JG Barlassina, C Rivolta, C Nolte, IM Snieder, H Van der Klauw, MM Van Vliet-Ostaptchouk, JV Gejman, PV Shi, JX Jacobs, KB Wang, ZM Bakker, SJL Leach, IM Navis, G van der Harst, P Martin, NG Medland, SE Montgomery, GW Yang, J Chasman, DI Ridker, PM Rose, LM Lehtimaki, T Raitakari, O Absher, D Iribarren, C Basart, H Hovingh, KG Hypponen, E Power, C Anderson, D Beilby, JP Hui, JN Jolley, J Sager, H Bornstein, SR Schwarz, PEH Kristiansson, K Perola, M Lindstrom, J Swift, AJ Uusitupa, M Atalay, M Lakka, TA Rauramaa, R Bolton, JL Fowkes, G Fraser, RM Price, JF Fischer, K KrjutAikov, K Metspalu, A Mihailov, E Langenberg, C Luan, JA Ong, KK Chines, PS Keinanen-Kiukaanniemi, SM Saaristo, TE Edkins, S Franks, PW Hallmans, G Shungin, D Morris, AD Palmer, CNA Erbel, R Moebus, S Nothen, MM Pechlivanis, S Hveem, K Narisu, N Hamsten, A Humphries, SE Strawbridge, RJ Tremoli, E Grallert, H Thorand, B Illig, T Koenig, W Muller-Nurasyid, M Peters, A Boehm, BO Kleber, ME Marz, W Winkelmann, BR Kuusisto, J Laakso, M Arveiler, D Cesana, G Kuulasmaa, K Virtamo, J Yarnell, JWG Kuh, D Wong, A Lind, L de Faire, U Gigante, B Magnusson, PKE Pedersen, NL Dedoussis, G Dimitriou, M Kolovou, G Kanoni, S Stirrups, K Bonnycastle, LL Njolstad, I Wilsgaard, T Ganna, A Rehnberg, E Hingorani, A Kivimaki, M Kumari, M Assimes, TL Barroso, IS Boehnke, M Borecki, IB Deloukas, P Fox, CS Frayling, T Groop, LC Haritunians, T Hunter, D Ingelsson, E Kaplan, R Mohlke, KL O'Connell, JR Schlessinger, D Strachan, DP Stefansson, K van Duijn, CM Abecasis, GR McCarthy, MI Hirschhorn, JN Qi, L Loos, RJF Lindgren, CM North, KE Heid, IM AF Randall, Joshua C. Winkler, Thomas W. Kutalik, Zoltan Berndt, Sonja I. Jackson, Anne U. Monda, Keri L. Kilpelaeinen, Tuomas O. Esko, Tonu Maegi, Reedik Li, Shengxu Workalemahu, Tsegaselassie Feitosa, Mary F. Croteau-Chonka, Damien C. Day, Felix R. Fall, Tove Ferreira, Teresa Gustafsson, Stefan Locke, Adam E. Mathieson, Iain Scherag, Andre Vedantam, Sailaja Wood, Andrew R. Liang, Liming Steinthorsdottir, Valgerdur Thorleifsson, Gudmar Dermitzakis, Emmanouil T. Dimas, Antigone S. Karpe, Fredrik Min, Josine L. Nicholson, George Clegg, Deborah J. Person, Thomas Krohn, Jon P. Bauer, Sabrina Buechler, Christa Eisinger, Kristina Bonnefond, Amelie Froguel, Philippe Hottenga, Jouke-Jan Prokopenko, Inga Waite, Lindsay L. Harris, Tamara B. Smith, Albert Vernon Shuldiner, Alan R. McArdle, Wendy L. Caulfield, Mark J. Munroe, Patricia B. Gronberg, Henrik Chen, Yii-Der Ida Li, Guo Beckmann, Jacques S. Johnson, Toby Thorsteinsdottir, Unnur Teder-Laving, Maris Khaw, Kay-Tee Wareham, Nicholas J. Zhao, Jing Hua Amin, Najaf Oostra, Ben A. Kraja, Aldi T. Province, Michael A. Cupples, L. Adrienne Heard-Costa, Nancy L. Kaprio, Jaakko Ripatti, Samuli Surakka, Ida Collins, Francis S. Saramies, Jouko Tuomilehto, Jaakko Jula, Antti Salomaa, Veikko Erdmann, Jeanette Hengstenberg, Christian Loley, Christina Schunkert, Heribert Lamina, Claudia Wichmann, H. Erich Albrecht, Eva Gieger, Christian Hicks, Andrew A. Johansson, Asa Pramstaller, Peter P. Kathiresan, Sekar Speliotes, Elizabeth K. Penninx, Brenda Hartikainen, Anna-Liisa Jarvelin, Marjo-Riitta Gyllensten, Ulf Boomsma, Dorret I. Campbell, Harry Wilson, James F. Chanock, Stephen J. Farrall, Martin Goel, Anuj Medina-Gomez, Carolina Rivadeneira, Fernando Estrada, Karol Uitterlinden, Andre G. Hofman, Albert Zillikens, M. Carola den Heijer, Martin Kiemeney, Lambertus A. Maschio, Andrea Hall, Per Tyrer, Jonathan Teumer, Alexander Voelzke, Henry Kovacs, Peter Toenjes, Anke Mangino, Massimo Spector, Tim D. Hayward, Caroline Rudan, Igor Hall, Alistair S. Samani, Nilesh J. Attwood, Antony Paul Sambrook, Jennifer G. Hung, Joseph Palmer, Lyle J. Lokki, Marja-Liisa Sinisalo, Juha Boucher, Gabrielle Huikuri, Heikki Lorentzon, Mattias Ohlsson, Claes Eklund, Niina Eriksson, Johan G. Barlassina, Cristina Rivolta, Carlo Nolte, Ilja M. Snieder, Harold Van der Klauw, Melanie M. Van Vliet-Ostaptchouk, Jana V. Gejman, Pablo V. Shi, Jianxin Jacobs, Kevin B. Wang, Zhaoming Bakker, Stephan J. L. Leach, Irene Mateo Navis, Gerjan van der Harst, Pim Martin, Nicholas G. Medland, Sarah E. Montgomery, Grant W. Yang, Jian Chasman, Daniel I. Ridker, Paul M. Rose, Lynda M. Lehtimaki, Terho Raitakari, Olli Absher, Devin Iribarren, Carlos Basart, Hanneke Hovingh, Kees G. Hyppoenen, Elina Power, Chris Anderson, Denise Beilby, John P. Hui, Jennie Jolley, Jennifer Sager, Hendrik Bornstein, Stefan R. Schwarz, Peter E. H. Kristiansson, Kati Perola, Markus Lindstrom, Jaana Swift, Amy J. Uusitupa, Matti Atalay, Mustafa Lakka, Timo A. Rauramaa, Rainer Bolton, Jennifer L. Fowkes, Gerry Fraser, Ross M. Price, Jackie F. Fischer, Krista KrjutAikov, Kaarel Metspalu, Andres Mihailov, Evelin Langenberg, Claudia Luan, Jian'an Ong, Ken K. Chines, Peter S. Keinanen-Kiukaanniemi, Sirkka M. Saaristo, Timo E. Edkins, Sarah Franks, Paul W. Hallmans, Goran Shungin, Dmitry Morris, Andrew David Palmer, Colin N. A. Erbel, Raimund Moebus, Susanne Noethen, Markus M. Pechlivanis, Sonali Hveem, Kristian Narisu, Narisu Hamsten, Anders Humphries, Steve E. Strawbridge, Rona J. Tremoli, Elena Grallert, Harald Thorand, Barbara Illig, Thomas Koenig, Wolfgang Mueller-Nurasyid, Martina Peters, Annette Boehm, Bernhard O. Kleber, Marcus E. Maerz, Winfried Winkelmann, Bernhard R. Kuusisto, Johanna Laakso, Markku Arveiler, Dominique Cesana, Giancarlo Kuulasmaa, Kari Virtamo, Jarmo Yarnell, John W. G. Kuh, Diana Wong, Andrew Lind, Lars de Faire, Ulf Gigante, Bruna Magnusson, Patrik K. E. Pedersen, Nancy L. Dedoussis, George Dimitriou, Maria Kolovou, Genovefa Kanoni, Stavroula Stirrups, Kathleen Bonnycastle, Lori L. Njolstad, Inger Wilsgaard, Tom Ganna, Andrea Rehnberg, Emil Hingorani, Aroon Kivimaki, Mika Kumari, Meena Assimes, Themistocles L. Barroso, Ine S. Boehnke, Michael Borecki, Ingrid B. Deloukas, Panos Fox, Caroline S. Frayling, Timothy Groop, Leif C. Haritunians, Talin Hunter, David Ingelsson, Erik Kaplan, Robert Mohlke, Karen L. O'Connell, Jeffrey R. Schlessinger, David Strachan, David P. Stefansson, Kari van Duijn, Cornelia M. Abecasis, Goncalo R. McCarthy, Mark I. Hirschhorn, Joel N. Qi, Lu Loos, Ruth J. F. Lindgren, Cecilia M. North, Kari E. Heid, Iris M. CA DIAGRAM Consortium MAGIC Investigators TI Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits SO PLOS GENETICS LA English DT Article ID BODY-MASS INDEX; WAIST-HIP RATIO; FAT DISTRIBUTION; ENZYME-ACTIVITIES; ADULT HEIGHT; PPAR-GAMMA; RISK; VARIANTS; METAANALYSIS; OBESITY AB Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5x10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits. C1 [Randall, Joshua C.; Ripatti, Samuli; Attwood, Antony Paul; Edkins, Sarah; Kanoni, Stavroula; Stirrups, Kathleen; Barroso, Ine S.; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Randall, Joshua C.; Maegi, Reedik; Ferreira, Teresa; Mathieson, Iain; Dimas, Antigone S.; Min, Josine L.; Krohn, Jon P.; Prokopenko, Inga; McCarthy, Mark I.; Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Kutalik, Zoltan; Beckmann, Jacques S.; Johnson, Toby; Rivolta, Carlo] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kutalik, Zoltan; Johnson, Toby] Swiss Inst Bioinformat, Lausanne, Switzerland. [Berndt, Sonja I.; Chanock, Stephen J.; Shi, Jianxin; Jacobs, Kevin B.; Wang, Zhaoming] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Jackson, Anne U.; Locke, Adam E.; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Monda, Keri L.; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. 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[Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Kovacs, Peter] Univ Leipzig, Interdisciplinary Ctr Clin Res, D-04109 Leipzig, Germany. [Toenjes, Anke] Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany. [Toenjes, Anke] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Hayward, Caroline] Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Neuronal Remodelling, Leeds, W Yorkshire, England. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. 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[Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Groop, Leif C.] Lund Univ, Dept Clin Sci, Lund Univ Diabet Ctr, Malmo, Sweden. [Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Hunter, David; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hunter, David; Qi, Lu] Harvard Univ, Sch Med, Boston, MA USA. [Kaplan, Robert] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [van Duijn, Cornelia M.] Leiden Univ, Med Ctr, Ctr Med Syst Biol, Leiden, Netherlands. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX3 7LJ, England. [Loos, Ruth J. F.] Mt Sinai Sch Med, Child Hlth & Dev Inst, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY USA. RP Randall, JC (reprint author), Wellcome Trust Sanger Inst, Cambridge, England. EM ruth.loos@mssm.edu; celi@well.ox.ac.uk; kari_north@unc.edu; iris.heid@klinik.uni-regensburg.de RI Erdmann, Jeanette/P-7513-2014; Yang, Jian/A-5852-2010; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Colaus, PsyColaus/K-6607-2013; Wong, Andrew/M-8899-2016; Magnusson, Patrik/C-4458-2017; Beckmann, Jacques S /A-9772-2008; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Grallert, Harald/B-3424-2013; Bakker, Stephan/J-4023-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Montgomery, Grant/B-7148-2008; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Johansson, Asa/G-5270-2011; Thorand, Barbara/B-5349-2014; Peters, Annette/A-6117-2011; van der Klauw, Melanie/A-2138-2014; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Strawbridge, Rona/H-5422-2012; Medland, Sarah/C-7630-2013; Boehm, Bernhard/F-8750-2015; Deloukas, Panos/B-2922-2013; Hypponen, Elina/B-2596-2014; Kiemeney, Lambertus/D-3357-2009; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008; Palmer, Lyle/K-3196-2014; Fall, Tove/O-7226-2014 OI Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Medina-Gomez, Carolina/0000-0001-7999-5538; Eriksson, Johan/0000-0002-2516-2060; Kaprio, Jaakko/0000-0002-3716-2455; Rivolta, Carlo/0000-0002-0733-9950; Sinisalo, Juha/0000-0002-0169-5137; Kleber, Marcus/0000-0003-0663-7275; Scherag, Andre/0000-0002-9406-4704; Kumari, Meena/0000-0001-9716-1035; Kuulasmaa, Kari/0000-0003-2165-1411; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Nothen, Markus/0000-0002-8770-2464; Karpe, Fredrik/0000-0002-2751-1770; Fraser, Ross/0000-0003-0488-2592; Esko, Tonu/0000-0003-1982-6569; Kristiansson, Kati/0000-0003-4688-107X; Locke, Adam/0000-0001-6227-198X; Erdmann, Jeanette/0000-0002-4486-6231; Lakka, Timo/0000-0002-9199-2871; Gigante, Bruna/0000-0003-4508-7990; Gieger, Christian/0000-0001-6986-9554; Franks, Paul/0000-0002-0520-7604; Cupples, L. Adrienne/0000-0003-0273-7965; Shungin, Dmitry/0000-0001-7900-5856; Day, Felix/0000-0003-3789-7651; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; TREMOLI, ELENA/0000-0002-0929-6106; Magi, Reedik/0000-0002-2964-6011; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Yang, Jian/0000-0003-2001-2474; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Beckmann, Jacques S /0000-0002-9741-1900; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Heard-Costa, Nancy/0000-0001-9730-0306; Bakker, Stephan/0000-0003-3356-6791; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Johansson, Asa/0000-0002-2915-4498; Thorand, Barbara/0000-0002-8416-6440; van der Klauw, Melanie/0000-0001-7178-009X; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Strawbridge, Rona/0000-0001-8506-3585; Medland, Sarah/0000-0003-1382-380X; Deloukas, Panos/0000-0001-9251-070X; Hypponen, Elina/0000-0003-3670-9399; Kiemeney, Lambertus/0000-0002-2368-1326; Palmer, Colin/0000-0002-6415-6560; Palmer, Lyle/0000-0002-1628-3055; FU Aarno Koskelo Foundation; Academy of Finland [40758, 41071, 77299, 102318, 104781, 110413, 117787, 117844, 118065, 118590, 120315, 120386, 121584, 123885, 124243, 124282, 125876, 126925, 129269, 129293, 129322, 129378, 129494, 129680, 139635, 211497, 213506, 250207, 1114194]; Academy of Finland Centre of Excellence in Complex Disease Genetics; ALF/LUA research grant in Gothenburg; Agency for Science, Technology, and Research of Singapore (A*STAR); Althingi (the Icelandic Parliament); American Heart Association [0730094N]; Australian Research Council (ARC) [DP0770096, DP1093900]; Biocentrum Helsinki; Boston Medical Center; Boston University School of Medicine; British Diabetes Association; BDA Research; British Heart Foundation (BHF) [PG/02/128, PG/07/133/24260, RG2008/08, RG2008/014]; Cancer Research UK [C490/A8339, C490/A10124]; Central Norway Health Authority; Centre Hospitalier Universitaire Vaudois; Chief Scientist Office of Scotland; City of Kuopio; Deutsche Forschungsgemeinschaft; Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD); Diabetes UK; Donald W. Reynolds Foundation; Dresden University of Technology Funding Grant; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Kidney Foundation [E033]; Dutch Inter University Cardiology Institute Netherlands (ICIN); EMGO Institute for Health and Care Research (EMGO+); Emil Aaltonen Foundation; Erasmus Medical Center; Erasmus University; Estonian Government [SF0180142s08]; Estonian Biocentre Centre of Excellence in Genomics; European Commission [FP5-QLG2-CT-2002-00896, FP5-QLG2-CT-2002-01254, FP5-QLRT-2001-01254, FP6-LSHM-CT-2004-005272, FP6-LSHM-CT-2004-503485, FP6-LSHG-CT-2004-518153, FP6-LSHG-CT-2006-018947, FP6-LSHM-CT-2006-037593, FP6-LSHM-CT-2006-037697, FP6-LSHM-CT-2007-037273, FP7-HEALTH-201413, FP7-HEALTH-201536, FP7-HEALTH-201550, FP7-HEALTH-201668, FP7-HEALTH-201865, FP7-HEALTH-230374, FP7-HEALTH-245536, FP7-HEALTH-261433]; Directorate C-Public Health [2004310]; Marie Curie Intra-European Fellowship, EURO-BLCS, Framework 5 award [QLG1-CT-2000-01643]; European Regional Development Fund; European Science Foundation (ESF); Federal State of Mecklenburg-West Pomerania; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Funding Agency for Technology and Innovation (TEKES) [40058/07, 70103/06]; Finnish Heart Association; Finnish Medical Society; Finnish Ministry of Education and Culture (OKM) [627: 2004-2011]; Finnish Ministry of Health and Social Affairs [5254]; Finnish National Institute for Health and Welfare; Finnish Slot Machine Association (RAY); Folkhalsan Research Foundation; Fondation LeDucq; Foundation for Life and Health in Finland; Genetic Association Information Network (GAIN); German Diabetes Association; German Federal Ministry of Education and Research (BMBF) [01KU0908A, 01AK803A-H, 01IG07015G, 01GS0823, 01GS0834, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012, 01ER1206]; German Research Center for Environmental Health; GlaxoSmithKline; Goteborg Medical Society; The Great Wine Estates of the Margaret River region of Western Australia; Greek General Secretary of Research and Technology (PENED); Healthway, Western Australia; Heinz Nixdorf Foundation; Helmholtz Zentrum Munchen; Helsinki University Central Hospital; Hjartavernd (the Icelandic Heart Association); Hospital district of Pirkanmaa, South Ostrobothnia; Central Finland; International Stichting Alzheimer Onderzoek (ISAO); Italian Ministry of Health; John D. and Catherine T. MacArthur Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institutet; Stockholm County Council [560183, 562183]; Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes [6-FY-09-507]; Medical Research Foundation of Umea University; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Ministry of Science, Education and Sports of the Republic of Croatia [108-1080315-0302]; Montreal Heart Institute Foundation; The Municipal Health Care Center and Hospital in Jakobstad; Municipality of Nijmegen; Municipality of Rotterdam; Narpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Health and Medical Research Council of Australia (NHMRC) [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601, 1011506]; Netherlands Brain Foundation; Netherlands Centre for Medical Systems Biology (CMSB); Netherlands Ministry of Health, Welfare and Sport; Netherlands Organization for Scientific Research (NWO) [014-93-015, 050-060-810, 40-0056-98-9032, 175-010-2005011, 175-010-2007-006, 184-021-007, 311-60-008, 400-05-717, 480-04-004, 480-05-003, 904-61-090, 904-61-193, 911-03-012, 916-761-70, 985-10-002, SPI 56-464-14192]; Neuroscience Campus Amsterdam (NCA); NHS Support for Science Funding Programme; Nord-Trondelag County Council; Nordic Center of Cardiovascular Research (NCCR); Nordic Centre of Excellence in Disease Genetics; Nordic Centre of Excellence in Systems Biology [070014]; Northern Netherlands Collaboration of Provinces (SNN); Norwegian Institute of Public Health; Norwegian Research Council [185764]; Norwegian University of Science and Technology (NTNU); Novo Nordisk Foundation; Ollqvist Foundation; Orion-Farmos Research Foundation; Paavo Nurmi Foundation; Paivikki and Sakari Sohlberg Foundation; Paul Michael Donovan Charitable Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Province of Groningen; Radboud University Nijmegen Medical Centre; Royal Swedish Academy of Science; Sardstedt AG Co.; Siemens Healthcare; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South Tyrolean Sparkasse Foundation; Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Diabetes Association; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Research Council [0593, 8691, 2006-3832, K2007-66X-20270-01-3, K2010-52X-20229-05-3, K2010-54X-09894-19-3]; Swedish Society for Medical Research; Swedish Society of Medicine; Swiss National Science Foundation [310000-112552, 33CSCO-122661]; Tampere Tuberculosis Foundation; Torsten and Ragnar Soderberg Foundation; UK Economic and Social Research Council (ESRC); UK Medical Research Council (MRC) [G0000649, G0601261, G9521010D, G0000934, G0500539, G0600705]; Centre for Obesity and Related Metabolic Disease; Centre of Epidemiology for Child Health; PrevMetSyn/SALVE; MRC-GSK pilot programme [85374]; UK National Institute for Health Research (NIHR); Cambridge Biomedical Research Centre; CamStrad; Comprehensive Biomedical Research Centre; London Cardiovascular Biomedical Research Unit; Oxford Biomedical Research Centre [RP-PG-0310-1002]; University Hospital Essen; University Hospital Kuopio; University Hospital Oulu; University Hospital Tampere; University Hospital Turku; University of Groningen; University of Lausanne; University of Leipzig; University of Tromso; University Medical Center Groningen; University of Tartu; US Department of Agriculture (USDA) National Research Initiative Competitive Grant [2007-35205-17883]; US National Cancer Institute (NCI); US National Heart, Lung, and Blood Institute (NHLBI) [268200625226C, 268201100005C, 268201100006C, 268201100007C, 268201100008C, 268201100009C, 268201100010C, 268201100011C, 268201100012C, 5R01HL087679-02, 1RL1MH083268-01]; US National Human Genome Research Institute (NHGRI); US National Institute of Allergy and Infectious Diseases (NIAID); US National Institute of Child Health and Human Development (NICHD); US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); US National Institutes of Health (NIH) [5R01MH63706: 02, K23DK080145, M01RR16500, N01AG12100, N01AG12109, N01HC25195, N01HC35129, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85084, N01HC85085, N01HC85086, N01HC85239, N01HG65403, N02HL64278, P01CA87969, P30DK063491, P30DK072488, R01AA007535, R01AA014041, R01AA013320, R01AA013321, R01AA013326, R01AG004563, R01AG008724, R01AG008861, R01AG010175, R01AG013196, R01AG015928, R01AG020098, R01AG023629, R01AG027058, R01AG028555, R01CA047988, R01CA049449, R01CA050385, R01CA065725, R01CA067262, R01DA12854, R01DK062370, R01DK072193, R01DK073490, R01DK075681, R01DK075787, R01DK089256, R01HD042157, R01HG002651, R01HL036310, R01HL043851, R01HL059367, R01HL071981, R01HL075366, R01HL086694, R01HL087641, R01HL087647, R01HL087652, R01HL087676, R01HL087679, R01HL087700, R01HL088215, R01HL105756, R01HS006516, R01LM010098, R01MH059565, R01MH059566, R01MH059571, R01MH059586, R01MH059587, R01MH059588, R01MH060870, R01MH060879, R01MH061675, R01MH067257, R01MH079469, R01MH079470, R01MH081800, RL1MH083268, U01CA098233, U01DK062418, U01HG004402, U01HL069757, U01HL072515, U01HL080295, U01HL084729, U01HL084756, U24MH068457, U54RR020278, UL1RR025005, UL1RR033176, Z01HG000024]; US National Institute of Neurological Disorders and Stroke (NINDS); Vasa Health Care Center; Narpes Health Care Center; Korsholm Health Care Center; Vastra Gotaland Foundation; VU University Amsterdam; Stanford University; Wellcome Trust [068545/Z/02, 069224, 072960, 075491, 076113/B/04/Z, 076113/K/04/Z, 079557, 079895, 081682, 083270, 084183/Z/07/Z, 085301, 086596/Z/08/Z, 089061/Z/09/Z, 089062/Z/09/Z, 090532/Z/09/Z, 098051]; Go-DARTS; WT Research Career Development Fellowship; WT Career Development Award; WT Centre for Human Genetics; WT Clinical Research Facility; WT Sanger Institute; Scottish Health Informatics Programme; Yrjo Jahnsson Foundation [56358]; British Heart Foundation FX Funding for this study was provided by the Aarno Koskelo Foundation; the Academy of Finland (40758, 41071, 77299, 102318, 104781, 110413, 117787, 117844, 118065, 118590, 120315, 120386, 121584, 123885, 124243, 124282, 125876, 126925, 129269, 129293, 129322, 129378, 129494, 129680, 139635, 211497, 213506, 250207, 1114194); the Academy of Finland Centre of Excellence in Complex Disease Genetics; the ALF/LUA research grant in Gothenburg; the Agency for Science, Technology, and Research of Singapore (A*STAR); Althingi (the Icelandic Parliament); the American Heart Association (0730094N); the Australian Research Council (ARC; grants DP0770096 and DP1093900); Biocentrum Helsinki; the Boston Medical Center; Boston University School of Medicine; the British Diabetes Association; BDA Research; the British Heart Foundation (BHF; PG/02/128, PG/07/133/24260, RG2008/08, RG2008/014); Cancer Research UK (C490/A8339, C490/A10124); the Central Norway Health Authority; Centre Hospitalier Universitaire Vaudois; the Chief Scientist Office of Scotland; the City of Kuopio; Deutsche Forschungsgemeinschaft; Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD); Diabetes UK; the Donald W.; Reynolds Foundation; Dresden University of Technology Funding Grant; the Dutch Brain Foundation; the Dutch Diabetes Research Foundation; the Dutch Kidney Foundation (E033); Dutch Inter University Cardiology Institute Netherlands (ICIN); the EMGO Institute for Health and Care Research (EMGO+); the Emil Aaltonen Foundation; the Erasmus Medical Center; Erasmus University; the Estonian Government (SF0180142s08); the Estonian Biocentre Centre of Excellence in Genomics; European Commission (FP5-QLG2-CT-2002-00896, FP5-QLG2-CT-2002-01254, FP5-QLRT-2001-01254, FP6-LSHM-CT-2004-005272, FP6-LSHM-CT-2004-503485, FP6-LSHG-CT-2004-518153, FP6-LSHG-CT-2006-018947, FP6-LSHM-CT-2006-037593, FP6-LSHM-CT-2006-037697, FP6-LSHM-CT-2007-037273, FP7-HEALTH-201413, FP7-HEALTH-201536, FP7-HEALTH-201550, FP7-HEALTH-201668, FP7-HEALTH-201865, FP7-HEALTH-230374, FP7-HEALTH-245536, FP7-HEALTH-261433), the Directorate C-Public Health (grant 2004310), the Marie Curie Intra-European Fellowship, EURO-BLCS, Framework 5 award (QLG1-CT-2000-01643); the European Regional Development Fund; the European Science Foundation (ESF); Federal State of Mecklenburg-West Pomerania; the Finnish Cultural Foundation; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Funding Agency for Technology and Innovation (TEKES; 40058/07 and 70103/06); the Finnish Heart Association; Finnish Medical Society; the Finnish Ministry of Education and Culture (OKM; 627: 2004-2011); the Finnish Ministry of Health and Social Affairs (5254); the Finnish National Institute for Health and Welfare; the Finnish Slot Machine Association (RAY); the Folkhalsan Research Foundation; the Fondation LeDucq; the Foundation for Life and Health in Finland; the Genetic Association Information Network (GAIN); the German Diabetes Association; the German Federal Ministry of Education and Research (BMBF; 01KU0908A, 01AK803A-H, 01IG07015G, 01GS0823, 01GS0834, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012, 01ER1206); the German Research Center for Environmental Health; GlaxoSmithKline; Goteborg Medical Society; The Great Wine Estates of the Margaret River region of Western Australia; Greek General Secretary of Research and Technology (PENED 2003); Healthway, Western Australia; the Heinz Nixdorf Foundation; Helmholtz Zentrum Munchen; Helsinki University Central Hospital; Hjartavernd (the Icelandic Heart Association); Hospital district of Pirkanmaa, South Ostrobothnia, and Central Finland; the International Stichting Alzheimer Onderzoek (ISAO); Italian Ministry of Health; John D. and Catherine T.; MacArthur Foundation; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International (JDRF); Karolinska Institutet; Stockholm County Council (560183, 562183); Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes (6-FY-09-507); Medical Research Foundation of Umea University; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Ministry of Science, Education and Sports of the Republic of Croatia (108-1080315-0302); Montreal Heart Institute Foundation; The Municipal Health Care Center and Hospital in Jakobstad; Municipality of Nijmegen; Municipality of Rotterdam; Narpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Health and Medical Research Council of Australia (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506); Netherlands Brain Foundation; Netherlands Centre for Medical Systems Biology (CMSB); Netherlands Ministry of Health, Welfare and Sport; Netherlands Organization for Scientific Research (NWO; 014-93-015, 050-060-810, 40-0056-98-9032, 175-010-2005011, 175-010-2007-006, 184-021-007, 311-60-008, 400-05-717, 480-04-004, 480-05-003, 904-61-090, 904-61-193, 911-03-012, 916-761-70, 985-10-002, SPI 56-464-14192); Neuroscience Campus Amsterdam (NCA); NHS Support for Science Funding Programme; Nord-Trondelag County Council; Nordic Center of Cardiovascular Research (NCCR); Nordic Centre of Excellence in Disease Genetics, Nordic Centre of Excellence in Systems Biology (070014); Northern Netherlands Collaboration of Provinces (SNN); Norwegian Institute of Public Health; Norwegian Research Council (project number 185764); Norwegian University of Science and Technology (NTNU); Novo Nordisk Foundation; Ollqvist Foundation; Orion-Farmos Research Foundation; Paavo Nurmi Foundation; Paivikki and Sakari Sohlberg Foundation; Paul Michael Donovan Charitable Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Province of Groningen; Radboud University Nijmegen Medical Centre; Royal Swedish Academy of Science; Sardstedt AG & Co.; Siemens Healthcare; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland (4/26/2010); South Tyrolean Sparkasse Foundation; Susan G.; Komen Breast Cancer Foundation; Swedish Cancer Society, Swedish Cultural Foundation in Finland; Swedish Diabetes Association; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Research Council (0593, 8691, 2006-3832, K2007-66X-20270-01-3, K2010-52X-20229-05-3, and K2010-54X-09894-19-3), Swedish Society for Medical Research; Swedish Society of Medicine; Swiss National Science Foundation (310000-112552, 33CSCO-122661); Tampere Tuberculosis Foundation; Torsten and Ragnar Soderberg Foundation; UK Economic and Social Research Council (ESRC); UK Medical Research Council (MRC; G0000649, G0601261, G9521010D, G0000934, G0500539, G0600705), Centre for Obesity and Related Metabolic Disease, Centre of Epidemiology for Child Health, PrevMetSyn/SALVE, MRC-GSK pilot programme (grant ID 85374); UK National Institute for Health Research (NIHR); Cambridge Biomedical Research Centre, CamStrad, Comprehensive Biomedical Research Centre, London Cardiovascular Biomedical Research Unit, Oxford Biomedical Research Centre, (RP-PG-0310-1002); University Hospital Essen; University Hospital Kuopio; University Hospital Oulu; University Hospital Tampere; University Hospital Turku; University of Groningen; University of Lausanne; University of Leipzig; University of Tromso; University Medical Center Groningen; University of Tartu; US Department of Agriculture (USDA) National Research Initiative Competitive Grant (2007-35205-17883); US National Cancer Institute (NCI); US National Heart, Lung, and Blood Institute (NHLBI; 268200625226C, 268201100005C, 268201100006C, 268201100007C, 268201100008C, 268201100009C, 268201100010C, 268201100011C, 268201100012C, 5R01HL087679-02, and 1RL1MH083268-01); US National Human Genome Research Institute (NHGRI), US National Institute of Allergy and Infectious Diseases (NIAID), US National Institute of Child Health and Human Development (NICHD), US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), US National Institutes of Health (NIH; 5R01MH63706: 02, K23DK080145, M01RR16500, N01AG12100, N01AG12109, N01HC25195, N01HC35129, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85084, N01HC85085, N01HC85086, N01HC85239, N01HG65403, N02HL64278, P01CA87969, P30DK063491, P30DK072488, R01AA007535, R01AA014041, R01AA013320, R01AA013321, R01AA013326, R01AG004563, R01AG008724, R01AG008861, R01AG010175, R01AG013196, R01AG015928, R01AG020098, R01AG023629, R01AG027058, R01AG028555, R01CA047988, R01CA049449, R01CA050385, R01CA065725, R01CA067262, R01DA12854, R01DK062370, R01DK072193, R01DK073490, R01DK075681, R01DK075787, R01DK089256, R01HD042157, R01HG002651, R01HL036310, R01HL043851, R01HL059367, R01HL071981, R01HL075366, R01HL086694, R01HL087641, R01HL087647, R01HL087652, R01HL087676, R01HL087679, R01HL087700, R01HL088215, R01HL105756, R01HS006516, R01LM010098, R01MH059565, R01MH059566, R01MH059571, R01MH059586, R01MH059587, R01MH059588, R01MH060870, R01MH060879, R01MH061675, R01MH067257, R01MH079469, R01MH079470, R01MH081800, RL1MH083268, U01CA098233, U01DK062418, U01HG004402, U01HL069757, U01HL072515, U01HL080295, U01HL084729, U01HL084756, U24MH068457, U54RR020278, UL1RR025005, UL1RR033176, Z01HG000024); US National Institute of Neurological Disorders and Stroke (NINDS); Vasa, Narpes and Korsholm Health Care Centers; Vastra Gotaland Foundation; VU University Amsterdam; Walter E. Nichols, M. D.; and Eleanor Nichols endowments at Stanford University; Wellcome Trust (068545/Z/02, 069224, 072960, 075491, 076113/B/04/Z, 076113/K/04/Z, 079557, 079895, 081682, 083270, 084183/Z/07/Z, 085301, 086596/Z/08/Z, 089061/Z/09/Z, 089062/Z/09/Z, 090532/Z/09/Z, 098051), Go-DARTS, WT Research Career Development Fellowship, WT Career Development Award, WT Centre for Human Genetics, WT Clinical Research Facility, WT Sanger Institute, Scottish Health Informatics Programme; and the Yrjo Jahnsson Foundation (56358). More details of acknowledgements can be found in Text S2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; I have read the journal's policy and we have the following conflicts: Kari Stefansson, Valgerdur Steinthorsdottir, and Gudmar Thorleifsson are employed by deCODE Genetics with stock/stock options in the company. Ines Barroso and spouse own stock in Incyte Ltd and GlaxoSmithKline. Nilesh J Samani holds a Chair supported by the British Heart Foundation and is an NIHR Senior Investigator. NR 82 TC 95 Z9 95 U1 4 U2 55 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2013 VL 9 IS 6 AR e1003500 DI 10.1371/journal.pgen.1003500 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 175HX UT WOS:000321222600005 PM 23754948 ER PT J AU Venkova-Canova, T Baek, JH FitzGerald, PC Blokesch, M Chattoraj, DK AF Venkova-Canova, Tatiana Baek, Jong Hwan FitzGerald, Peter C. Blokesch, Melanie Chattoraj, Dhruba K. TI Evidence for Two Different Regulatory Mechanisms Linking Replication and Segregation of Vibrio cholerae Chromosome II SO PLOS GENETICS LA English DT Article ID P1 PLASMID REPLICATION; PSEUDOMONAS-AERUGINOSA; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; DNA-REPLICATION; F-PLASMID; INITIATOR GENE; PROTEIN DNAA; PARS SITES; H-NS AB Understanding the mechanisms that coordinate replication initiation with subsequent segregation of chromosomes is an important biological problem. Here we report two replication-control mechanisms mediated by a chromosome segregation protein, ParB2, encoded by chromosome II of the model multichromosome bacterium, Vibrio cholerae. We find by the ChIP-chip assay that ParB2, a centromere binding protein, spreads beyond the centromere and covers a replication inhibitory site (a 39-mer). Unexpectedly, without nucleation at the centromere, ParB2 could also bind directly to a related 39-mer. The 39-mers are the strongest inhibitors of chromosome II replication and they mediate inhibition by binding the replication initiator protein. ParB2 thus appears to promote replication by out-competing initiator binding to the 39-mers using two mechanisms: spreading into one and direct binding to the other. We suggest that both these are novel mechanisms to coordinate replication initiation with segregation of chromosomes. C1 [Venkova-Canova, Tatiana; Baek, Jong Hwan; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Blokesch, Melanie] Ecole Polytech Fed Lausanne, Global Hlth Inst, Sch Life Sci, Lausanne, Switzerland. RP Venkova-Canova, T (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM chattoraj@nih.gov RI Blokesch, Melanie/A-4057-2013 FU Center for Cancer Research, NCI, NIH; Swiss National Science Foundation [31003A_127029] FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH, and funding from the Swiss National Science Foundation (grant 31003A_127029 to MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 12 Z9 13 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2013 VL 9 IS 6 AR e1003579 DI 10.1371/journal.pgen.1003579 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 175HX UT WOS:000321222600052 PM 23818869 ER PT J AU Amano, T Hirata, T Falco, G Monti, M Sharova, LV Amano, M Sheer, S Hoang, HG Piao, Y Stagg, CA Yamamizu, K Akiyama, T Ko, MSH AF Amano, Tomokazu Hirata, Tetsuya Falco, Geppino Monti, Manuela Sharova, Lioudmila V. Amano, Misa Sheer, Sarah Hoang, Hien G. Piao, Yulan Stagg, Carole A. Yamamizu, Kohei Akiyama, Tomohiko Ko, Minoru S. H. TI Zscan4 restores the developmental potency of embryonic stem cells SO NATURE COMMUNICATIONS LA English DT Article ID MOUSE ES CELLS; TETRAPLOID COMPLEMENTATION; EFFICIENT DERIVATION; GENOMIC STABILITY; GENE-EXPRESSION; MICE; PCR; PLURIPOTENCY; MICROARRAY; GENERATION AB The developmental potency of mouse embryonic stem (ES) cells, which is the ability to contribute to a whole embryo, is known to deteriorate during long-term cell culture. Previously, we have shown that ES cells oscillate between Zscan4(-) and Zscan4(+) states, and the transient activation of Zscan4 is required for the maintenance of telomeres and genome stability of ES cells. Here we show that increasing the frequency of Zscan4 activation in mouse ES cells restores and maintains their developmental potency in long-term cell culture. Injection of a single ES cell with such increased potency into a tetraploid blastocyst gives rise to an entire embryo with a higher success rate. These results not only provide a means to rejuvenate ES cells by manipulating Zscan4 expression, but also indicate the active roles of Zscan4 in the long-term maintenance of ES cell potency. C1 [Amano, Tomokazu; Hirata, Tetsuya; Falco, Geppino; Monti, Manuela; Sharova, Lioudmila V.; Amano, Misa; Sheer, Sarah; Hoang, Hien G.; Piao, Yulan; Stagg, Carole A.; Yamamizu, Kohei; Akiyama, Tomohiko; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med, Tokyo 1608582, Japan. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@z7.keio.jp RI Amano, Tomokazu/F-9720-2013; OI Ko, Minoru/0000-0002-3530-3015 FU National Institute on Aging, National Institutes of Health FX We would like to thank Yong Qian, Dawood Dudekula and Hong Yu for technical assistance. This work was in part supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 35 TC 25 Z9 25 U1 5 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 1966 DI 10.1038/ncomms2966 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207SM UT WOS:000323624100034 PM 23739662 ER PT J AU Chen, JH Repunte-Canonigo, V Kawamura, T Lefebvre, C Shin, W Howell, LL Hemby, SE Harvey, BK Califano, A Morales, M Koob, GF Sanna, PP AF Chen, Jihuan Repunte-Canonigo, Vez Kawamura, Tomoya Lefebvre, Celine Shin, William Howell, Leonard L. Hemby, Scott E. Harvey, Brandon K. Califano, Andrea Morales, Marisela Koob, George F. Sanna, Pietro Paolo TI Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor SO NATURE COMMUNICATIONS LA English DT Article ID NEUROTROPHIC FACTOR; EXPRESSION; RECEPTOR; SYSTEMS; REWARD; GENE; RATS; NEUROBIOLOGY; CONNECTIONS; PHENOTYPE AB Proteoglycans like syndecan-3 have complex signaling roles in addition to their function as structural components of the extracellular matrix. Here, we show that syndecan-3 in the lateral hypothalamus has an unexpected new role in limiting compulsive cocaine intake. In particular, we observe that syndecan-3 null mice self-administer greater amounts of cocaine than wild-type mice. This effect can be rescued by re-expression of syndecan-3 in the lateral hypothalamus with an adeno-associated viral vector. Adeno-associated viral vector delivery of syndecan-3 to the lateral hypothalamus also reduces motivation for cocaine in normal mice. Syndecan-3 limits cocaine intake by modulating the effects of glial-cell-line-derived neurotrophic factor, which uses syndecan-3 as an alternative receptor. Our findings indicate syndecan-3-dependent signaling as a novel therapeutic target for the treatment of cocaine addiction. C1 [Chen, Jihuan; Repunte-Canonigo, Vez; Kawamura, Tomoya; Sanna, Pietro Paolo] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Lefebvre, Celine; Shin, William; Califano, Andrea] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [Shin, William; Califano, Andrea] Columbia Univ, Dept Biol Sci, New York, NY 10032 USA. [Howell, Leonard L.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30076 USA. [Hemby, Scott E.] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27101 USA. [Harvey, Brandon K.; Morales, Marisela] NIDA, Intramural Res Program, Neuronal Networks Sect, Baltimore, MD 21224 USA. [Califano, Andrea] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. RP Sanna, PP (reprint author), Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. EM psanna@scripps.edu RI Lefebvre, Celine/E-6290-2013; koob, george/P-8791-2016 FU NIH [DA13821, DA004398, DA027129, DA010344, DA006634, CA121852, GM085659]; [AA007456] FX Supported by NIH grants DA13821, DA004398, DA027129, DA010344, DA006634, CA121852, GM085659; JC was supported by training grant AA007456. We thank Ofer Reizes of the Lerner Research Institute at the Cleveland Clinic Foundation, Luca Mologni of the University of Milano-Bicocca, and S. Barak Caine of the Mclean Hospital and Harvard Medical School for helpful discussion. NR 35 TC 5 Z9 5 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 1955 DI 10.1038/ncomms2955 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207SM UT WOS:000323624100023 PM 23736082 ER PT J AU Childs-Disney, JL Stepniak-Konieczna, E Tran, T Yildirim, I Park, H Chen, CZ Hoskins, J Southall, N Marugan, JJ Patnaik, S Zheng, W Austin, CP Schatz, GC Sobczak, K Thornton, CA Disney, MD AF Childs-Disney, Jessica L. Stepniak-Konieczna, Ewa Tuan Tran Yildirim, Ilyas Park, HaJeung Chen, Catherine Z. Hoskins, Jason Southall, Noel Marugan, Juan J. Patnaik, Samarjit Zheng, Wei Austin, Chris P. Schatz, George C. Sobczak, Krzysztof Thornton, Charles A. Disney, Matthew D. TI Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules SO NATURE COMMUNICATIONS LA English DT Article ID MUSCLEBLIND PROTEINS; CUG REPEATS; GENE-EXPRESSION; BINDING PROTEIN; SEQUESTRATION; DESIGN; TRANSCRIPTS; MBNL1; DM1 AB The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by(exp)anded, non-coding r(CUG) repeats (r(CUG)(exp)). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)(exp) and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)(exp). This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)(exp) and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1. C1 [Childs-Disney, Jessica L.; Tuan Tran; Park, HaJeung; Disney, Matthew D.] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA. [Stepniak-Konieczna, Ewa; Sobczak, Krzysztof] Adam Mickiewicz Univ, Inst Mol Biol & Biotechnol, Dept Gene Express, PL-61251 Poznan, Poland. [Tuan Tran] SUNY Buffalo, Dept Chem, Buffalo, NY 14260 USA. [Yildirim, Ilyas; Schatz, George C.] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA. [Chen, Catherine Z.; Southall, Noel; Marugan, Juan J.; Patnaik, Samarjit; Zheng, Wei; Austin, Chris P.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Hoskins, Jason; Thornton, Charles A.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. RP Disney, MD (reprint author), Scripps Res Inst, Dept Chem, 130 Scripps Way 3A1, Jupiter, FL 33458 USA. EM Disney@scripps.edu RI Hoskins, Jason/F-5672-2012; Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Hoskins, Jason/0000-0001-6944-1996; Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Scripps Research Institute; Muscular Dystrophy Association [158552]; National Institutes of Health [3R01GM079235-02S1, 1R01GM079235-01A2, AR049077, U54NS48843]; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; Marigold Foundation; PS-OC Center of the NIH/NCI [1U54CA143869-01]; Foundation for Polish Science-TEAM programme; European Union within European Regional Development Fund FX We thank Don Mackenzie from the Marigold Foundation for his support of this research project in particular and DM1 research in general and Amit Kumar for preliminary studies; and Professor Glenn E. Morris (Wolfson Centre for Inherited Neuromuscular Disease) for generously providing the MB1a antibody (anti-MBNL1). Funding for this work was provided by the Scripps Research Institute, the Muscular Dystrophy Association (158552 to MDD), the National Institutes of Health (3R01GM079235-02S1 and 1R01GM079235-01A2 to MDD; AR049077 and U54NS48843 to CAT), the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Marigold Foundation postdoctoral fellowship, the PS-OC Center of the NIH/NCI (grant 1U54CA143869-01; I.Y. and G. C. S.), and the Foundation for Polish Science-TEAM programme co-financed by the European Union within the European Regional Development Fund (E. S-K and K.S.). NR 44 TC 33 Z9 34 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 2044 DI 10.1038/ncomms3044 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207TI UT WOS:000323626400018 PM 23806903 ER PT J AU Feng, Q Vickers, KC Anderson, MP Levin, MG Chen, W Harrison, DG Wilke, RA AF Feng, Q. Vickers, K. C. Anderson, M. P. Levin, M. G. Chen, W. Harrison, D. G. Wilke, R. A. TI A common functional promoter variant links CNR1 gene expression to HDL cholesterol level SO NATURE COMMUNICATIONS LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; DENSITY-LIPOPROTEIN CHOLESTEROL; CANNABINOID-1 RECEPTOR BLOCKER; RISK-FACTORS; CLINICAL-IMPLICATIONS; CARDIOMETABOLIC RISK; OVERWEIGHT PATIENTS; METABOLIC SYNDROME; REDUCES OBESITY; BASAL INSULIN AB Type 1 cannabinoid receptor blockers increase high-density lipoprotein cholesterol levels. Although genetic variation in the type 1 cannabinoid receptor-encoded by the CNR1 gene-is known to influence high-density lipoprotein cholesterol level as well, human studies conducted to date have been limited to genetic markers such as haplotype-tagging single nucleotide polymorphisms. Here we identify rs806371 in the CNR1 promoter as the causal variant. We re-sequence the CNR1 gene and genotype all variants in a DNA biobank linked to comprehensive electronic medical records. By testing each variant for association with high-density lipoprotein cholesterol level in a clinical practice-based setting, we localize a putative functional allele to a 100-bp window in the 5'-flanking region. Assessment of variants in this window for functional impact on electrophoretic mobility shift assay identifies rs806371 as a novel regulatory binding element. Reporter gene assays confirm that rs806371 reduces gene expression, thereby linking CNR1 gene variation to high-density lipoprotein cholesterol level in humans. C1 [Feng, Q.; Vickers, K. C.; Chen, W.; Harrison, D. G.; Wilke, R. A.] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37203 USA. [Vickers, K. C.; Anderson, M. P.; Levin, M. G.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Feng, Q (reprint author), Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37203 USA. EM QiPing.Feng@vanderbilt.edu FU NIH NHLBI Intramural Research Funds; CNR1 gene [20100707]; [UL1 RR024975]; [R01 DK080007] FX This work was funded by UL1 RR024975 and R01 DK080007 (Dr Wilke). Dr Vickers was also supported in part by NIH NHLBI Intramural Research Funds. We wish to thank Dr Alan Remaley at NIH for helpful comments during the preparation of the manuscript, and Dr Mark Rieder, in the Department of Genome Sciences at University of Washington, for oversight during the sequencing of the CNR1 gene (Contract# 20100707). We also wish to thank Dr Wei-Qi Wei, in the Department of Biomedical Informatics at Vanderbilt University, for his demographic summary of the entire EMR-linked biobank. NR 43 TC 3 Z9 3 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 1973 DI 10.1038/ncomms2973 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207SM UT WOS:000323624100041 PM 23748922 ER PT J AU Soekadar, SR Witkowski, M Cossio, EG Birbaumer, N Robinson, SE Cohen, LG AF Soekadar, Surjo R. Witkowski, Matthias Cossio, Eliana G. Birbaumer, Niels Robinson, Stephen E. Cohen, Leonardo G. TI In vivo assessment of human brain oscillations during application of transcranial electric currents SO NATURE COMMUNICATIONS LA English DT Article ID DIRECT-CURRENT STIMULATION; MAGNETIC STIMULATION; MOTOR CORTEX; FMRI SIGNAL; MEG; MAGNETOENCEPHALOGRAPHY; PERFORMANCE; MEMORY; COMMUNICATION; LOCALIZATION AB Brain oscillations reflect pattern formation of cell assemblies' activity, which is often disturbed in neurological and psychiatric diseases like depression, schizophrenia and stroke. In the neurobiological analysis and treatment of these conditions, transcranial electric currents applied to the brain proved beneficial. However, the direct effects of these currents on brain oscillations have remained an enigma because of the inability to record them simultaneously. Here we report a novel strategy that resolves this problem. We describe accurate reconstructed localization of dipolar sources and changes of brain oscillatory activity associated with motor actions in primary cortical brain regions undergoing transcranial electric stimulation. This new method allows for the first time direct measurement of the effects of non-invasive electrical brain stimulation on brain oscillatory activity and behavior. C1 [Soekadar, Surjo R.; Witkowski, Matthias; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Soekadar, Surjo R.; Witkowski, Matthias; Cossio, Eliana G.] Univ Tubingen Hosp, Appl Neurotechnol Lab, Dept Psychiat & Psychotherapy, D-72076 Tubingen, Germany. [Soekadar, Surjo R.; Witkowski, Matthias; Cossio, Eliana G.; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72076 Tubingen, Germany. [Birbaumer, Niels] IRCCS, Osped San Camillo, I-30126 Venice, Italy. [Robinson, Stephen E.] NIMH, MEG Core Facil, NIH, Bethesda, MD 20892 USA. RP Soekadar, SR (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM surjo.soekadar@uni-tuebingen.de OI Soekadar, Surjo R./0000-0003-1280-5538 FU National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Mental Health (NIMH), Bethesda, Maryland, USA; German Federal Ministry of Education and Research (BMBF) [Forderzeichen 01GQ0831, 16SV5840]; Deutsche Forschungsgemeinschaft (DFG); European Union [FP7-ICT-2011-288551] FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Mental Health (NIMH), Bethesda, Maryland, USA, the German Federal Ministry of Education and Research (BMBF, Forderzeichen 01GQ0831, 16SV5840), the Deutsche Forschungsgemeinschaft (DFG) and the European Union (FP7-ICT-2011-288551). We thank Sook-Lei Liew for her help in preparing the manuscript. NR 60 TC 34 Z9 35 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 2032 DI 10.1038/ncomms3032 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207TI UT WOS:000323626400006 PM 23787780 ER PT J AU Wang, L Chang, JJ Varghese, D Dellinger, M Kumar, S Best, AM Ruiz, J Bruick, R Pena-Llopis, S Xu, JJ Babinski, DJ Frantz, DE Brekken, RA Quinn, AM Simeonov, A Easmon, J Martinez, ED AF Wang, Lei Chang, Jianjun Varghese, Diana Dellinger, Michael Kumar, Subodh Best, Anne M. Ruiz, Julio Bruick, Richard Pena-Llopis, Samuel Xu, Junjie Babinski, David J. Frantz, Doug E. Brekken, Rolf A. Quinn, Amy M. Simeonov, Anton Easmon, Johnny Martinez, Elisabeth D. TI A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth SO NATURE COMMUNICATIONS LA English DT Article ID GENE-EXPRESSION; EPIGENETIC-MODULATORS; STRUCTURAL INSIGHTS; BREAST-CANCER; JMJD2 FAMILY; CELLS; IDENTIFICATION; PROLIFERATION; DEACETYLASES; SPECIFICITY AB The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of alpha-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance. C1 [Wang, Lei; Chang, Jianjun; Varghese, Diana; Dellinger, Michael; Kumar, Subodh; Best, Anne M.; Brekken, Rolf A.; Martinez, Elisabeth D.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Best, Anne M.; Martinez, Elisabeth D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Ruiz, Julio; Bruick, Richard; Xu, Junjie; Babinski, David J.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Pena-Llopis, Samuel] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA. [Frantz, Doug E.] UT San Antonio, Dept Chem, San Antonio, TX 78249 USA. [Brekken, Rolf A.] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA. [Quinn, Amy M.; Simeonov, Anton] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. [Easmon, Johnny] Leopold Franzens Univ, Dept Pharmaceut Chem, A-6020 Innsbruck, Austria. RP Martinez, ED (reprint author), Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. EM elisabeth.martinez@utsouthwestern.edu FU Sara and Frank McKnight Graduate Student Fellowship; Burroughs Wellcome Fund; NCI [CA095471, K22CA11871703, R01CA12526901]; NCRR, NIH [C06 RR 15437-01]; DoD [W81XWH0910365]; University of Texas SPORE in Lung Cancer [P50-CA70907]; DCF (Nolan Miller Lung Cancer grant); NCI Cancer Center [1P30 CA142543-01] FX We are deeply indebted to Drs David J. Mangelsdorf and John D. Minna for generous sharing of resources, insightful discussions and general project support. We are grateful to Drs A. Smith and J. Richardson for assistance with histology, Drs C. Cummins and Z. Wang for help with mass spectrometry, and Dr A. Jadhav for compound informatics. Cell lines were kindly provided by Dr J. Minna, Dr C. Lewis, Dr D. Euhus and Dr J. T. Hsieh. We are grateful to Dr Luc Girard for the gift of the DIVISA and Matrix software. We thank Dr S. Vega-Rubin-de-Celis, Dr K. Gardner, Dr T. Scheuermann, Dr S. Hoffman, Dr S. Kliewer, Dr C. M. Chiang, Dr H. Yu, Dr J. Rizo-Rey, Dr Sam John, Dr E. Komives and members of the Minna and Mangelsdorf/Kliewer laboratories for helpful discussions. J. C. R. is a Howard Hughes Medical Institute Scholar and was supported by a Sara and Frank McKnight Graduate Student Fellowship. R. K. B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund and the NCI (CA095471). This investigation was partly conducted in a facility constructed with support from the Research Facilities Improvement Program (Grant # C06 RR 15437-01) from the NCRR, NIH. This project was partly funded by the NCI (K22CA11871703 and R01CA12526901 to E. D. M.), by the DoD (W81XWH0910365 to E. D. M.), by the University of Texas SPORE in Lung Cancer (P50-CA70907 to J. D. M.) and by the DCF (Nolan Miller Lung Cancer grant to E. D. M.). The authors acknowledge the assistance of the Genomics Shared Resource at the Harold C. Simmons Cancer Center, which is supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 66 Z9 66 U1 1 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 2035 DI 10.1038/ncomms3035 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207TI UT WOS:000323626400009 PM 23792809 ER PT J AU Xiao, JB Huang, ZH Chen, CZ Agoulnik, IU Southall, N Hu, X Jones, RE Ferrer, M Zheng, W Agoulnik, AI Marugan, JJ AF Xiao, Jingbo Huang, Zaohua Chen, Catherine Z. Agoulnik, Irina U. Southall, Noel Hu, Xin Jones, Raisa E. Ferrer, Marc Zheng, Wei Agoulnik, Alexander I. Marugan, Juan J. TI Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1 SO NATURE COMMUNICATIONS LA English DT Article ID PROTEIN-COUPLED RECEPTOR-7; ENDOTHELIAL GROWTH-FACTOR; LEUCINE-RICH REPEAT; FAMILY PEPTIDES; BINDING-SITES; EXPRESSION; LGR7; HYPERTENSION; ACTIVATION; SERELAXIN AB The anti-fibrotic, vasodilatory and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases, and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodelling capacity of these peptide hormones is difficult to study in chronic settings because of their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin/insulin-like family peptide receptor 1 agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of relaxin/insulin-like family peptide receptor 1 activation. C1 [Xiao, Jingbo; Chen, Catherine Z.; Southall, Noel; Hu, Xin; Jones, Raisa E.; Ferrer, Marc; Zheng, Wei; Marugan, Juan J.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Huang, Zaohua; Agoulnik, Alexander I.] Florida Int Univ, Dept Human & Mol Genet, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Agoulnik, Irina U.] Florida Int Univ, Dept Cellular Biol & Pharmacol, Herbert Wertheim Coll Med, Miami, FL 33199 USA. RP Marugan, JJ (reprint author), NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM maruganj@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Agoulnik, Irina/0000-0003-4889-0324; Agoulnik, Alexander/0000-0001-6587-6845 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681, R03MH085705]; Intramural Research Program of the National Human Genome Research Institute (NHGRI); National Center for Advancing Translational Sciences (NCATS); National Institutes of Health (NIH); Faculty Research Support Program of the Florida International University FX We acknowledge Dr O. D. Sherwood at the University of Illinois at Urbana-Champaign for providing porcine relaxin; Dr G. D. Bryant-Greenwood at the University of Hawaii and Dr A. Kern at the Scripps Research Institute, Florida, for providing HEK293 cells stably transfected with RXFP1, Dr S. Y. Hsu at Stanford University for HEK293 cells stably transfected with RXFP2; and Dr R. A. D. Bathgate at Howard Florey Institute, Melbourne, for the mouse RXFP1 construct and RXFP3 data. We also thank Drs X. Xu and A. Wang at NCATS for assessment of oral bioavailability in mice, and Dr A. L. Rheingold at the UCSD for the X-ray analysis of compound 8. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (U54MH084681 and R03MH085705 to A.I.A.), the Intramural Research Program of the National Human Genome Research Institute (NHGRI) and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) and the Faculty Research Support Program of the Florida International University. NR 35 TC 16 Z9 16 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 1953 DI 10.1038/ncomms2953 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207SM UT WOS:000323624100021 PM 23764525 ER PT J AU Zhang, T Park, KA Li, Y Byun, HS Jeon, J Lee, Y Hong, JH Kim, JM Huang, SM Choi, SW Kim, SH Sohn, KC Ro, H Lee, JH Lu, T Stark, GR Shen, HM Liu, ZG Park, J Hur, GM AF Zhang, Tiejun Park, Kyeong Ah Li, Yuwen Byun, Hee Sun Jeon, Juhee Lee, Yoonjung Hong, Jang Hee Kim, Jin Man Huang, Song-Mei Choi, Seung-Won Kim, Seon-Hwan Sohn, Kyung-Cheol Ro, Hyunju Lee, Ji Hoon Lu, Tao Stark, George R. Shen, Han-Ming Liu, Zheng-Gang Park, Jongsun Hur, Gang Min TI PHF20 regulates NF-kappa B signalling by disrupting recruitment of PP2A to p65 SO NATURE COMMUNICATIONS LA English DT Article ID ACETYLTRANSFERASE MOF; LYSINE METHYLATION; IMMUNE-RESPONSES; EFFECTOR PROTEIN; ACTIVATION; INFLAMMATION; PHOSPHORYLATION; TRANSCRIPTION; ACETYLATION; PHOSPHATASE AB Constitutive NF-kappa B activation in cancer cells is caused by defects in the signalling network responsible for terminating the NF-kappa B response. Here we report that plant homeodomain finger protein 20 (PHF20) maintains NF-kappa B in an active state in the nucleus by inhibiting the interaction between PP2A and p65. We show that PHF20 induces canonical NF-kappa B signalling by increasing the DNA-binding activity of NF-kappa B subunit p65. In PHF20 overexpressing cells, the termination of tumour necrosis factor-induced p65 phosphorylation is impaired whereas upstream signalling events triggered by tumour necrosis factor are unaffected. This effect strictly depends on the interaction between PHF20 and methylated lysine residues of p65, which hinders recruitment of PP2A to p65, thereby maintaining p65 in a phosphorylated state. We further show that PHF20 levels correlate with p65 phosphorylation levels in human glioma specimens. Our work identifies PHF20 as a novel regulator of NF-kappa B activation and suggests that elevated expression of PHF20 may drive constitutive NF-kappa B activation in some cancers. C1 [Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen; Byun, Hee Sun; Jeon, Juhee; Lee, Yoonjung; Hong, Jang Hee; Park, Jongsun; Hur, Gang Min] Chungnam Natl Univ, Dept Pharmacol, Coll Med, Infect Signaling Network Res Ctr, Taejon 301747, South Korea. [Zhang, Tiejun; Park, Kyeong Ah; Li, Yuwen; Byun, Hee Sun; Jeon, Juhee; Lee, Yoonjung; Hong, Jang Hee; Kim, Jin Man; Park, Jongsun; Hur, Gang Min] Chungnam Natl Univ, Res Inst Med Sci, Coll Med, Infect Signaling Network Res Ctr, Taejon 301747, South Korea. [Zhang, Tiejun; Choi, Seung-Won; Kim, Seon-Hwan] Chungnam Natl Univ, Dept Neurosurg, Coll Med, Taejon 301747, South Korea. [Kim, Jin Man; Huang, Song-Mei] Chungnam Natl Univ, Dept Pathol, Coll Med, Taejon 301747, South Korea. [Sohn, Kyung-Cheol] Chungnam Natl Univ, Dept Dermatol, Coll Med, Taejon 301747, South Korea. [Ro, Hyunju] Chungnam Natl Univ, Dept Biol Sci, Coll Biosci & Biotechnol, Taejon 306764, South Korea. [Lee, Ji Hoon] Amherst Coll, Dept Phys, Amherst, MA 01002 USA. [Lu, Tao] Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. [Stark, George R.] Cleveland Clin Fdn, Lerner Res Inst, Dept Mol Genet, Cleveland, OH 44195 USA. [Shen, Han-Ming] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore. [Liu, Zheng-Gang] NCI, Cell & Cellular Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Park, J (reprint author), Chungnam Natl Univ, Dept Pharmacol, Coll Med, Infect Signaling Network Res Ctr, Taejon 301747, South Korea. EM insulin@cnu.ac.kr; gmhur@cnu.ac.kr RI SHEN, Han-Ming/B-5942-2011 OI SHEN, Han-Ming/0000-0001-7369-5227 FU National Research Foundation of Korea (NRF); Korea government (MEST) [20070054932]; National R&D Program for Cancer Control Ministry of Health and Welfare, Republic of Korea [0720560]; Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [A121183] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 20070054932), and a grant from the National R&D Program for Cancer Control Ministry of Health and Welfare, Republic of Korea (No: 0720560). This work was also supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A121183). NR 45 TC 21 Z9 21 U1 4 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUN PY 2013 VL 4 AR 2062 DI 10.1038/ncomms3062 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208HK UT WOS:000323668400005 PM 23797602 ER PT J AU Krueger, F Parasuraman, R Moody, L Twieg, P de Visser, E McCabe, K O'Hara, M Lee, MR AF Krueger, Frank Parasuraman, Raja Moody, Lara Twieg, Peter de Visser, Ewart McCabe, Kevin O'Hara, Martin Lee, Mary R. TI Oxytocin selectively increases perceptions of harm for victims but not the desire to punish offenders of criminal offenses SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE oxytocin; empathy; third-party decision-making; neurolaw; antisocial personality disorder; psychopathy ID 3RD-PARTY PUNISHMENT; PROSOCIAL BEHAVIOR; GENDER-DIFFERENCES; SOCIAL-BEHAVIOR; HUMAN BRAIN; EMPATHY; HUMANS; NEUROPEPTIDES; ANGER; EMOTIONS AB The neuropeptide oxytocin functions as a hormone and neurotransmitter and facilitates complex social cognition and approach behavior. Given that empathy is an essential ingredient for third-party decision-making in institutions of justice, we investigated whether exogenous oxytocin modulates empathy of an unaffected third-party toward offenders and victims of criminal offenses. Healthy male participants received intranasal oxytocin or placebo in a randomized, double-blind, placebo-controlled, between-subjects design. Participants were given a set of legal vignettes that described an event during which an offender engaged in criminal offenses against victims. As an unaffected third-party, participants were asked to rate those criminal offenses on the degree to which the offender deserved punishment and how much harm was inflicted on the victim. Exogenous oxytocin selectively increased third-party decision-makers' perceptions of harm for victims but not the desire to punish offenders of criminal offenses. We argue that oxytocin promoted empathic concern for the victim, which in turn increased the tendency for prosocial approach behavior regarding the interpersonal relationship between an unaffected third-party and a fictional victim in the criminal scenarios. Future research should explore the context- and person-dependent nature of exogenous oxytocin in individuals with antisocial personality disorder and psychopathy, in whom deficits in empathy feature prominently. C1 [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Krueger, Frank; Parasuraman, Raja; Moody, Lara; de Visser, Ewart] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Twieg, Peter; McCabe, Kevin] George Mason Univ, Dept Econ, Fairfax, VA 22030 USA. [O'Hara, Martin] Fairfax Hosp, Virginia Hosp Ctr, Falls Church, VA 22030 USA. [Lee, Mary R.] NIDA, Neuroimaging Res Branch, Baltimore, MD USA. RP Krueger, F (reprint author), George Mason Univ, Dept Mol Neurosci, 4400 Univ Dr,Mail Stop 2A1, Fairfax, VA 22030 USA. EM fkrueger@gmu.edu OI McCabe, Kevin/0000-0003-0544-157X FU NIH, NIDA; Air Force Office of Scientific Research (AFOSR) [FA9550-10-1-0385]; Center of Excellence in Neuroergonomics, Technology, and Cognition (CENTEC) FX This research was supported in part by the Intramural Research Program of the NIH, NIDA and funded by Air Force Office of Scientific Research (AFOSR) Grant FA9550-10-1-0385 to Raja Parasuraman and the Center of Excellence in Neuroergonomics, Technology, and Cognition (CENTEC). NR 47 TC 15 Z9 15 U1 2 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JUN PY 2013 VL 8 IS 5 BP 494 EP 498 DI 10.1093/scan/nss026 PG 5 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 208CF UT WOS:000323653000002 PM 22368214 ER PT J AU Reed, CE Fenton, SE AF Reed, Casey E. Fenton, Suzanne E. TI Exposure to diethylstilbestrol during sensitive life stages: A legacy of heritable health effects SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE diethylstilbestrol; DES; cancer; development; fetal basis of adult disease; breast; pregnancy ID IN-UTERO; CANCER-RISK; BREAST-CANCER; FOLLOW-UP; DEVELOPMENTAL EXPOSURE; GENE-EXPRESSION; BISPHENOL-A; WOMEN; PREGNANCY; MICE AB Diethylstilbestrol (DES) is a potent estrogen mimic that was predominantly used from the 1940s to the 1970s by pregnant women in hopes of preventing miscarriage. Decades later, DES is known to enhance breast cancer risk in exposed women and cause a variety of birth-related adverse outcomes in their daughters such as spontaneous abortion, second trimester pregnancy loss, preterm delivery, stillbirth, and neonatal death. Additionally, children exposed to DES in utero suffer from sub/infertility and cancer of reproductive tissues. DES is a pinnacle compound that demonstrates the fetal basis of adult disease. The mechanisms of cancer and endocrine disruption induced by DES are not fully understood. Future studies should focus on common target tissue pathways affected and the health of the DES grandchildren. Birth Defects Research (Part C) 99:134-146, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Reed, Casey E.; Fenton, Suzanne E.] NIEHS, Dept Hlth & Human Serv, Div NTP, Natl Toxicol Program NTP Labs Branch,NIH, Res Triangle Pk, NC 27709 USA. RP Fenton, SE (reprint author), NIEHS, POB 12233,MD E1-08,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM fentonse@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102785-01, ZIA ES102785-02, ZIA ES102785-03] NR 71 TC 23 Z9 23 U1 3 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-975X J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD JUN PY 2013 VL 99 IS 2 SI SI BP 134 EP 146 DI 10.1002/bdrc.21035 PG 13 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 203VH UT WOS:000323321600006 PM 23897597 ER PT J AU Kitikoon, P Nelson, MI Killian, ML Anderson, TK Koster, L Culhane, MR Vincent, AL AF Kitikoon, Pravina Nelson, Martha I. Killian, Mary Lea Anderson, Tavis K. Koster, Leo Culhane, Marie R. Vincent, Amy L. TI Genotype patterns of contemporary reassorted H3N2 virus in US swine SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID INFLUENZA-A VIRUSES; UNITED-STATES; GENETIC EVOLUTION; H1N1 2009; HUMANS; TRANSMISSION; PHYLOGENIES; PIGS AB To understand the evolution of swine-origin H3N2v influenza viruses that have infected 320 humans in the USA since August 2011, we performed a phylogenetic analysis at a whole genome scale of North American swine influenza viruses (n = 200). All viral isolates evolved from the prototypical North American H3 cluster 4 (c4), with evidence for further diversification into subclusters. At least ten distinct reassorted H3N2/pandemic H1 N1 (rH3N2p) genotypes were identified in swine. Genotype 1 (G1) was most frequently detected in swine and all human H3N2v viruses clustered within a single G1 clade. These data suggest that the genetic requirements for transmission to humans may be restricted to a specific subset of swine viruses. Mutations at putative antigenic sites as well as reduced serological cross-reactivity among the H3 subclusters suggest antigenic drift of these contemporary viruses. C1 [Kitikoon, Pravina; Anderson, Tavis K.; Vincent, Amy L.] USDA ARS, Natl Anim Dis Ctr, Virus & Prion Dis Res Unit, Ames, IA 50010 USA. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Killian, Mary Lea; Koster, Leo] USDA APHIS, Natl Vet Serv Labs, Ames, IA 50010 USA. [Culhane, Marie R.] Univ Minnesota, Coll Vet Med, Vet Diagnost Lab, St Paul, MN 55108 USA. RP Vincent, AL (reprint author), USDA ARS, Natl Anim Dis Ctr, Virus & Prion Dis Res Unit, POB 70, Ames, IA 50010 USA. EM amy.vincent@ars.usda.gov FU USDA-ARS; USDA-APHIS-VS FX We are grateful to the pork producers and swine veterinarians for participating in the USDA-National Animal Health Laboratory Network (NAHLN) Influenza Virus Surveillance System for swine. We acknowledge Dr Sabrina Swenson (NVSL-USDA-APHIS) and Dr John Korslund (CEAH-USDA-APHIS) for kindly sharing swine influenza genetic and surveillance data from the NAHLN Influenza Virus Surveillance System for swine. Thank you to Alicia Janas-Martindale (NVSL-USDA-APHIS) for assistance in virus isolation whole-genome sequencing. Thank you to Dr Marcus Kehrli (NADC-USDA-ARS) for critical reading of the manuscript. Funding was provided by USDA-ARS and USDA-APHIS-VS. Mention of trade names Or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. USDA is an equal opportunity provider and employer. NR 24 TC 30 Z9 30 U1 1 U2 14 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2013 VL 94 BP 1236 EP 1241 DI 10.1099/vir.0.51839-0 PN 6 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 170GJ UT WOS:000320838100012 PM 23695819 ER PT J AU Trask, SD Wetzel, JD Dermody, TS Patton, JT AF Trask, Shane D. Wetzel, J. Denise Dermody, Terence S. Patton, John T. TI Mutations in the rotavirus spike protein VP4 reduce trypsin sensitivity but not viral spread SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VIRUS-MEMBRANE-FUSION; SINGLE-PARTICLE; INFECTIVITY; ENHANCEMENT; CLEAVAGE; KINETICS AB Infectious entry of the nonenveloped rotavirus virion requires proteolysis of the spike protein VP4 to mediate conformational changes associated with membrane penetration. We sequenced and characterized an isolate that was cultured in the absence of trypsin and found that it is more resistant to proteolysis than WT virus. A substitution mutation abrogates one of the defined trypsin-cleavage sites, suggesting that blocking proteolysis at this site reduces the overall kinetics of proteolysis. Kinetic analysis of the membrane penetration-associated conformational change indicated that the 'fold-back' of the mutant spike protein is slower than that of WT. Despite these apparent biochemical defects, the mutant virus replicates in an identical manner to the WT virus. These findings enhance an understanding of VP4 functions and establish new strategies to interrogate rotavirus cell entry. C1 [Trask, Shane D.; Patton, John T.] NIAID, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. [Wetzel, J. Denise; Dermody, Terence S.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. [Wetzel, J. Denise; Dermody, Terence S.] Vanderbilt Univ, Sch Med, Elizabeth B Lamb Ctr Pediat Res, Nashville, TN 37232 USA. [Dermody, Terence S.] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. RP Patton, JT (reprint author), NIAID, Lab Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, [Z01 AI000788]; National Institutes of Health [R01 AI32539]; National Institute of Allergy and Infectious Diseases, National Institutes of Health and the Elizabeth B. Lamb Center for Pediatric Research FX We thank Philip R. Dormitzer and Kristen M. Ogden for helpful discussions and scientific advice. This work was supported by Public Health Service award Z01 AI000788 from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (S. D. T. and J. T. P.), R01 AI32539 (T. S. D.) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and the Elizabeth B. Lamb Center for Pediatric Research. NR 19 TC 1 Z9 1 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2013 VL 94 BP 1296 EP 1300 DI 10.1099/vir.0.050674-0 PN 6 PG 5 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 170GJ UT WOS:000320838100018 PM 23426355 ER PT J AU Favret, S Binet, F Lapalme, E Leboeuf, D Carbadillo, J Rubic, T Picard, E Mawambo, G Tetreault, N Joyal, JS Chemtob, S Sennlaub, F SanGiovanni, JP Guimond, M Sapieha, P AF Favret, Sandra Binet, Francois Lapalme, Eric Leboeuf, Dominique Carbadillo, Jose Rubic, Tina Picard, Emilie Mawambo, Gaelle Tetreault, Nicolas Joyal, Jean-Sebastien Chemtob, Sylvain Sennlaub, Florian SanGiovanni, John Paul Guimond, Martin Sapieha, Przemyslaw TI Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions SO AGING-US LA English DT Article DE AMD; GPR91; geographic atrophy; microglia; succinate; metabolite receptor ID PROTEIN-COUPLED RECEPTORS; MACULAR DEGENERATION; BRUCHS MEMBRANE; UNITED-STATES; DISEASE; PREVALENCE; DEPOSITS; DRUSEN; CELLS; PATHOGENESIS AB Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovasculature in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form may accompany it. Here we provide the first evidence for the protective role of the Retinal Pigment Epithelium (RPE)-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the outer retina. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in the SUCNR1 gene. In mice, outer retinal expression of SUCNR1 is observed in the RPE as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1-/- mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch's membrane and a buildup of subretinal microglia. The accumulation of microglia in Sucnr1-deficient mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wildtype microglia into Sucnr1-/- mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD and thus broaden our understanding of this clinically unmet need. C1 [Favret, Sandra; Binet, Francois; Lapalme, Eric; Joyal, Jean-Sebastien; Chemtob, Sylvain; Sapieha, Przemyslaw] Univ Montreal, Res Ctr, Dept Ophthalmol, Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. [Lapalme, Eric; Mawambo, Gaelle; Tetreault, Nicolas; Sapieha, Przemyslaw] Univ Montreal, Res Ctr, Dept Biochem, Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. [Leboeuf, Dominique] Univ Montreal, Res Ctr, Dept Immunol, Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. [Carbadillo, Jose; Rubic, Tina] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. [Picard, Emilie] Univ Paris 06, Paris, France. [Picard, Emilie] Univ Descartes, Paris, France. [Picard, Emilie] 2 INSERM, CRC UMRS872, Team 17, Paris, France. [Sennlaub, Florian] INSERM, U968, F-75012 Paris, France. [Sennlaub, Florian] CNRS, UMR 7210, Paris, France. [Sennlaub, Florian] UPMC Univ Paris 06, UMR S 968, Inst Vis, Paris, France. [Sennlaub, Florian] Hop Hotel Dieu, AP HP, Serv Ophtalmol, Ctr Rech Ophtalmol, F-75006 Paris, France. [Favret, Sandra; Binet, Francois; SanGiovanni, John Paul] NEI, Clin Trials Branch, Bethesda, MD 20892 USA. RP Sapieha, P (reprint author), Univ Montreal, Res Ctr, Dept Ophthalmol, Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. EM Mike.Sapieha@umontreal.ca OI Sennlaub, Florian/0000-0003-4412-1341 FU Canada Research Chair in Retinal Cell Biology; Alcon Research Institute New Investigator Award; Canadian Institutes of Health Research [221478]; Canadian Diabetes Association [OG-3-11-3329-PS]; Natural Sciences and Engineering Research Council of Canada [418637]; Foundation Fighting Blindness Canada; Reseau de Recherche en Sante de la Vision du Quebec; Fonds de la Recherche en Sante du Quebec (FRSQ) fellowship; Maisonneuve-Rosemont Hospital Foundation FX PS holds a Canada Research Chair in Retinal Cell Biology and the Alcon Research Institute New Investigator Award. This work was supported by grants from the Canadian Institutes of Health Research (221478), the Canadian Diabetes Association (OG-3-11-3329-PS), the Natural Sciences and Engineering Research Council of Canada (418637) and The Foundation Fighting Blindness Canada. Support was also provided by the Reseau de Recherche en Sante de la Vision du Quebec. FB holds a Fonds de la Recherche en Sante du Quebec (FRSQ) fellowship. Additional funding was provided by the Maisonneuve-Rosemont Hospital Foundation. We would like to thank Johanne Ouellette and Dr. Ribeiro-Da-Silva for electron microscopy. We thank Dr. Emily Chew for comments on the manuscript. NR 42 TC 11 Z9 12 U1 0 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JUN PY 2013 VL 5 IS 6 BP 427 EP 444 PG 18 WC Cell Biology SC Cell Biology GA 195CS UT WOS:000322679600007 PM 23833031 ER PT J AU Martina, JA Puertollano, R AF Martina, Jose A. Puertollano, Rosa TI RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis SO AUTOPHAGY LA English DT Editorial Material DE autophagy; lysosomes; MITF; RRAG; MTORC1; TFEB AB When the levels of intracellular amino acids are high, RRAG GTPases recruit MTORC1 to lysosomes and promote its activation. We found that RRAGs also recruit specific MTORC1 substrates to the lysosomal surface, thus facilitating MTORC1-mediated phosphorylation and regulation. In particular, active RRAGs interact with the transcription factor EB (TFEB), the master regulator of a gene network that promotes lysosomal biogenesis and autophagy. Redistribution to lysosomes is critical for MTORC1-dependent inactivation of TFEB under nutrient-rich conditions. Therefore, RRAGs play a critical role coordinating nutrient availability and cellular clearance. C1 [Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov FU NIH, National Heart, Lung, and Blood Institute (NHLBI) FX This project was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI). NR 0 TC 6 Z9 6 U1 0 U2 0 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 JUN 1 PY 2013 VL 9 IS 6 BP 928 EP 930 DI 10.4161/auto.24371 PG 3 WC Cell Biology SC Cell Biology GA 201WO UT WOS:000323173900014 PM 23524842 ER PT J AU Lee, JJ Chow, CC AF Lee, James J. Chow, Carson C. TI The causal meaning of Fisher's average effect SO GENETICS RESEARCH LA English DT Article ID NATURAL-SELECTION; FUNDAMENTAL THEOREM; POPULATION-GENETICS; ASSOCIATION; VARIANTS; HEIGHT; EXCESS; LOCI AB In order to formulate the Fundamental Theorem of Natural Selection, Fisher defined the average excess and average effect of a gene substitution. Finding these notions to be somewhat opaque, some authors have recommended reformulating Fisher's ideas in terms of covariance and regression, which are classical concepts of statistics. We argue that Fisher intended his two averages to express a distinction between correlation and causation. On this view, the average effect is a specific weighted average of the actual phenotypic changes that result from physically changing the allelic states of homologous genes. We show that the statistical and causal conceptions of the average effect, perceived as inconsistent by Falconer, can be reconciled if certain relationships between the genotype frequencies and non-additive residuals are conserved. There are certain theory-internal considerations favouring Fisher's original formulation in terms of causality; for example, the frequency-weighted mean of the average effects equaling zero at each locus becomes a derivable consequence rather than an arbitrary constraint. More broadly, Fisher's distinction between correlation and causation is of critical importance to gene-trait mapping studies and the foundations of evolutionary biology. C1 [Lee, James J.; Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Lee, JJ (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM leejj5@mail.nih.gov FU NIDDK, NIH FX We thank A. W. F. Edwards for sharing his unpublished work and his correspondence with the late Douglas Falconer, Sabin Lessard for helpfully answering one of our queries, and the reviewers for comments and suggestions that have greatly improved this paper. This work was supported by the Intramural Research Programme of the NIDDK, NIH. NR 59 TC 8 Z9 8 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0016-6723 J9 GENET RES JI Genet. Res. PD JUN PY 2013 VL 95 IS 2-3 BP 89 EP 109 DI 10.1017/S0016672313000074 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA 200BB UT WOS:000323039700008 PM 23938113 ER PT J AU Batton, B Li, L Newman, NS Das, A Watterberg, KL Yoder, BA Faix, RG Laughon, MM Stoll, BJ Van Meurs, KP Carlo, WA Poindexter, BB Bell, EF Sanchez, PJ Ehrenkranz, RA Goldberg, RN Laptook, AR Kennedy, KA Frantz, ID Shankaran, S Schibler, K Higgins, RD Walsh, MC AF Batton, Beau Li, Lei Newman, Nancy S. Das, Abhik Watterberg, Kristi L. Yoder, Bradley A. Faix, Roger G. Laughon, Matthew M. Stoll, Barbara J. Van Meurs, Krisa P. Carlo, Waldemar A. Poindexter, Brenda B. Bell, Edward F. Sanchez, Pablo J. Ehrenkranz, Richard A. Goldberg, Ronald N. Laptook, Abbot R. Kennedy, Kathleen A. Frantz, Ivan D., III Shankaran, Seetha Schibler, Kurt Higgins, Rosemary D. Walsh, Michele C. CA Child Hlth Human Dev Neonatal Res TI Use of Antihypotensive Therapies in Extremely Preterm Infants SO PEDIATRICS LA English DT Article DE extremely preterm infant; antihypotensive therapy; blood pressure; hypotension ID BIRTH-WEIGHT INFANTS; ARTERIAL-BLOOD PRESSURE; CEREBRAL OXYGENATION; PREMATURE-INFANTS; INTENSIVE-CARE; RISK-FACTOR; HYPOTENSION; AGE; FEASIBILITY; HEMORRHAGE AB OBJECTIVE: To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial. METHODS: Prospective observational study of infants 23(0/7) to 26(6/7) weeks' gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity. RESULTS: Of 367 infants enrolled, 203 (55%) received at least 1 anti-hypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates. CONCLUSIONS: Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated. C1 [Batton, Beau; Newman, Nancy S.; Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Batton, Beau] So Illinois Univ, Sch Med, Dept Pediat, Springfield, IL 62794 USA. [Li, Lei] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Yoder, Bradley A.; Faix, Roger G.] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Laughon, Matthew M.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Poindexter, Brenda B.] Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Kennedy, Kathleen A.] Univ Texas Houston, Med Sch Houston, Dept Pediat, Houston, TX USA. [Frantz, Ivan D., III] Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Div Newborn Med, Boston, MA USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Schibler, Kurt] Cincinnati Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH USA. [Schibler, Kurt] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Batton, B (reprint author), So Illinois Univ, Sch Med, Dept Pediat, Div Neonatol, POB 19676, Springfield, IL 62794 USA. EM bbatton@siumed.edu FU National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Best Pharmaceuticals for Children Act FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support, including funding from the Best Pharmaceuticals for Children Act, for the Neonatal Research Network's Early Blood Pressure Observational Study. Funded by the National Institutes of Health (NIH). NR 40 TC 26 Z9 27 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2013 VL 131 IS 6 BP E1865 EP E1873 DI 10.1542/peds.2012-2779 PG 9 WC Pediatrics SC Pediatrics GA 197HH UT WOS:000322840200021 PM 23650301 ER PT J AU Schoch, CL AF Schoch, C. L. TI Improving the veracity of sequence data in GenBank SO PHYTOPATHOLOGY LA English DT Meeting Abstract CT APS-MSA Joint Meeting CY AUG 10-14, 2013 CL Austin, TX SP APS, MSA C1 [Schoch, C. L.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2013 VL 103 IS 6 SU 2 BP 128 EP 128 PG 1 WC Plant Sciences SC Plant Sciences GA 196TM UT WOS:000322799500708 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI To dream the impossible dream: universal influenza vaccination SO CURRENT OPINION IN VIROLOGY LA English DT Article ID T-CELL RESPONSES; VIRUS HEMAGGLUTININ; IMMUNE-RESPONSE; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; ANTIGENIC STRUCTURE; A VIRUSES; EPITOPES; VACCINES; HA AB Year in and year out, influenza viruses exact a deadly and expensive toll on humanity. Current vaccines simply do not keep pace with viral immune evasion, providing partial protection, at best, among various age groups. A quantum leap in understanding the basic principles of the adaptive and innate immune responses to influenza viruses offers the opportunity to develop vaccines that forestall, and potentially ultimately defeat, influenza virus antigenic variation. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov FU Intramural NIH HHS [ZIA AI001104-03, ZIA AI001055-02, ZIA AI001014-06] NR 59 TC 15 Z9 15 U1 1 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD JUN PY 2013 VL 3 IS 3 BP 316 EP 321 DI 10.1016/j.coviro.2013.05.008 PG 6 WC Virology SC Virology GA 191MD UT WOS:000322416300014 PM 23835048 ER PT J AU Falzarano, D Feldmann, H AF Falzarano, Darryl Feldmann, Heinz TI Vaccines for viral hemorrhagic fevers - progress and shortcomings SO CURRENT OPINION IN VIROLOGY LA English DT Article ID RIFT-VALLEY FEVER; BORNE ENCEPHALITIS-VIRUS; NONHUMAN-PRIMATES; EBOLA-VIRUS; YELLOW-FEVER; LASSA FEVER; INACTIVATED VACCINE; MARBURG VIRUSES; CLINICAL-TRIAL; RENAL SYNDROME AB With a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. In the past decade this has not been due to a lack of the ability to develop Vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. The two exceptions to this are vaccines against Dengue virus (DENV) and Rift Valley fever virus (RVFV), which recently have seen significant progress in putting forward new and improved vaccines, respectively. Experimental vaccines for filoviruses and Lassa virus (LASV) do exist but are hindered by a lack of financial interest and only partially or ill-defined correlates/mechanisms of protection that could be assessed in clinical trials. C1 [Falzarano, Darryl; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 75 TC 18 Z9 18 U1 2 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD JUN PY 2013 VL 3 IS 3 BP 343 EP 351 DI 10.1016/j.coviro.2013.04.007 PG 9 WC Virology SC Virology GA 191MD UT WOS:000322416300017 PM 23773330 ER PT J AU Falgairolle, M Ceccato, JC de Seze, M Herbin, M Cazalets, JR AF Falgairolle, Melanie Ceccato, Jean-Charles de Seze, Mathieu Herbin, Marc Cazalets, Jean-Rene TI Metachronal propagation of motor activity SO FRONTIERS IN BIOSCIENCE-LANDMARK LA English DT Article DE Spinal cord; Electrophysiology; Locomotion; Motor control; CPG; Network evolution; Review ID CENTRAL PATTERN GENERATOR; LAMPREY SPINAL-CORD; LOCOMOTOR-LIKE ACTIVITY; CENTRAL NERVOUS-SYSTEM; INTERSEGMENTAL COORDINATION; LARVAL ZEBRAFISH; MEDICINAL LEECH; XENOPUS-EMBRYOS; RHYTHM GENERATION; LIMB MOVEMENTS AB A diverse array of biomechanical systems has evolved to satisfy locomotor requirements (reptation, swimming, walking, etc.) and in all cases, successful behabior achievement requires the integrated functioning of various segments, to ensure the appropriate positioning of the different body regions. From comparative studies on a variety of invertebrate and vertebrate organisms, it is now established that the basic motor patterns underlying limb and/or trunk movements during locomotion are driven by central networks of neurons, so-called central pattern generators (CPGs). In limbless animals such as leech, lamprey, snakes... body propulsion is driven by alternate left-right trunk muscle contractions that occur sequentially (or metachronally) along the body length. Here, we highlight some common principles of motor control involving metachronal activity that are shared by multisegmental systems. In a first step we will review systems in which the neural mechanisms the that underlie modular linear distribution have been extensively studied. Finally, we will review modeling studies that have been performed to better understand the fundamental mechanisms that underlie metachronal propagation C1 [Falgairolle, Melanie; Ceccato, Jean-Charles] NINDS, Sect Dev Biol, NIH, Bethesda, MD 20892 USA. [de Seze, Mathieu] Ctr Hosp Univ Pellegrin, Serv Med Phys & Readaptat, EA Handicap & Syst Nerveux 4136, Bordeaux, France. [Herbin, Marc] Museum Natl Hist Nat, UMR MNHN CNRS 7179, Dpt EGB, CP 55, F-75231 Paris 05, France. [Cazalets, Jean-Rene] Univ Bordeaux 2, CNRS UMR 5287, F-33076 Bordeaux, France. RP Cazalets, JR (reprint author), Univ Bordeaux 2, CNRS UMR 5287, Bat 2,2E Etage,146 Rue Leo Saignat, F-33076 Bordeaux, France. EM jean-rene.cazalets@u-bordeaux2.fr RI Cazalets, Jean-Rene/D-7851-2014 NR 132 TC 5 Z9 5 U1 1 U2 16 PU FRONTIERS IN BIOSCIENCE INC PI IRVINE PA 16471 SCIENTIFIC WAY, IRVINE, CA 92618 USA SN 1093-9946 J9 FRONT BIOSCI-LANDMRK JI Front. Biosci. PD JUN 1 PY 2013 VL 18 BP 820 EP 837 DI 10.2741/4146 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 172OA UT WOS:000321012500004 PM 23747850 ER PT J AU Ip, E Zhang, Q Rejeski, J Harris, T Kritchevsky, S AF Ip, Edward Zhang, Qiang Rejeski, Jack Harris, Tammy Kritchevsky, Stephen TI Partially Ordered Mixed Hidden Markov Model for the Disablement Process of Older Adults SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Continuation ratio model; EM algorithm; Generalized linear model; Health ABC study; Latent Markov model ID DISABILITY; STATES; TRANSITIONS; RECOVERY; LIKELIHOOD; REGRESSION; MORTALITY; EXTENSION; DYNAMICS; MOBILITY AB At both the individual and societal levels, the health and economic burden of disability in older adults is enormous in developed countries, including the U.S. Recent studies have revealed that the disablement process in older adults often comprises episodic periods of impaired functioning and periods that are relatively free of disability, amid a secular and natural trend of decline in functioning. Rather than an irreversible, progressive event that is analogous to a chronic disease, disability is better conceptualized and mathematically modeled as states that do not necessarily follow a strict linear order of good to bad. Statistical tools, including Markov models, which allow bidirectional transition between states, and random effects models, which allow individual-specific rate of secular decline, are pertinent. In this article, we propose a mixed effects, multivariate, hidden Markov model to handle partially ordered disability states. The model generalizes the continuation ratio model for ordinal data in the generalized linear model literature and provides a formal framework for testing the effects of risk factors and/or an intervention on the transitions between different disability states. Under a generalization of the proportional odds ratio assumption, the proposed model circumvents the problem of a potentially large number of parameters when the number of states and the number of covariates are substantial. We describe a maximum likelihood method for estimating the partially ordered, mixed effects model and show how the model can be applied to a longitudinal dataset that consists of N = 2903 older adults followed for 10 years in the Health Aging and Body Composition Study. We further statistically test the effects of various risk factors upon the probabilities of transition into various severe disability states. The result can be used to inform geriatric and public health science researchers who study the disablement process. Supplementary materials for this article are available online. C1 [Ip, Edward] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Zhang, Qiang] Dept Biostat Sci, Winston Salem, NC 27157 USA. [Rejeski, Jack] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Harris, Tammy] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Kritchevsky, Stephen] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA. RP Ip, E (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. EM eip@wakehealth.edu; qizhang@wakehealth.edu; rejeski@wfu.edu; harrista@nia.nih.gov; skritche@wakehealth.edu OI Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health [R01AG031827A, U01HL101066-01, P30 AG21332] FX The research was supported by the following grants from the National Institutes of Health: R01AG031827A, U01HL101066-01, and P30 AG21332. NR 47 TC 9 Z9 11 U1 0 U2 9 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2013 VL 108 IS 502 BP 370 EP 384 DI 10.1080/01621459.2013.770307 PG 15 WC Statistics & Probability SC Mathematics GA 182FS UT WOS:000321727700002 PM 24058222 ER PT J AU Kim, S Chen, Z Zhang, ZW Simons-Morton, BG Albert, PS AF Kim, Sungduk Chen, Zhen Zhang, Zhiwei Simons-Morton, Bruce G. Albert, Paul S. TI Bayesian Hierarchical Poisson Regression Models: An Application to a Driving Study With Kinematic Events SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Longitudinal count data; Over-dispersion; Random effect; Serial correlation; Teenage driving ID GENERALIZED LINEAR-MODELS; SERIES COUNT DATA; MONTE-CARLO; TIME-SERIES; GIBBS SAMPLER; COMPUTATION; CRASHES AB Although there is evidence that teenagers are at a high risk of crashes in the early months after licensure, the driving behavior of these teenagers is not well understood. The Naturalistic Teenage Driving Study (NTDS) is the first U.S. study to document continuous driving performance of newly licensed teenagers during their first 18 months of licensure. Counts of kinematic events such as the number of rapid accelerations are available for each trip, and their incidence rates represent different aspects of driving behavior. We propose a hierarchical Poisson regression model incorporating overdispersion, heterogeneity, and serial correlation as well as a semiparametric mean structure. Analysis of the NTDS data is carried out with a hierarchical Bayesian framework using reversible jump Markov chain Monte Carlo algorithms to accommodate the flexible mean structure. We show that driving with a passenger and night driving decrease kinematic events, while having risky friends increases these events. Further the within-subject variation in these events is comparable to the between-subject variation. This methodology will be useful for other intensively collected longitudinal count data, where event rates are low and interest focuses on estimating the mean and variance structure of the process. Supplementary materials for this article are available online. C1 [Kim, Sungduk; Chen, Zhen; Zhang, Zhiwei; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Kim, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. EM kims2@mail.nih.gov; chenzhe@mail.nih.gov; zhangz7@mail.mih.gov; nzortonb@mail.mih.gov; albertp@mail.mih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3405] FX Sungduk Kim is Staff Scientist (E-mail. kims2@mail.nih.gov), Zhen Chen is Investigator (E-mail: chenzhe@mail.nih.gov), and Zhiwei Zhang is Investigator (E-mail: zhangz7@mail.nih.gov), Biostatistics and Bioinformatics Branch, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20852. Bruce G. Simons-Morton is Senior Investigator, Prevention Research Branch, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20852 (E-mail: mortonb@mail.nih.gov). Paul S. Albert is Senior Investigator, Biostatistics and Bioinformatics Branch, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20852 (E-mail: albertp@mail.nih.gov). The authors thank the Editor, the Associate Editor, and two referees for their helpful comments and suggestions that have improved the article. This research was supported by the intramural research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract # N01-HD-5-3405). NR 28 TC 5 Z9 5 U1 2 U2 13 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2013 VL 108 IS 502 BP 494 EP 503 DI 10.1080/01621459.2013.770702 PG 10 WC Statistics & Probability SC Mathematics GA 182FS UT WOS:000321727700011 PM 24076760 ER PT J AU Liang, FM Song, QF Yu, K AF Liang, Faming Song, Qifan Yu, Kai TI Bayesian Subset Modeling for High-Dimensional Generalized Linear Models SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Bayesian classification; Posterior consistency; Stochastic approximation Monte Carlo; Sure variable screening; Variable selection ID FALSE DISCOVERY RATE; VARIABLE-SELECTION; STOCHASTIC-APPROXIMATION; CONJUGATE PRIORS; FEATURE SPACE; MONTE-CARLO; REGRESSION; ALGORITHM; CLASSIFICATION; REGULARIZATION AB This article presents a new prior setting for high-dimensional generalized linear models, which leads to a Bayesian subset regression (BSR) with the maximum a posteriori model approximately equivalent to the minimum extended Bayesian information criterion model. The consistency of the resulting posterior is established under mild conditions. Further, a variable screening procedure is proposed based on the marginal inclusion probability, which shares the same properties of sure screening and consistency with the existing sure independence screening (SIS) and iterative sure independence screening (ISIS) procedures. However, since the proposed procedure makes use of joint information from all predictors, it generally outperforms SIS and ISIS in real applications. This article also makes extensive comparisons of BSR with the popular penalized likelihood methods, including Lasso, elastic net, SIS, and ISIS. The numerical results indicate that BSR can generally outperform the penalized likelihood methods. The models selected by BSR tend to be sparser and, more importantly, of higher prediction ability. In addition, the performance of the penalized likelihood methods tends to deteriorate as the number of predictors increases, while this is not significant for BSR. Supplementary materials for this article are available online. C1 [Liang, Faming; Song, Qifan] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Liang, FM (reprint author), Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. EM fliang@stat.tamu.edu; qsong@stat.tamu.edu; yuka@mail.nih.gov FU National Science Foundation [DMS-1007457, DMS-1106494]; King Abdullah University of Science and Technology (KAUST) [KUS-C1-016-04] FX Faming Liang is Professor, Department of Statistics, Texas A&M University, College Station, TX 77843-3143 (E-mail: fliang@stat.tamu.edu). Qifan Song is Graduate Student, Department of Statistics, Texas A&M University, College Station, TX 77843-3143 (E-mail: qsong@stat.tamu.edu). Kai Yu is Investigator, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, MD 20892-7335 (E-mail: yuka@mail.nih.gov). Liang's research was partially supported by grants from the National Science Foundation (DMS-1007457 and DMS-1106494) and the award (KUS-C1-016-04) made by King Abdullah University of Science and Technology (KAUST). The authors thank Dr. Chris Hans for sending us the lymph data, and thank the editor, associate editor, and two referees for their constructive comments that have led to significant improvement of this article. NR 46 TC 6 Z9 6 U1 1 U2 15 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2013 VL 108 IS 502 BP 589 EP 606 DI 10.1080/01621459.2012.761942 PG 18 WC Statistics & Probability SC Mathematics GA 182FS UT WOS:000321727700019 ER PT J AU Fisher, VR Scott, MK Tremblay, CA Beaulieu, GP Ward, DC Byrne, KM AF Fisher, Virginia R. Scott, Mary K. Tremblay, Christine A. Beaulieu, Gregory P. Ward, Dawn C. Byrne, Karen M. TI Disseminated Intravascular Coagulation: Laboratory Support for Management and Treatment SO LABMEDICINE LA English DT Review DE disseminated intravascular coagulation; hemostasis; thrombocytopenia; coagulation; fresh frozen plasma ID DISEASE AB Disseminated intravascular coagulation (DIC) is a condition in which hemostasis is altered, resulting in unregulated activation of the coagulation cascade. The hallmarks of DIC are thrombosis (from excess clotting), bleeding (from consumption of the coagulation proteins), and thrombocytopenia and anemia (from mechanical destruction of red cells and platelets by coagulation in the microvasculature). DIC is not an isolated disease, it is a symptom of another illness such as endothelial trauma, sepsis, malignancy, or a complication of pregnancy. Therefore, treatment of the underlying medical condition and supportive care with blood products is the mainstay of therapy for DIC. Measurement of platelet count, prothrombin time/activated partial thromboplastin time (PT/aPTT), fibrinogen, and D-dimer, can help diagnose DIC, but treating with blood components only to correct abnormal laboratory tests may not be efficacious. Replenishing coagulation factors, platelets, and red cells should be attempted cautiously as dictated by the clinical scenario. In this report, we discuss the role of the blood bank in helping to manage DIC in hematologic malignancy. C1 [Fisher, Virginia R.; Scott, Mary K.; Tremblay, Christine A.; Beaulieu, Gregory P.; Ward, Dawn C.; Byrne, Karen M.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Byrne, KM (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM KByrne@cc.nih.gov NR 13 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 J9 LABMEDICINE JI Labmedicine PD SUM PY 2013 VL 44 IS 3 BP 205 EP 209 DI 10.1309/LMTCAVNHBUGWTP7K PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 190MQ UT WOS:000322344600002 ER PT J AU Dehay, B Martinez-Vicente, M Caldwell, GA Caldwell, KA Yue, ZY Cookson, MR Klein, C Vila, M Bezard, E AF Dehay, Benjamin Martinez-Vicente, Marta Caldwell, Guy A. Caldwell, Kim A. Yue, Zhenyue Cookson, Mark R. Klein, Christine Vila, Miquel Bezard, Erwan TI Lysosomal impairment in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Review DE Parkinson's disease; ATP13A2; glucocerebrosidase; lysosome; neurodegeneration; Lewy body ID CHAPERONE-MEDIATED AUTOPHAGY; P-TYPE ATPASE; LEWY BODY DISEASES; ALPHA-SYNUCLEIN; IN-VIVO; GAUCHER-DISEASE; CELL-DEATH; GLUCOCEREBROSIDASE MUTATIONS; ATP13A2; DEGRADATION AB Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of -synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, -synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to -synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to -synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function. (c) 2013 Movement Disorder Society C1 [Dehay, Benjamin; Bezard, Erwan] Univ Bordeaux Segalen, Inst Neurodegenerat Dis, CNRS, UMR 5293, F-33076 Bordeaux, France. [Martinez-Vicente, Marta; Vila, Miquel] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Vall dHebron Res Inst, Neurodegenerat Dis Res Grp, Barcelona, Spain. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL USA. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Dept Neurol, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL 35294 USA. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Dept Neurobiol, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL USA. [Yue, Zhenyue] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Neurol, New York, NY USA. [Yue, Zhenyue] Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Neurosci, New York, NY USA. [Cookson, Mark R.] NIH, Cell Biol & Gene Express Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Klein, Christine] Med Univ Lubeck, Inst Neurogenet, D-23538 Lubeck, Germany. [Vila, Miquel] Autonomous Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain. [Vila, Miquel] Catalan Inst Res & Adv Studies, Barcelona, Spain. RP Dehay, B (reprint author), Univ Bordeaux Segalen, IMN, CNRS, UMR 5293, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM benjamin.dehay@u-bordeaux2.fr RI Martinez-Vicente, Marta/K-4312-2014; di Ronza, Alberto/H-7674-2016; OI Martinez-Vicente, Marta/0000-0001-7053-2625; di Ronza, Alberto/0000-0002-9813-5143; Bezard, Erwan/0000-0002-0410-4638 FU European Commission [FP7-PEOPLE-2009-ERG256303]; Fondation pour la Recherche Medicale; Agence Nationale de la Recherche [ANR-08-MNP-018, ANR-07-MNP-Trafinlid]; Volkswagen Foundation; Hermann and Lilly Schilling Foundation; MEFOPA (FP7); Fondo de Investigacion Sanitaria-Instituto de Salud Carlos III, Spain; Ministerio de Investigacion, Desarrollo e Inovacion, Spain; US National Institutes of Health, National Institute of Neurological Disorders and Stroke [R01NS060123, NS060809, RNS055683]; Michael J. Fox Foundation; National Institutes of Health, National Institute on Aging; National Institutes of Health [1R15NS075684] FX This work was supported by a Marie Curie Reintegration Grant from the European Commission (FP7-PEOPLE-2009-ERG256303; to B.D.); by a Fondation pour la Recherche Medicale grant (to B.D.), by Agence Nationale de la Recherche grants (ANR-08-MNP-018; ANR-07-MNP-Trafinlid; to E.B.); by the Volkswagen Foundation, the Hermann and Lilly Schilling Foundation, and MEFOPA (FP7) (to C.K.); by Fondo de Investigacion Sanitaria-Instituto de Salud Carlos III, Spain (to M.V. and M.M.-V.); by Ministerio de Investigacion, Desarrollo e Inovacion, Spain (to M.M.-V); and by US National Institutes of Health, National Institute of Neurological Disorders and Stroke grants (R01NS060123, NS060809, RNS055683) and the Michael J. Fox Foundation (to Z.Y.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (to M.R.C.) and by National Institutes of Health grant 1R15NS075684 (to G.A.C.) NR 81 TC 97 Z9 99 U1 8 U2 34 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2013 VL 28 IS 6 BP 725 EP 732 DI 10.1002/mds.25462 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 171PJ UT WOS:000320941200008 PM 23580333 ER PT J AU Heindel, JJ Schug, TT AF Heindel, Jerrold J. Schug, Thaddeus T. TI The Perfect Storm for Obesity SO OBESITY LA English DT Article ID EXPOSURE AB Obesity rates have risen steadily in the United States and around the world over the past century, with a marked escalation within the past two decades. Conventional wisdom within the medical community is that the burgeoning obesity epidemic is the product of poor nutrition and lack of exercise, but increasingly researchers are questioning whether those factors are wholly responsible. Emerging research about alternative factors is setting the stage for today's "Perfect Storm" for obesity. C1 [Heindel, Jerrold J.; Schug, Thaddeus T.] Natl Inst Environm Sci, Div Extramural Res & Training, Cellular Organ & Syst Pathobiol Branch, Res Triangle Pk, NC USA. RP Schug, TT (reprint author), Natl Inst Environm Sci, Div Extramural Res & Training, Cellular Organ & Syst Pathobiol Branch, Res Triangle Pk, NC USA. EM schugt@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 5 TC 4 Z9 4 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD JUN PY 2013 VL 21 IS 6 BP 1079 EP 1080 DI 10.1002/oby.20222 PG 2 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 192LV UT WOS:000322487000002 PM 23784921 ER PT J AU Shomaker, LB Tanofsky-Kraff, M Mooreville, M Reina, SA Courville, AB Field, SE Matheson, BE Brady, SM Yanovski, SZ Yanovski, JA AF Shomaker, Lauren B. Tanofsky-Kraff, Marian Mooreville, Mira Reina, Samantha A. Courville, Amber B. Field, Sara E. Matheson, Brittany E. Brady, Sheila M. Yanovski, Susan Z. Yanovski, Jack A. TI Links of Adolescent- and Parent-Reported Eating in the Absence of Hunger with Observed Eating in the Absence of Hunger SO OBESITY LA English DT Article ID ENERGY-INTAKE; BEHAVIOR QUESTIONNAIRE; HISPANIC CHILDREN; PUBERTAL CHANGES; OVERWEIGHT; PATTERNS; OBESITY; GIRLS; VALIDATION; PREDICTORS AB Objective: Eating in the absence of hunger (EAH) typically was assessed by measuring snack intake after consumption of a meal. There were no validated self-report measures of EAH. The relationship of adolescent self-report and parent-reported EAH to adolescents' measured intake in the absence of hunger was examined. Design and Methods: Ninety adolescents completed the Eating in the Absence of Hunger Questionnaire for Children and Adolescents (EAH-C) to describe eating when not hungry. Parents described children's EAH on a parallel version designed for parents (EAH-P). In a randomized crossover study, adolescent EAH in response to external cues was measured as snack intake after a lunch meal standardized to provide 50% of daily energy requirements and after a large array (>10,000 kcal). Results: Parents' reports of children's EAH in response to external cues were associated with greater EAH after both meals, adjusting for body composition, sex, age, race, puberty, and meal intake. Adolescent-reported EAH was unrelated or showed an inverse association with observed EAH. Conclusions: Parent-reported EAH showed a positive association with adolescents' observed EAH and may be a useful research and clinical tool for assessing EAH in response to external cues in conditions when laboratory assessments are not feasible. C1 [Shomaker, Lauren B.; Tanofsky-Kraff, Marian; Mooreville, Mira; Reina, Samantha A.; Field, Sara E.; Matheson, Brittany E.; Brady, Sheila M.; Yanovski, Susan Z.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Shomaker, Lauren B.; Tanofsky-Kraff, Marian; Field, Sara E.; Matheson, Brittany E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol MPS, Bethesda, MD 20814 USA. [Courville, Amber B.] NIH, Ctr Clin, Dept Nutr, Bethesda, MD 20892 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM mtanofsky@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637 FU NICHD National Research Service Award [1F32HD056762]; NICHD Career Development Award [K99HD069516]; NIDDK [1R01DK080906]; USUHS [R072IC]; NICHD [ZIAHD000641]; NIMHD; OBSSR FX NICHD National Research Service Award 1F32HD056762 and Career Development Award K99HD069516 (to L. Shomaker), NIDDK grant 1R01DK080906 and USUHS grant R072IC (to M. Tanofsky-Kraff), and NICHD Intramural Research Program grant ZIAHD000641 with supplemental funding from NIMHD and OBSSR (to J. Yanovski). NR 40 TC 6 Z9 6 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD JUN PY 2013 VL 21 IS 6 BP 1243 EP 1250 DI 10.1002/oby.20218 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 192LV UT WOS:000322487000027 PM 23913735 ER PT J AU Xiao, ZX Jiang, Q Willette-Brown, J Hu, YL AF Xiao, Zuoxiang Jiang, Qun Willette-Brown, Jami Hu, Yinling TI Mouse model resembling human lung cancer SO ONCOTARGET LA English DT Editorial Material ID IKK-ALPHA; DIFFERENTIATION; CARCINOMAS C1 [Xiao, Zuoxiang; Jiang, Qun; Willette-Brown, Jami; Hu, Yinling] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Hu, YL (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM huy2@mail.nih.gov RI Jiang, Qun/A-1358-2014 NR 8 TC 0 Z9 0 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 JUN PY 2013 VL 4 IS 6 BP 810 EP 811 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 193SB UT WOS:000322580700005 PM 23868856 ER PT J AU Escobar, T Yu, CR Muljo, SA Egwuagu, CE AF Escobar, Thelma Yu, Cheng-Rong Muljo, Stefan A. Egwuagu, Charles E. TI STAT3 Activates miR-155 in Th17 Cells and Acts in Concert to Promote Experimental Autoimmune Uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE EAU; STAT3; miR-155; uveitis; Th17 cells ID CD4(+) T-CELLS; MICRORNA-155 EXPRESSION; MULTIPLE-SCLEROSIS; INFLAMMATION; DIFFERENTIATION; UVEORETINITIS; REGULATOR; DISEASE; PHASE; GENE AB PURPOSE. MicroRNA-155 (miR-155) and STAT3 are implicated in uveitis and pathogenic mechanisms of CNS autoimmune diseases. In our study, we used miR-155(-/-) mice and mice with targeted STAT3 deletion in T cells (CD4-STAT3KO) to investigate roles of miR-155 and STAT3 in the development of experimental autoimmune uveitis (EAU), a mouse model of human uveitis. METHODS. We induced EAU in WT, miR-155(-/-), or CD4-STAT3KO mice by immunization with interphotoreceptor retinoid-binding protein/complete Freund's adjuvant (IRBP/CFA)or adoptive transfer of T cells. EAU was assessed by funduscopy and histology. RNA expression was analyzed by quantitative PCR (qPCR), while cytokine production was assessed by fluorescence-activated cell sorting (FACS). RESULTS. We used a combination of genomic and genetic tools to provide the first evidence that STAT3 binds directly to the miR-155 locus and that STAT3 is required for miR-155 expression. Furthermore, STAT3-dependent increase in miR-155 expression in vivo correlated temporally with onset of EAU, and miR-155(-/-) or CD4-STAT3KO mice did not suffer EAU. CD4(+) lymph node cells from IRBP-immunized WT mice transferred EAU to naive wild-type (WT) and miR-155(-/-) mice, while miR-155(-/-) IRBP-specific T cells did not. CONCLUSIONS. Although miR-155 and STAT3 have been implicated in the etiology of multiple sclerosis (MS), uveitis, or rheumatoid arthritis, their exact roles in these diseases are unclear. We show here for the first time to our knowledge that STAT3 regulates miR-155 expression in Th17 cells. We show further that STAT3 and miR-155 form an axis that promotes the expansion of pathogenic Th17 cells that mediate uveitis. Thus, STAT3 and miR-155 may be therapeutic targets for treating uveitis and other Th17-mediated inflammatory disorders. C1 [Escobar, Thelma; Muljo, Stefan A.] NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Cheng-Rong; Egwuagu, Charles E.] NEI, Lab Immunol, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM Stefan.Muljo@nih.gov; egwuaguc@nei.nih.gov RI Muljo, Stefan/F-5671-2015 OI Muljo, Stefan/0000-0003-1013-446X FU Intramural Research Program of the NEI; NIAID, National Institutes of Health (NIH) FX Supported by the Intramural Research Program of the NEI and NIAID, National Institutes of Health (NIH). The authors alone are responsible for the content and writing of the paper. NR 30 TC 23 Z9 25 U1 0 U2 10 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2013 VL 54 IS 6 BP 4017 EP 4025 DI 10.1167/iovs.13-11937 PG 9 WC Ophthalmology SC Ophthalmology GA 173YW UT WOS:000321120700026 PM 23674757 ER PT J AU Timms, AE Dorschner, MO Wechsler, J Choi, KY Kirkwood, R Girirajan, S Baker, C Eichler, EE Korvatska, O Roche, KW Horwitz, MS Tsuang, DW AF Timms, Andrew E. Dorschner, Michael O. Wechsler, Jeremy Choi, Kyu Yeong Kirkwood, Robert Girirajan, Santhosh Baker, Carl Eichler, Evan E. Korvatska, Olena Roche, Katherine W. Horwitz, Marshall S. Tsuang, Debby W. TI Support for the N-Methyl-D-Aspartate Receptor Hypofunction Hypothesis of Schizophrenia From Exome Sequencing in Multiplex Families SO JAMA PSYCHIATRY LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; ASSOCIATION; GENETICS; PROTEIN; RISK; SUSCEPTIBILITY; TRANSLOCATION; INDIVIDUALS; SYNAPSES; PATHWAYS AB Importance: Schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment. Objective: To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia. Design: We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families with schizophrenia. Setting: Probands and their family members were recruited from academic medical centers. Participants: We intended to identify rare disease-causing mutations in 5 large families where schizophrenia transmission appears consistent with single-gene inheritance. Intervention: Array comparative genomic hybridization was used to identify copy number variants, while exome sequencing was used to identify variants shared in all affected individuals and linkage analysis was used to further filter shared variants of interest. Analysis of select variants was performed in cultured cells to assess their functional consequences. Main Outcome Measures: Rare inherited disease-related genetic mutations. Results: No segregating rare copy number variants were detected by array comparative genomic hybridization. However, in all 5 families, exome sequencing detected rare protein-altering variants in 1 of 3 genes associated with the N-methyl-D-aspartate (NMDA) receptor. One pedigree shared a missense and frameshift substitution of GRM5, encoding the metabotropic glutamate receptor subtype 5 (mGluR5), which is coupled to the NMDA receptor and potentiates its signaling; the frameshift disrupts binding to the scaffolding protein tamalin and increases mGluR5 internalization. Another pedigree transmitted a missense substitution in PPEF2, encoding a calmodulin-binding protein phosphatase, which we show influences mGluR5 levels. Three pedigrees demonstrated different missense substitutions within LRP1B, encoding a low-density lipoprotein receptor-related protein tied to both the NMDA receptor and located in a chromosome 2q22 region previously strongly linked to schizophrenia. Conclusions and Relevance: Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developing schizophrenia and suggests potential novel therapeutic targets. C1 [Timms, Andrew E.; Wechsler, Jeremy; Kirkwood, Robert; Horwitz, Marshall S.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Dorschner, Michael O.; Tsuang, Debby W.] Univ Washington, Sch Med, Dept Psychiat, Seattle, WA USA. [Girirajan, Santhosh; Baker, Carl; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Korvatska, Olena] Univ Washington, Sch Med, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Dorschner, Michael O.; Tsuang, Debby W.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Choi, Kyu Yeong; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. [Girirajan, Santhosh] Penn State Univ, Dept Biochem & Mol Biol, State Coll, PA USA. [Girirajan, Santhosh] Penn State Univ, Dept Anthropol, State Coll, PA USA. RP Tsuang, DW (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 182 GRECC,1660 S Columbian Way, Seattle, WA 98108 USA. EM dwt1@uw.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Roche, Katherine/0000-0001-7282-6539 FU National Institutes of Health, US Department of Veterans Affairs; Brain and Behavior Research Foundation; Office of Research and Development Medical Research Service, Department of Veterans Affairs; National Alliance for Research on Schizophrenia and Depression; Consortium on the Genetics of Schizophrenia [R01MH065558]; VA Merit Review; National Institute of Health, National Institute of General Medical Sciences [T32GM007454] FX This work was supported by the National Institutes of Health, US Department of Veterans Affairs, and the Brain and Behavior Research Foundation. Additional material is based on work supported by the Office of Research and Development Medical Research Service, Department of Veterans Affairs. Specific funding was provided by a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (Dr Tsuang), Consortium on the Genetics of Schizophrenia grant R01MH065558 (Dr Tsuang), VA Merit Review (Dr Tsuang), and National Institute of Health, National Institute of General Medical Sciences grant T32GM007454 (Dr Timms). NR 48 TC 51 Z9 52 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUN PY 2013 VL 70 IS 6 BP 582 EP 590 DI 10.1001/jamapsychiatry.2013.1195 PG 9 WC Psychiatry SC Psychiatry GA 188PK UT WOS:000322204700007 PM 23553203 ER PT J AU Adams, NB Lutsey, PL Folsom, AR Herrington, DH Sibley, CT Zakai, NA Ades, S Burke, GL Cushman, M AF Adams, N. B. Lutsey, P. L. Folsom, A. R. Herrington, D. H. Sibley, C. T. Zakai, N. A. Ades, S. Burke, G. L. Cushman, M. TI Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE blood coagulation; fibrinolysis; inflammation; risk factor; statins; thrombosis ID CARDIOVASCULAR RISK-FACTORS; COA REDUCTASE INHIBITORS; FUTURE VENOUS THROMBOSIS; INTIMA-MEDIA THICKNESS; DEEP-VEIN THROMBOSIS; D-DIMER; SUBCLINICAL ATHEROSCLEROSIS; LEIDEN THROMBOPHILIA; PLASMA-LEVELS; FACTOR-VIII AB BackgroundHMG-CoA reductase inhibitors (statins) reduce the risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers; however, the mechanism for the reduction in VTE risk is unknown. AimIn a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk. MethodsCross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women aged 45-84years, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race and sex-adjusted mean hemostatic factor levels were compared between statin users and non-users, and multivariable linear regression models were used to assess associations of statin use with hemostatic factors, adjusted for age, race/ethnicity, education, income, aspirin use, hormone replacement therapy (in women), and major cardiovascular risk factors. ResultsParticipants using statins had lower adjusted levels of D-dimer (-9%), C-reactive protein (-21%) and factorVIII (-3%) than non-users (P<0.05). Homocysteine and von Willebrand factor levels were non-significantly lower with statin use. Higher fibrinogen (2%) and plasminogen activator inhibitor-1 (22%) levels were observed among statin users than among non-users (P<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors with statin use. ConclusionsFindings of lower D-dimer, FVIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and non-users is warranted. C1 [Adams, N. B.; Zakai, N. A.; Ades, S.; Cushman, M.] Univ Vermont, Dept Med, Colchester, VT 05446 USA. [Lutsey, P. L.; Folsom, A. R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Herrington, D. H.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Cardiol, Winston Salem, NC USA. [Sibley, C. T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Burke, G. L.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Zakai, N. A.; Cushman, M.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. RP Cushman, M (reprint author), Univ Vermont, Dept Med, 208 South Pk Dr, Colchester, VT 05446 USA. EM mary.cushman@uvm.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-RR-024156, UL1-RR-025005] FX 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. This research was supported by contracts N01-HC-95159 to N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-RR-024156 and UL1-RR-025005 from NCRR. NR 39 TC 23 Z9 23 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUN PY 2013 VL 11 IS 6 BP 1078 EP 1084 DI 10.1111/jth.12223 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 175UR UT WOS:000321259600010 PM 23565981 ER PT J AU Abaan, OD Bilke, S AF Abaan, Ogan D. Bilke, Sven TI 104th American Association For Cancer Research (AACR) Annual Meeting; Breakthroughs In Science And Technology Changing Cancer Care SO ACS CHEMICAL BIOLOGY LA English DT Editorial Material ID SUSCEPTIBILITY LOCI; IDENTIFICATION C1 [Abaan, Ogan D.; Bilke, Sven] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Abaan, OD (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM abaano@mail.nih.gov; bilkes@mail.nih.gov NR 7 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUN PY 2013 VL 8 IS 6 BP 1097 EP 1100 DI 10.1021/cb400366r PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 172DD UT WOS:000320979300001 PM 24491168 ER PT J AU Venditti, V Ghirlando, R Clore, GM AF Venditti, Vincenzo Ghirlando, Rodolfo Clore, G. Marius TI Structural Basis for Enzyme I Inhibition by alpha-Ketoglutarate SO ACS CHEMICAL BIOLOGY LA English DT Article ID GLYCOSE PHOSPHOTRANSFERASE SYSTEM; RESIDUAL DIPOLAR COUPLINGS; N-TERMINAL DOMAIN; ESCHERICHIA-COLI; SEDIMENTATION-VELOCITY; ANALYTICAL ULTRACENTRIFUGATION; MACROMOLECULES; METABOLISM; PROTEIN; EQUILIBRIUM AB Creating new bacterial strains in which carbon and nitrogen metabolism are uncoupled is potentially very useful for optimizing yields of microbial produced chemicals from renewable carbon sources. However, the mechanisms that balance carbon and nitrogen consumption in bacteria are poorly understood. Recently, alpha-ketoglutarate (alpha KG), the carbon substrate for ammonia assimilation, has been observed to inhibit Escherichia colt enzyme I (El), the first component of the bacterial phosphotransferase system (PTS), thereby providing a direct biochemical link between central carbon and nitrogen metabolism. Here we investigate the El-alpha KG interaction by NMR and enzymatic assays. We show that alpha KG binds with a K-D of similar to 2.2 M at the active site of El, acting as a competitive inhibitor. In addition, we use molecular docking simulations to derive a structural model of the enzyme inhibitor complex that is fully consistent with NMR and analytical ultracentrifugation data. We expect that the EI-alpha KG structure presented here will provide a starting point for structure-based design of El mutants resistant to alpha KG. C1 [Venditti, Vincenzo; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH; NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank N. Fawzi and Y. Takayama for helpful discussions. This work was supported by funds from the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 37 TC 8 Z9 8 U1 2 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUN PY 2013 VL 8 IS 6 BP 1232 EP 1240 DI 10.1021/cb400027q PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 172DD UT WOS:000320979300018 PM 23506042 ER PT J AU Yin, ZJ Comellas-Aragones, M Chowdhury, S Bentley, P Kaczanowska, K BenMohamed, L Gildersleeve, JC Finn, MG Huang, XF AF Yin, Zhaojun Comellas-Aragones, Marta Chowdhury, Sudipa Bentley, Philip Kaczanowska, Katarzyna BenMohamed, Lbachir Gildersleeve, Jeffrey C. Finn, M. G. Huang, Xuefei TI Boosting Immunity to Small Tumor-Associated Carbohydrates with Bacteriophage Q beta Capsids SO ACS CHEMICAL BIOLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; CANCER VACCINES; TN ANTIGEN; ANTICANCER VACCINES; B-CELL; ANTIBODY-RESPONSES; CONJUGATE VACCINE; BREAST-CANCER; MOSAIC-VIRUS; INDUCTION AB The development of an effective immunotherapy is an attractive strategy toward cancer treatment. Tumor associated carbohydrate antigens (TACAs) are overexpressed on a variety of cancer cell surfaces, which present tempting targets for anticancer vaccine development. However, such carbohydrates are often poorly immunogenic. To overcome this challenge, we show here that the display of a very weak TACA, the monomeric Tn antigen, on bacteriophage Q beta virus-like particles elicits powerful humoral responses to the carbohydrate. The effects of adjuvants, antigen display pattern, and vaccine dose on the strength and subclasses of antibody responses were established. The local density of antigen rather than the total amount of antigen administered was found to be crucial for induction of high Tn-specific IgG titers. The ability to display antigens in an organized and high density manner is a key advantage of virus-like particles such as Q beta, as vaccine carriers. Glycan microarray analysis showed that the antibodies generated were highly selective toward Tn antigens Furthermore, Q beta elicited much higher levels of IgG antibodies than other types of virus like particles, and the IgG antibodies produced reacted strongly with the native Tn antigens on human leukemia cells. Thus, Q beta presents a highly attractive platform for the development of carbohydrate-based anticancer vaccines. C1 [Yin, Zhaojun; Bentley, Philip; Huang, Xuefei] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Comellas-Aragones, Marta; Kaczanowska, Katarzyna; Finn, M. G.] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Comellas-Aragones, Marta; Kaczanowska, Katarzyna; Finn, M. G.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Chowdhury, Sudipa; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [BenMohamed, Lbachir] Univ Calif Irvine, Cellular & Mol Immunol Lab, Gavin Herbert Eye Inst, Sch Med, Irvine, CA 92697 USA. RP Finn, MG (reprint author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM mgfinn@scripps.edu; xuefei@chemistry.msu.edu RI Gildersleeve, Jeffrey/N-3392-2014; Huang, Xuefei/G-3371-2014 FU National Cancer Institute [R01CA149451-01A1]; Marie Curie Actions [VLPsiR-NA-FP7-PEOPLE-2009-IOF-254069]; National Institutes of Health, NCI FX We are grateful to the National Cancer Institute (R01CA149451-01A1) and the Marie Curie Actions (VLPsiR-NA-FP7-PEOPLE-2009-IOF-254069 M.C.-A.) for financial support of our work. This work was also supported in part by the intramural research program of the National Institutes of Health, NCI. We thank T. Zhang and S. Kim for helpful discussions, Z. Polonskaya and B. Laufer for assistance with Q beta conjugates, and T. Carter for assistance with the graphics. NR 57 TC 26 Z9 26 U1 4 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUN PY 2013 VL 8 IS 6 BP 1253 EP 1262 DI 10.1021/cb400060x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 172DD UT WOS:000320979300020 PM 23505965 ER PT J AU Konze, KD Ma, A Li, FL Barsyte-Lovejoy, D Parton, T MacNevin, CJ Liu, F Gao, C Huang, XP Kuznetsova, E Rougie, M Jiang, A Pattenden, SG Norris, JL James, LI Roth, BL Brown, PJ Frye, SV Arrowsmith, CH Hahn, KM Wang, GG Vedadi, M Jin, J AF Konze, Kyle D. Ma, Anqi Li, Fengling Barsyte-Lovejoy, Dalia Parton, Trevor MacNevin, Christopher J. Liu, Feng Gao, Cen Huang, Xi-Ping Kuznetsova, Ekaterina Rougie, Marie Jiang, Alice Pattenden, Samantha G. Norris, Jacqueline L. James, Lindsey I. Roth, Bryan L. Brown, Peter J. Frye, Stephen V. Arrowsmith, Cheryl H. Hahn, Klaus M. Wang, Gang Greg Vedadi, Masoud Jin, Jian TI An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1 SO ACS CHEMICAL BIOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITOR; B-CELL LYMPHOMAS; HISTONE METHYLTRANSFERASE; SELECTIVE INHIBITORS; DRUG DISCOVERY; G9A; METHYLATION; PROTEIN; CHROMATIN; POTENT AB EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, the first orally bioavailable inhibitor that has high in vitro potency for wildtype and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domahis. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non epigenetic targets, competitive with the cofactor SAM and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels M cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2(Y64IN) mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analogue of UNC1999 with potency >1,000-fold lower than that of UNC1999 as a negative control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399), which enriched EZH2 in pull-down studies, and a UNC1999-dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease. C1 [Konze, Kyle D.; Ma, Anqi; Liu, Feng; Gao, Cen; Pattenden, Samantha G.; Norris, Jacqueline L.; James, Lindsey I.; Frye, Stephen V.; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Parton, Trevor; Wang, Gang Greg] Univ N Carolina, Dept Biochem & Biophys, Sch Med, Chapel Hill, NC 27599 USA. [MacNevin, Christopher J.; Rougie, Marie; Hahn, Klaus M.] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Jiang, Alice; Roth, Bryan L.] Univ N Carolina, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Frye, Stephen V.; Hahn, Klaus M.; Wang, Gang Greg; Jin, Jian] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Li, Fengling; Barsyte-Lovejoy, Dalia; Kuznetsova, Ekaterina; Brown, Peter J.; Arrowsmith, Cheryl H.; Vedadi, Masoud] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. RP Jin, J (reprint author), Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM jianjin@unc.edu RI Wang, G Greg/L-6666-2014; Roth, Bryan/F-3928-2010 OI Wang, G Greg/0000-0002-7210-9940; FU University Cancer Research Fund; Carolina Partnership from University of North Carolina at Chapel Hill; V Foundation for Cancer Research; Canada Foundation for Innovation [1097737]; Eli Lilly Canada; GlaxoSmithKline; Ontario Ministry of Economic Development and Innovation; Novartis Research Foundation; Pfizer; AbbVie; Takeda; Janssen; Boehringer Ingelheim; Wellcome Trust; Genome Canada [OGI-055]; NIH/NCI "Pathway to Independence" Award in Cancer Research [R00CA151683]; American Cancer Society [119169-PF-10-183-01-TBE]; National Institutes of Health [GM057464, GM094663] FX We thank Wenhwa Lee for graphical design and illustration and the University Cancer Research Fund and Carolina Partnership from University of North Carolina at Chapel Hill and the V Foundation for Cancer Research for financial support. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canada Foundation for Innovation, Eli Lilly Canada, GlaxoSmithKline, the Ontario Ministry of Economic Development and Innovation, the Novartis Research Foundation, Pfizer, AbbVie, Takeda, Janssen, Boehringer Ingelheim, and the Wellcome Trust. This project was also funded by Genome Canada through the Ontario Genomics Institute per research agreement OGI-055. G.G.W. is supported by NIH/NCI "Pathway to Independence" Award in Cancer Research (R00CA151683) and a Junior Scholar award of the V Foundation for Cancer Research. This research was also supported by funding from the American Cancer Society (C.J.M., 119169-PF-10-183-01-TBE) and the National Institutes of Health (K.M.H., GM057464 and GM094663). NR 47 TC 131 Z9 132 U1 3 U2 58 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUN PY 2013 VL 8 IS 6 BP 1324 EP 1334 DI 10.1021/cb400133J PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 172DD UT WOS:000320979300027 PM 23614352 ER PT J AU Tsai, HT Marshall, JL Weiss, SR Huang, CY Warren, JL Freedman, AN Fu, AZ Sansbury, LB Potosky, AL AF Tsai, H. -T. Marshall, J. L. Weiss, S. R. Huang, C. -Y. Warren, J. L. Freedman, A. N. Fu, A. Z. Sansbury, L. B. Potosky, A. L. TI Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study SO ANNALS OF ONCOLOGY LA English DT Article DE adverse events; arterial thromboembolic events; bevacizumab; cardiac death; congestive heart failure ID ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED PHASE-III; ARTERIAL THROMBOEMBOLIC EVENTS; 1ST-LINE TREATMENT; PROPENSITY SCORES; FACTOR RECEPTOR; FLUOROURACIL; COMBINATION; TRIALS; CAPECITABINE AB Background: Cardiovascular risk attributable to bevacizumab (Avastin (R), BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged >= 65. Patients and methods: We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events. Results: We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20-2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF. Conclusions: In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients. C1 [Tsai, H. -T.; Fu, A. Z.; Potosky, A. L.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Marshall, J. L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Weiss, S. R.] Univ Maryland, Sch Pharm, Ctr Drug Safety, Baltimore, MD 21201 USA. [Weiss, S. R.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Huang, C. -Y.] NIAID, Biostat Res Branch, Div Clin Res, Bethesda, MD 20892 USA. [Warren, J. L.; Freedman, A. N.; Sansbury, L. B.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Tsai, HT (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, 3300 Whitehaven St,NW,Suite 4100,Rm 4137, Washington, DC 20007 USA. EM ht92@georgetown.edu FU National Cancer Institute [HSSN261201000330P, P30CA051008] FX The project described above was supported by Award Number HSSN261201000330P and P30CA051008 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 32 TC 13 Z9 13 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2013 VL 24 IS 6 BP 1574 EP 1579 DI 10.1093/annonc/mdt019 PG 6 WC Oncology SC Oncology GA 168XO UT WOS:000320741500023 PM 23429865 ER PT J AU Yang, WS Shun, XO Gao, J Li, HL Cai, H Yang, G Ji, BT Rothman, N Gao, YT Zheng, W Xiang, YB AF Yang, W. S. Shun, X. O. Gao, J. Li, H. L. Cai, H. Yang, G. Ji, B. T. Rothman, N. Gao, Y. T. Zheng, W. Xiang, Y. B. TI Prospective evaluation of type 2 diabetes mellitus on the risk of primary liver cancer in Chinese men and women SO ANNALS OF ONCOLOGY LA English DT Article DE China; cohort study; primary liver cancer; type 2 diabetes ID BODY-MASS INDEX; HEPATOCELLULAR-CARCINOMA; PHYSICAL-ACTIVITY; VIRAL-HEPATITIS; LIFE-STYLE; FOLLOW-UP; HEALTH; PREVALENCE; SHANGHAI; POPULATION AB Background: No prospective study has investigated the relationship between type 2 diabetes mellitus (T2DM) and the risk of primary liver cancer (PLC) in mainland China, and little is known about the effect of diabetes duration on PLC risk. Design: Data from two population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002-2006 and the Shanghai Women's Health Study, SWHS, 1996-2000) were thus used to assess the associations among T2DM, diabetes duration and PLC risk in Chinese population. Results: During follow-up through 2009, 344 incident PLC cases were identified among 60 183 men and 73 105 women. T2DM is significantly associated with the increased risk of PLC in both men [hazard ratio (HR) = 1.63, 95% confidence interval (CI) 1.06-2.51] and women (HR = 1.64, 95% CI 1.03-2.61). The highest risk of incident liver cancer was observed in the first 5 years after diabetes diagnosis, and decreased substantially with the prolonged diabetes duration (P-trend < 0.001). No synergistic interaction in the development of PLC was found between diabetes and other known risk factors. Conclusions: T2DM is associated with the increased risk of subsequent liver cancer within 5 years after diagnosis in Chinese population, suggesting that hyperinsulinaemia rather than hyperglycaemia is more likely to be a primary mediator for this association. C1 [Yang, W. S.] Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200433, Peoples R China. [Yang, W. S.; Gao, J.; Li, H. L.; Xiang, Y. B.] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, State Key Lab Oncogene & Related Genes,Renji Hosp, Shanghai 200032, Peoples R China. [Yang, W. S.; Gao, J.; Li, H. L.; Gao, Y. T.; Xiang, Y. B.] Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, Dept Epidemiol,Renji Hosp, Shanghai 200032, Peoples R China. [Shun, X. O.; Cai, H.; Yang, G.; Zheng, W.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Ji, B. T.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Xiang, YB (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, State Key Lab Oncogene & Related Genes,Renji Hosp, 25,Lane 2200,Xie Tu Rd, Shanghai 200032, Peoples R China. EM ybxiang@shsci.org FU State Key Project Specialized for Infectious Diseases of China [2008ZX10002-015, 2012ZX10002008-002]; United States National Institutes of Health [R37 CA070867, R01CA82729, R01 HL095931] FX This work was supported by funds from the State Key Project Specialized for Infectious Diseases of China [Nos. 2008ZX10002-015 and 2012ZX10002008-002], and from the United States National Institutes of Health [R37 CA070867, R01CA82729 and R01 HL095931]. NR 33 TC 12 Z9 16 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUN PY 2013 VL 24 IS 6 BP 1679 EP 1685 DI 10.1093/annonc/mdt017 PG 7 WC Oncology SC Oncology GA 168XO UT WOS:000320741500038 PM 23406734 ER PT J AU You, M Liu, YN Chen, YW Guo, JY Wu, J Fu, YJ Shen, R Qi, R Luo, WX Xia, NS AF You, Min Liu, Yanning Chen, Yingwei Guo, Jiyuan Wu, Jun Fu, Yajuan Shen, Rong Qi, Rui Luo, Wenxin Xia, Ningshao TI Maximizing Antibody Production in Suspension-Cultured Mammalian Cells by the Customized Transient Gene Expression Method SO BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY LA English DT Article DE transient gene expression; customized TGE; monoclonal antibody ID HAMSTER OVARY CELLS; RECOMBINANT PROTEIN-PRODUCTION; HIGH-LEVEL; TRANSFECTION; OPTIMIZATION; TEMPERATURE; DESIGN; VIRUS; LINES AB Due to the great diversity in protein expression productivity, a customized transient gene expression (TGE) method was used in the present study to optimize transient expression of three antibodies. Several factors, including host cells, temperature, valproic acid (VPA) treatment, various vectors, and additives were optimized independently and then combined to form a customized TGE protocol for each antibody. In the event, the optimized TGE conditions for three antibodies were different from each other. Compared with the TGE in CO-S cells by pCDNA3.1 expression vector, the expression productivities of 8C11 cAb, 37 hAb, and 10F7 cAb showed 16-fold, 293-fold, and 19-fold increases respectively by the customized TGE method. For 8C11 cAb, coexpressing L-chain and H-chain on different plasmids led to higher yields. The customized TGE method is an alternative approach that can greatly improve the expression productivity of a variety of recombinant proteins. C1 [You, Min; Liu, Yanning; Guo, Jiyuan; Wu, Jun; Fu, Yajuan; Shen, Rong; Qi, Rui; Luo, Wenxin; Xia, Ningshao] Xiamen Univ, Sch Life Sci, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361102, Peoples R China. [Chen, Yingwei] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Luo, WX (reprint author), Xiamen Univ, Sch Life Sci, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361102, Peoples R China. EM wxluo@xmu.edu.cn FU National Natural Science Foundation of China [81161120415]; Significant New Drug Creation, Special Science and Technology Major Projects [2011ZX09102-009-12]; International Cooperation and Exchange Project [2012DFH30020]; Policy Guidance Project of the Ministry Science and Technology [2011FU125Z04] FX This study was supported by the National Natural Science Foundation of China (grant no. 81161120415), Significant New Drug Creation, Special Science and Technology Major Projects (grant no. 2011ZX09102-009-12), the International Cooperation and Exchange Project (grant no. 2012DFH30020), and the Policy Guidance Project of the Ministry Science and Technology (grant no. 2011FU125Z04). NR 31 TC 2 Z9 2 U1 3 U2 18 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0916-8451 EI 1347-6947 J9 BIOSCI BIOTECH BIOCH JI Biosci. Biotechnol. Biochem. PD JUN PY 2013 VL 77 IS 6 BP 1207 EP 1213 DI 10.1271/bbb.120968 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry, Applied; Food Science & Technology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry; Food Science & Technology GA 182DT UT WOS:000321722600011 PM 23748758 ER PT J AU Huang, B Cohen, JR Fernando, RI Hamilton, DH Litzinger, MT Hodge, JW Palena, C AF Huang, B. Cohen, J. R. Fernando, R. I. Hamilton, D. H. Litzinger, M. T. Hodge, J. W. Palena, C. TI The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies SO CELL DEATH & DISEASE LA English DT Article DE EMT; Brachyury; therapeutic resistance; CDKN1A ID EPITHELIAL-MESENCHYMAL TRANSITION; CARCINOMA-CELLS; CANCER-CELLS; LUNG-CANCER; STEM-CELLS; GENE; P21; PHARMACOKINETICS; EXPRESSION; PHENOTYPE AB The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been characterized as a driver of the epithelial-to-mesenchymal switch of human carcinomas. In the current investigation, we present data demonstrating that in two different human lung carcinoma models expression of Brachyury strongly correlates with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. We also demonstrate that chemotherapy treatment in vitro selects for tumor cells with high levels of Brachyury and that the degree of resistance to therapy correlates with the level of Brachyury expression. In vitro and in vivo, human lung carcinoma cells with higher levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb and CDKN1A (p21). Chromatin immunoprecipitation and luciferase reporter assays revealed that Brachyury binds to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapeutic resistance associated with Brachyury expression. Finally, we demonstrate that in vivo treatment of tumor xenografts with chemotherapy results in the selective growth of resistant tumors characterized by high levels of Brachyury expression. Altogether, these results suggest that Brachyury expression may attenuate cell cycle progression, enabling tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas. C1 [Huang, B.; Cohen, J. R.; Fernando, R. I.; Hamilton, D. H.; Litzinger, M. T.; Hodge, J. W.; Palena, C.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B14,MSC 1750, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute and National Institutes of Health FX We thank Dr. Jeffrey Schlom for critical review of the manuscript, Margie Duberstein for technical assistance and Debra Weingarten for editorial assistance. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute and National Institutes of Health. NR 42 TC 31 Z9 31 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JUN PY 2013 VL 4 AR e682 DI 10.1038/cddis.2013.208 PG 12 WC Cell Biology SC Cell Biology GA 173WE UT WOS:000321111700033 PM 23788039 ER PT J AU Palavicini, JP Wang, H Bianchi, E Xu, S Rao, JS Kang, DE Lakshmana, MK AF Palavicini, J. P. Wang, H. Bianchi, E. Xu, S. Rao, J. S. Kang, D. E. Lakshmana, M. K. TI RanBP9 aggravates synaptic damage in the mouse brain and is inversely correlated to spinophilin levels in Alzheimer's brain synaptosomes SO CELL DEATH & DISEASE LA English DT Article DE RanBP9; spinophilin; transgenic mice; synaptosomes; spines; mitochondrial activity ID AMYLOID PRECURSOR PROTEIN; DENDRITIC SPINE ALTERATIONS; SCAFFOLDING PROTEIN; PYRAMIDAL NEURONS; TRANSGENIC MICE; PIVOTAL ROLE; TG2576 MICE; DISEASE; MITOCHONDRIA; DEMENTIA AB We previously demonstrated that overexpression of RanBP9 led to enhanced A beta generation in a variety of cell lines and primary neuronal cultures, and subsequently, we confirmed increased amyloid plaque burden in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin protein levels when RanBP9 is overexpressed. At 12 months of age, we found spinophilin levels reduced by 70% (P<0.001) in the cortex of AP Delta E9/RanBP9 mice compared with that in wild-type (WT) controls. In the hippocampus, the spinophilin levels were reduced by 45% (P<0.01) in the APDE9/RanBP9 mice. Spinophilin immunoreactivity was also reduced by 22% (P<0.01) and 12% (P<0.05) in the cortex of AP Delta E9/RanBP9 and AP Delta E9 mice, respectively. In the hippocampus, the reductions were 27% (P<0.001) and 14% (P<0.001) in the AP Delta E9/RanBP9 and AP Delta E9 mice, respectively. However, in the cerebellum, spinophilin levels were not altered in either AP Delta E9 or AP Delta E9/RanBP9 mice. Additionally, synaptosomal functional integrity was reduced under basal conditions by 39% (P<0.001) in the AP Delta E9/RanBP9 mice and similar to 23% (P<0.001) in the AP Delta E9 mice compared with that in WT controls. Under ATP- and KCl-stimulated conditions, we observed higher mitochondrial activity in the WT and AP Delta E9 mice, but lower in the AP Delta E9/RanBP9 mice. Significantly, we confirmed the inverse relationship between RanBP9-N60 and spinophilin in the synaptosomes of Alzheimer's brains. More importantly, both AP Delta E9 and AP Delta E9/RanBP9 mice showed impaired learning and memory skills compared to WT controls. These data suggest that RanBP9 might play a crucial role in the loss of spines and synapses in AD. C1 [Palavicini, J. P.; Wang, H.; Lakshmana, M. K.] Torrey Pines Inst Mol Studies, Neurobiol Sect, Port St Lucie, FL 34987 USA. [Bianchi, E.] Inst Pasteur, Dept Immunol, Lab Immuneregulat, F-75724 Paris, France. [Xu, S.] Florida Inst Technol, Melbourne, FL 32901 USA. [Rao, J. S.] NIA, Signal Transduct Unit, Brain Physiol & Metab Sect, NIH 9000, Bethesda, MD 20892 USA. [Kang, D. E.] USF Hlth Byrd Alzheimers Inst, Dept Mol Med, Tampa, FL 33612 USA. RP Lakshmana, MK (reprint author), Torrey Pines Inst Mol Studies, Neurobiol Sect, 11350 SW Village Pkwy, Port St Lucie, FL 34987 USA. EM mlakshmana@tpims.org RI Kang, David/E-5234-2012 FU National Institute of Aging (NIA)/NIH [1R03AG032064-01, 1R01AG036859-01]; PHS at the McLean Hospital [R24MH068855]; Harvard Brain Tissue Resource Center FX This work was supported by National Institute of Aging (NIA)/NIH grant numbers (1R03AG032064-01, M.K. Lakshmana), 1R01AG036859-01, M.K. Lakshmana). We are grateful to receive Alzheimer's and control brain tissues provided by the 'Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24MH068855' at the McLean Hospital. NR 42 TC 7 Z9 7 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JUN PY 2013 VL 4 AR e667 DI 10.1038/cddis.2013.183 PG 10 WC Cell Biology SC Cell Biology GA 173WE UT WOS:000321111700018 PM 23764848 ER PT J AU Yu, X Zhen, Y Yang, H Wang, H Zhou, Y Wang, E Marincola, FM Mai, C Chen, Y Wei, H Song, Y Lyu, X Ye, Y Cai, L Wu, Q Zhao, M Hua, S Fu, Q Zhang, Y Yao, K Liu, Z Li, X Fang, W AF Yu, X. Zhen, Y. Yang, H. Wang, H. Zhou, Y. Wang, E. Marincola, F. M. Mai, C. Chen, Y. Wei, H. Song, Y. Lyu, X. Ye, Y. Cai, L. Wu, Q. Zhao, M. Hua, S. Fu, Q. Zhang, Y. Yao, K. Liu, Z. Li, X. Fang, W. TI Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma (vol 4, e634, 2013) SO CELL DEATH & DISEASE LA English DT Correction C1 [Yu, X.; Zhen, Y.; Wang, H.; Zhou, Y.; Mai, C.; Chen, Y.; Wei, H.; Lyu, X.; Ye, Y.; Cai, L.; Wu, Q.; Zhao, M.; Hua, S.; Fu, Q.; Yao, K.; Liu, Z.; Li, X.; Fang, W.] Southern Med Univ, Dept Oncol, Canc Res Inst, Guangzhou 510515, Guangdong, Peoples R China. [Yang, H.] Guangdong Med Coll, Sch Pharm, Dongguan, Peoples R China. [Wang, E.; Marincola, F. M.] NIH, Warren G Magnuson Clin Ctr, Infect Dis & Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. [Song, Y.] Southern Med Univ, Dept Neurosurg, Nanfang Hosp, Guangzhou 510515, Guangdong, Peoples R China. [Zhang, Y.; Liu, Z.] Med Univ Guangzhou, Dept Pathol, Basic Sch, Guangzhou, Guangdong, Peoples R China. RP Fang, W (reprint author), Southern Med Univ, Dept Oncol, Canc Res Inst, Tonghe Rd, Guangzhou 510515, Guangdong, Peoples R China. EM narcissus_jane@163.com; narcissus_jane@163.com; xinli268@gmail.com; fangweiyi1975@yahoo.com.cn NR 1 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JUN PY 2013 VL 4 AR e672 DI 10.1038/cddis.2013.216 PG 1 WC Cell Biology SC Cell Biology GA 173WE UT WOS:000321111700023 ER PT J AU Lutter, EI Barger, AC Nair, V Hackstadt, T AF Lutter, Erika I. Barger, Alexandra C. Nair, Vinod Hackstadt, Ted TI Chlamydia trachomatis Inclusion Membrane Protein CT228 Recruits Elements of the Myosin Phosphatase Pathway to Regulate Release Mechanisms SO CELL REPORTS LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; RHO-ASSOCIATED KINASE; LIGHT-CHAIN; HOST-CELL; EPITHELIAL PERMEABILITY; MICROTUBULE NETWORK; DEVELOPMENTAL CYCLE; PHOSPHORYLATION; SUBUNIT; EGRESS AB Chlamydia trachomatis replicates within a membrane-bound compartment termed an inclusion. The inclusion membrane is modified by the insertion of multiple proteins known as Incs. In a yeast two-hybrid screen, an interaction was found between the inclusion membrane protein CT228 and MYPT1, a subunit of myosin phosphatase. MYPT1 was recruited peripherally around the inclusion, whereas the phosphorylated, inactive form was localized to active Src-family kinase-rich microdomains. Phosphorylated myosin light chain 2 (MLC2), myosin light chain kinase (MLCK), myosin IIA, and myosin IIB also colocalized with inactive MYPT1. The role of these proteins was examined in the context of host-cell exit mechanisms (i.e., cell lysis and extrusion of intact inclusions). Inhibition of myosin II or small interfering RNA depletion of myosin IIA, myosin IIB, MLC2, or MLCK reduced chlamydial extrusion, thus favoring lytic events as the primary means of release. These studies provide insights into the regulation of egress mechanisms by C. trachomatis. C1 [Lutter, Erika I.; Barger, Alexandra C.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. [Nair, Vinod] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. EM ted_hackstadt@nih.gov FU Intramural Research Program of the NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. We thank J. Sager and C. Dooley for excellent technical assistance; Drs. K. Hybiske, A. Omsland, L. Bauler, and D. Bublitz for critical reviews of the manuscript; and Heather Murphy and Anita Mora for graphic arts. We thank Dr. Ian Clarke for providing C. trachomatis B/Jali20. NR 55 TC 29 Z9 29 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN PY 2013 VL 3 IS 6 BP 1921 EP 1931 DI 10.1016/j.celrep.2013.04.027 PG 11 WC Cell Biology SC Cell Biology GA 184ON UT WOS:000321901200020 PM 23727243 ER PT J AU Morgani, SM Canham, MA Nichols, J Sharov, AA Migueles, RP Ko, MSH Brickman, JM AF Morgani, Sophie M. Canham, Maurice A. Nichols, Jennifer Sharov, Alexei A. Migueles, Rosa Portero Ko, Minoru S. H. Brickman, Joshua M. TI Totipotent Embryonic Stem Cells Arise in Ground-State Culture Conditions SO CELL REPORTS LA English DT Article ID LEUKEMIA INHIBITORY FACTOR; IMPLANTATION MOUSE EMBRYOS; PRIMITIVE ENDODERM; SELF-RENEWAL; DIFFERENTIATION; TROPHOBLAST; PLURIPOTENCY; BLASTOCYSTS; EXPRESSION; EPIBLAST AB Embryonic stem cells (ESCs) are derived from mammalian embryos during the transition from totipotency, when individual blastomeres can make all lineages, to pluripotency, when they are competent to make only embryonic lineages. ESCs maintained with inhibitors of MEK and GSK3 (2i) are thought to represent an embryonically restricted ground state. However, we observed heterogeneous expression of the extraembryonic endoderm marker Hex in 2i-cultured embryos, suggesting that 2i blocked development prior to epiblast commitment. Similarly, 2i ESC cultures were heterogeneous and contained a Hex-positive fraction primed to differentiate into trophoblast and extraembryonic endoderm. Single Hex-positive ESCs coexpressed epiblast and extraembryonic genes and contributed to all lineages in chimeras. The cytokine LIF, necessary for ESC self-renewal, supported the expansion of this population but did not directly support Nanog-positive epiblast-like ESCs. Thus, 2i and LIF support a totipotent state comparable to early embryonic cells that coexpress embryonic and extraembryonic determinants. C1 [Morgani, Sophie M.; Canham, Maurice A.; Migueles, Rosa Portero; Brickman, Joshua M.] Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland. [Morgani, Sophie M.; Brickman, Joshua M.] Univ Copenhagen, Danish Stem Cell Ctr, DK-2200 Copenhagen N, Denmark. [Nichols, Jennifer] Univ Cambridge, Wellcome Trust Ctr Stem Cell Res, Cambridge CB2 1QR, England. [Sharov, Alexei A.; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Sch Med, Dept Syst Med, Shinjuku Ku, Tokyo 160, Japan. RP Brickman, JM (reprint author), Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland. EM joshua.brickman@sund.ku.dk RI Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Brickman, Joshua/0000-0003-1580-7491 FU Medical Research Council (MRC) [G0701428]; Novo Nordisk Foundation; Intramural Research Program of the National Institutes of Health; National Institute on Aging [Z01AG AG000656, Z01AG000662]; MRC studentship FX We thank Lynsey Robertson, Sally Inverarity, Javier Martin Gonzalez, Kasper Bonderup, Ron Wilkie, Simon Monard, Gelo de la Cruz, and Valerie Wilson for technical assistance; Austin Smith, Heiko Lickert, and Ian Chambers for reagents; and Sophie Astrof, Sally Lowell, and the entire Brickman lab for critical discussion of this manuscript. This work was supported by grants from the Medical Research Council (MRC) (G0701428) and the Novo Nordisk Foundation (to J.M.B.), the Intramural Research Program of the National Institutes of Health, and the National Institute on Aging (Z01AG AG000656 and Z01AG000662 to M.S.H.K.). S.M.M. is supported by an MRC studentship, and J.M.B. is an MRC senior nonclinical fellow. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. S.M.M. conceived of and executed experiments and wrote the paper with J.M.B.; MA.C. generated the HV mice and ESCs; J.N. designed and executed the experiments and helped with embryo culture; A.A.S. analyzed RNA-seq data sets; R.P.M. executed experiments; M.S.H.K. supervised data analysis; and J.M.B. designed and supervised experiments and wrote the paper with S.M.M. NR 43 TC 71 Z9 71 U1 1 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN PY 2013 VL 3 IS 6 BP 1945 EP 1957 DI 10.1016/j.celrep.2013.04.034 PG 13 WC Cell Biology SC Cell Biology GA 184ON UT WOS:000321901200022 PM 23746443 ER PT J AU Martinez, P Gomez-Lopez, G Garcia, F Mercken, E Mitchell, S Flores, JM de Cabo, R Blasco, MA AF Martinez, Paula Gomez-Lopez, Gonzalo Garcia, Fernando Mercken, Evi Mitchell, Sarah Flores, Juana M. de Cabo, Rafael Blasco, Maria A. TI RAP1 Protects from Obesity through Its Extratelomeric Role Regulating Gene Expression SO CELL REPORTS LA English DT Article ID PROLIFERATOR-ACTIVATED-RECEPTOR; LIVER-X-RECEPTOR; PPAR-ALPHA; HUMAN TELOMERES; LIPID HOMEOSTASIS; SACCHAROMYCES-CEREVISIAE; GAMMA ACTIVATORS; MICE; BINDING; MOUSE AB RAP1 is part of shelterin, the protective complex at telomeres. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the nontelomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knockout mouse. These mice show early onset of obesity, which is more severe in females than in males. Rap1-deficient mice show accumulation of abdominal fat, hepatic steatosis, and high-fasting plasma levels of insulin, glucose, cholesterol, and alanine aminotransferase. Gene expression analyses of liver and visceral white fat from Rap1-deficient mice before the onset of obesity show deregulation of metabolic programs, including fatty acid, glucose metabolism, and PPAR alpha signaling. We identify Ppar alpha and Pgc1 alpha as key factors affected by Rap1 deletion in the liver. We show that RAP1 binds to Ppar alpha and Pgc1 alpha loci and modulates their transcription. These findings reveal a role for a telomere-binding protein in the regulation of metabolism. C1 [Martinez, Paula; Blasco, Maria A.] Spanish Natl Canc Res Ctr CNIO, Mol Oncol Program, Telomeres & Telomerase Grp, Madrid 28029, Spain. [Gomez-Lopez, Gonzalo] Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Program, Bioinformat Core Unit, Madrid 28029, Spain. [Garcia, Fernando] Spanish Natl Canc Res Ctr CNIO, Prote Core Unit, Biotechnol Program, Madrid 28029, Spain. [Mercken, Evi; Mitchell, Sarah; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Flores, Juana M.] Univ Complutense Madrid, Fac Veterinarian, Anim Surg & Med Dept, Madrid 28029, Spain. RP Blasco, MA (reprint author), Spanish Natl Canc Res Ctr CNIO, Mol Oncol Program, Telomeres & Telomerase Grp, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM mblasco@cnio.es RI Gomez-Lopez, Gonzalo/D-9123-2016; de Cabo, Rafael/J-5230-2016; Blasco , Maria A./M-1694-2014; OI , rafael/0000-0003-2830-5693; Gomez-Lopez, Gonzalo/0000-0002-4146-0551; de Cabo, Rafael/0000-0002-3354-2442; Blasco , Maria A./0000-0002-4211-233X; Garcia-Martinez, Fenando/0000-0003-3888-4326 FU European Research Council Project TEL STEM CELL [232854]; European Union FP7 [2007-A-20088, 2010-259749]; Spanish Ministry of Economy and Competitiveness [SAF2008-05384, CSD2007-00017]; Regional of Government of Madrid Project [S2010/BMD-2303]; AXA Research Fund (Life Risks Project); Lilly Preclinical Biomedicine Research Award (Fundacion Lilly, Spain); Fundacion Botin (Spain) FX We are indebted to S. West for RAP1 antibodies, R. Serrano for animal care, L.E. Donate for editing support, and D. Pisano for bioinformatic support. Research in the M.A.B. lab was funded by European Research Council Project TEL STEM CELL (GA#232854), European Union FP7 Projects 2007-A-20088 (MARK-AGE) and 2010-259749 (EuroBATS), Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, Regional of Government of Madrid Project S2010/BMD-2303 (ReCaRe), AXA Research Fund (Life Risks Project), the Lilly 2010 Preclinical Biomedicine Research Award (Fundacion Lilly, Spain), and the Fundacion Botin (Spain). M.A.B. conceived the original idea; M.A.B. and P.M. designed experiments and wrote the manuscript; P.M. performed most of the experiments; G.G.-L. performed the microarray analysis and FG de iTRAQ experiment; E.M., S.M., and R.d.C. carried out the indirect calorimetry measurements; and J.M.F. performed the pathology analyses. NR 60 TC 27 Z9 27 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN PY 2013 VL 3 IS 6 BP 2059 EP 2074 DI 10.1016/j.celrep.2013.05.030 PG 16 WC Cell Biology SC Cell Biology GA 184ON UT WOS:000321901200031 PM 23791526 ER PT J AU Hasson, SA Inglese, J AF Hasson, Samuel A. Inglese, James TI Innovation in academic chemical screening: filling the gaps in chemical biology SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID N-MYRISTOYLTRANSFERASE INHIBITORS; PLURIPOTENT STEM-CELLS; HIGH-THROUGHPUT; SMALL-MOLECULE; ZEBRAFISH EMBRYOS; SORTING SYSTEM; IDENTIFICATION; ASSAY; VERTEBRATE; DISCOVERY AB Academic screening centers across the world have endeavored to discover small molecules that can modulate biological systems. To increase the reach of functional-genomic and chemical screening programs, universities, research institutes, and governments have followed their industrial counterparts in adopting high-throughput paradigms. As academic screening efforts have steadily grown in scope and complexity, so have the ideas of what is possible with the union of technology and biology. This review addresses the recent conceptual and technological innovation that has been propelling academic screening into its own unique niche. In particular, high-content and whole-organism screening are changing how academics search for novel bioactive compounds. Importantly, we recognize examples of successful chemical probe development that have punctuated the changing technology landscape. C1 [Hasson, Samuel A.; Inglese, James] Natl Ctr Adv Translat Sci, NIH, Rockville, MD 20850 USA. [Hasson, Samuel A.] NINDS, NIH, Bethesda, MD 20892 USA. [Inglese, James] NHGRI, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), Natl Ctr Adv Translat Sci, NIH, Rockville, MD 20850 USA. EM jinglese@mail.nih.gov FU Intramural Research Program of the NIH; Pharmacology Research Associate Program FX This work was supported by the Intramural Research Program of the NIH and the Pharmacology Research Associate Program. We would like to thank the reviewers of this manuscript for their helpful and insightful suggestions. NR 84 TC 13 Z9 13 U1 2 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD JUN PY 2013 VL 17 IS 3 BP 329 EP 338 DI 10.1016/j.cbpa.2013.04.018 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 173PW UT WOS:000321092400003 PM 23683346 ER PT J AU Khangura, SK Greenwald, BD AF Khangura, Sajneet K. Greenwald, Bruce D. TI Endoscopic Management of Esophageal Cancer After Definitive Chemoradiotherapy SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE Esophageal cancer; Salvage therapies; Photodynamic therapy; Endoscopic mucosal resection; Cryotherapy ID SQUAMOUS-CELL CARCINOMA; POSITRON-EMISSION-TOMOGRAPHY; SALVAGE PHOTODYNAMIC THERAPY; LOCAL FAILURE; RADIOFREQUENCY ABLATION; BARRETTS-ESOPHAGUS; MUCOSAL RESECTION; NEOADJUVANT CHEMORADIOTHERAPY; ESOPHAGOGASTRIC JUNCTION; CHEMORADIATION THERAPY AB Background Concurrent chemoradiotherapy (CRT) is a potentially curative non-surgical option for locally advanced esophageal cancer, with pathological complete response (CR) ranging from 13 to 49 %. The rate of persistent and recurrent disease within the esophagus remains high at 40-60 %, and treatment of these tumors may improve disease-free survival. The aim of this review is to assess the efficacy of salvage endoscopic therapies for recurrent esophageal cancer. Methods Medline and Embase were searched for relevant studies published in the English-language literature that reported use of endoscopic modalities, including photodynamic therapy (PDT), endoscopic mucosal resection (EMR), and spray cryotherapy, as salvage therapies for esophageal cancer. Results A total of 12 studies were identified. In small case series of PDT, CR varied from 20 to 100 %, with 1-, 3-, and 5-year overall survival rates of 65-80, 34-47, and 36 %, respectively. Data from three studies of EMR in squamous cell cancer show CR in 50 % of cases, with 3- and 5-year overall survival of 56-81 and 49 %, respectively. Endoscopic spray cryotherapy has recently been used in this setting with an observed CR of 37.5 %. Conclusions Endoscopic salvage therapies are options for those patients with disease limited to the superficial esophageal wall and those who are unfit to undergo salvage esophagectomy. Widespread application of endoscopic salvage therapies is limited by the lack of awareness and guidelines for endoscopic surveillance post-CRT and limited data on the effectiveness of endoscopic therapies. C1 [Khangura, Sajneet K.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. [Khangura, Sajneet K.] Univ Maryland, Med Ctr, Div Gastroenterol & Hepatol, Baltimore, MD 21201 USA. [Greenwald, Bruce D.] Univ Maryland, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Baltimore, MD 21201 USA. RP Greenwald, BD (reprint author), Univ Maryland, Sch Med, Dept Med, Div Gastroenterol & Hepatol, 22 S Greene St,Rm N3W62, Baltimore, MD 21201 USA. EM skhangura@umc.edu; bgreenwa@medicine.umaryland.edu FU CSA Medical, Inc. FX Dr. Greenwald is a consultant for and serves on a medical advisory board for CSA Medical, Inc, the manufacturer of a spray cryotherapy device and has received research funding from CSA Medical, Inc. Dr. Khangura has received no research funding and has no conflicts of interest. NR 64 TC 1 Z9 1 U1 2 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUN PY 2013 VL 58 IS 6 BP 1477 EP 1485 DI 10.1007/s10620-012-2554-0 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 173HV UT WOS:000321070800007 PM 23325163 ER PT J AU Fontana, RJ Hayashi, P Bonkovsky, HL Kleiner, DE Kochhar, S Gu, JZ Ghabril, M AF Fontana, Robert J. Hayashi, Paul Bonkovsky, Herbert L. Kleiner, David E. Kochhar, Sweta Gu, Jiezhun Ghabril, Marwan TI Presentation and Outcomes with Clinically Apparent Interferon Beta Hepatotoxicity SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Multiple sclerosis; Biologic response modifiers; Drug-induced liver injury; Acute liver failure; Liver biopsy ID INDUCED LIVER-INJURY; MULTIPLE-SCLEROSIS; AUTOIMMUNE HEPATITIS; PROGRESSIVE MS; UNITED-STATES; FAILURE; PATIENT; ANTIBODIES; DISEASE; 1A AB Aims The aim of this study was to describe the presenting features and outcomes of consecutive patients with liver injury attributed to interferon beta. Methods The presenting features of eight subjects with clinically apparent liver injury attributed to interferon beta enrolled in the U. S. Drug-Induced Liver Injury Network (DILIN) prospective registry between 2004 and 2010 were reviewed and compared to 11 published reports of symptomatic hepatotoxicity. Results All eight of the DILIN patients were women, 75 % were Caucasian and the mean age was 49 years. Most subjects presented with an acute hepatocellular injury pattern and mean serum alanine aminotransferase (ALT) levels were 725 +/- 593 U/L. The median duration of interferon beta use before injury onset was 462 days, and four patients had been treated for more than a year. No patient had detectable antinuclear or smooth muscle antibodies. One patient died of acute liver failure and the remaining patients usually recovered within 2-3 months. Causality assessment scored three cases as definite, three highly likely, one probable and one possible. Eleven additional published cases were all women, mean age was 40 years, mean ALT at onset 840 U/L, and 7 (63 %) had autoantibodies. Liver histology in three cases from DILIN and nine from the literature commented upon centrilobular (zone 3) necrosis and infiltrates with lymphocytes and plasma cells. Conclusions Interferon beta hepatotoxicity occurs mostly in women and has a variable, but often prolonged time to onset. Most patients have self-limited acute hepatocellular liver injury but several have required liver transplantation or died of acute liver failure. Liver histology available in three cases demonstrated zone 3 necrosis and autoimmune features suggestive of an immunologic basis to this adverse drug reaction. C1 [Fontana, Robert J.; Kochhar, Sweta] Univ Michigan, Dept Internal Med, Div Gastroenterol, Med Sch,Med Ctr, Ann Arbor, MI 48109 USA. [Hayashi, Paul; Bonkovsky, Herbert L.] Univ N Carolina, Dept Internal Med, Chapel Hill, NC USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Med, Charlotte, NC 28203 USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Dept Res, Charlotte, NC 28203 USA. [Kleiner, David E.] NCI, NIH, Bethesda, MD 20892 USA. [Gu, Jiezhun] Duke Clin Res Inst, Durham, NC USA. [Ghabril, Marwan] Indiana Univ, Dept Internal Med, Indianapolis, IN 46204 USA. RP Fontana, RJ (reprint author), Univ Michigan, Dept Internal Med, Div Gastroenterol, Med Sch,Med Ctr, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu; swetasingh86@gmail.com OI Kleiner, David/0000-0003-3442-4453; Ghabril, Marwan/0000-0002-4784-3246 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK065184, U01DK065201, U01DK065211, U01DK065176]; National Cancer Institute; Salix Pharmaceuticals; Vertex; Gilead Sciences; Clinuvel, Inc; Novartis Pharmaceuticals FX The website http://dilin.dcri.duke.edu/publications-1 provides a complete listing of DILIN funding sources, DILIN sites, investigators, co-investigators, coordinators, and staff funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases, Grants No. U01DK065184 (University of Michigan, Ann Arbor, MI), U01DK065201 (University of North Carolina, Chapel Hill, NC; Carolinas Medical Center), U01DK065211 (Indiana University, Indianapolis, IN), U01DK065176 (Duke Clinical Research Institute, Durham, NC). This work was also supported in part by the Intramural Research Program of the National Cancer Institute.; Drs. Kleiner, Kochar, Gu, Hayashi, and Barnhart have no conflicts. Dr. Ghabril has received research support from Salix Pharmaceuticals. Dr. Fontana has been a consultant with Merck, Medtronic, Tibotec, and GlaxoSmithkline and also received grant/research support from Vertex and Gilead Sciences. Dr. Bonkovsky has provided consulting to Novartis Pharmaceuticals, Boehringer-Ingelheim, Lundbeck Pharmaceuticals and Clinuvel, Inc. He has also received Grant/Research Support from Vertex, Clinuvel, Inc, and Novartis Pharmaceuticals. NR 39 TC 8 Z9 8 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUN PY 2013 VL 58 IS 6 BP 1766 EP 1775 DI 10.1007/s10620-012-2553-1 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 173HV UT WOS:000321070800040 PM 23377559 ER PT J AU Jain, M Zhang, LS He, M Zhang, YQ Shen, M Kebebew, E AF Jain, Meenu Zhang, Lisa He, Mei Zhang, Ya-Qin Shen, Min Kebebew, Electron TI TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma SO ENDOCRINE-RELATED CANCER LA English DT Article DE adrenocortical carcinoma; TOP2A; TOP2 inhibitors; aclarubicin; invasion ID ACUTE MYELOID-LEUKEMIA; PHASE-II TRIAL; TOPOISOMERASE-II; GENE-EXPRESSION; PROGNOSTIC-FACTORS; ACLACINOMYCIN-A; CELL-DEATH; C-MYC; TUMORS; DOXORUBICIN AB Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was i) to evaluate TOP2A expression and function in human adrenocortical neoplasm and ACC cells and ii) to determine the anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 ACCs). In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth, and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cells. TOP2A mRNA and protein expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (P < 0.05). Knockdown of TOP2A gene expression in ACC cell lines significantly decreased cell proliferation, anchorage-independent growth, and invasion (P < 0.05). A screening assay in NCI-H295R cells showed that 11 of 14 TOP2A inhibitors had antiproliferative activity, 5 of the 14 TOP2A inhibitors had a higher antiproliferative activity than mitotane, and aclarubicin was the agent with the highest activity. Aclarubicin was validated to significantly decrease proliferation and tumor spheroid size in both NCI-H295R and SW13 ACC cell lines (P < 0.05). Our results suggest that TOP2A is overexpressed in ACC, regulates cellular proliferation and invasion in ACC cells, and is an attractive target for ACC therapy. Of the TOP2A inhibitors screened, aclarubicin is a good candidate agent to test in future clinical trials for patients with locally advanced and metastatic ACC. C1 [Jain, Meenu; Zhang, Lisa; He, Mei; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Zhang, Ya-Qin; Shen, Min] NIH, Natl Ctr Adv Translat Sci, CRC Hatfield Clin Res Ctr 10, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. EM electron.kebebew@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 46 TC 6 Z9 8 U1 0 U2 4 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2013 VL 20 IS 3 BP 361 EP 370 DI 10.1530/ERC-12-0403 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 172EI UT WOS:000320982400016 PM 23533247 ER PT J AU Vydelingum, NA Sorbara, L Wagner, P Srivastava, S AF Vydelingum, Nadarajen A. Sorbara, Lynn Wagner, Paul Srivastava, Sudhir TI Standards in molecular diagnostics for the discovery and validation of clinically useful cancer biomarkers SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review AB Recent discoveries in cancer biology have greatly increased the understanding of cancer at the molecular level, but translating this knowledge into clinically useful diagnostic tests has proved challenging. More efficient transfer of new molecular tests into patient care requires better standardization of laboratory practices, measurement methods and data management. The workshop assembled experts from National Cancer Institute, US FDA, National Institute of Standards and Technology, academia and industry, to address the most efficient approaches to biomarker standardization and validation. The workshop participants described the current state of research in molecular diagnostics standardization and addressed three questions: what has worked? What has not? And what needs improving? C1 [Vydelingum, Nadarajen A.; Sorbara, Lynn; Wagner, Paul; Srivastava, Sudhir] NCI, Canc Prevent Div, Rockville, MD 20850 USA. RP Vydelingum, NA (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vydelinn@mail.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 3 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUN PY 2013 VL 13 IS 5 BP 421 EP 423 DI 10.1586/ERM.13.28 PG 3 WC Pathology SC Pathology GA 167UT UT WOS:000320661300006 PM 23782249 ER PT J AU Raman, FS Nacif, MS Cater, G Gai, N Jones, J Li, DB Sibley, CT Liu, ST Bluemke, DA AF Raman, Fabio S. Nacif, Marcelo S. Cater, George Gai, Neville Jones, Jacquin Li, Debiao Sibley, Christopher T. Liu, Songtao Bluemke, David A. TI 3.0-T whole-heart coronary magnetic resonance angiography: comparison of gadobenate dimeglumine and gadofosveset trisodium SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Gadofosveset trisodium; Gadobenate dimeglumine; Coronary MRA ID MR-ANGIOGRAPHY; CONTRAST AGENT; GADOPENTETATE DIMEGLUMINE; DIAGNOSTIC-ACCURACY; ARTERY-DISEASE; GADOLINIUM; 3T; ASSOCIATION; MS-325; LIVER AB Gadolinium enhanced coronary magnetic resonance angiography (MRA) at 3 T appears to be superior to non-contrast methods. Gadofosveset is an intravascular contrast agent that may be well suited to this application. The purpose of this study was to perform an intra-individual comparison of gadofosveset and gadobenate for coronary MRA at 3 T. In this prospective randomized study, 22 study subjects [8 (36 %) male; 27.9 +/- A 6 years; BMI = 22.8 +/- A 2 kg/m(2)] underwent two studies using a contrast-enhanced inversion recovery three-dimensional fast low angle shot MRA at 3 T. The order of contrast agent administration was varied randomly, separated by an average of 30 +/- A 5 days, using either gadobenate dimeglumine (Gd-BOPTA; Bracco, 0.1 mmol/Kg) or gadofosveset trisodium (MS-325; Lantheus Med, 0.03 mmol/Kg). Acquisition time, signal-to-noise ratio (SNR) of coronary vessels and contrast-to-noise ratio (CNR) were evaluated. Of 308 coronary arteries and veins segment analyzed, overall SNR of coronary arteries and veins segments were not different for the two contrast agents (132 +/- A 79 for gadofosveset vs. 135 +/- A 78 for gadobenate, p = 0.69). Coronary artery CNR was greater for gadofosveset in comparison to gadobenate (73.5 +/- A 46.9 vs. 59.3 +/- A 75.7 respectively, p = 0.03). Gadofosveset-enhanced MRA images displayed better image quality than gadobenate-enhanced MRA images (2.77 +/- A 0.61 for gadofosveset vs. 2.11 +/- A 0.51, p < .001). Inter- and intra-reader variability was excellent (ICC > 0.90) for both contrast agents. Gadofosveset trisodium appears to show slightly better performance for coronary MRA at 3 T compared to gadobenate. C1 [Raman, Fabio S.; Nacif, Marcelo S.; Cater, George; Gai, Neville; Jones, Jacquin; Sibley, Christopher T.; Liu, Songtao; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Nacif, Marcelo S.] Univ Fed Fluminense, Dept Radiol, Niteroi, RJ, Brazil. [Nacif, Marcelo S.; Sibley, Christopher T.; Liu, Songtao; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, Bethesda, MD USA. [Li, Debiao] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Nacif, MS (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 1C355, Bethesda, MD 20892 USA. EM msnacif@gmail.com; bluemked@nih.gov OI Raman, Fabio/0000-0003-2393-9937; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) FX This research was supported by the NIH intramural research program. Clinical trial registration information-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01130545 (10-CC-0115). Funded by the National Institutes of Health (NIH) Intramural program. NR 31 TC 11 Z9 11 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JUN PY 2013 VL 29 IS 5 BP 1085 EP 1094 DI 10.1007/s10554-013-0192-z PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 177OO UT WOS:000321384900016 PM 23515949 ER PT J AU Chen, MY Steigner, ML Leung, SW Kumamaru, KK Schultz, K Mather, RT Arai, AE Rybicki, FJ AF Chen, Marcus Y. Steigner, Michael L. Leung, Steve W. Kumamaru, Kanako K. Schultz, Kurt Mather, Richard T. Arai, Andrew E. Rybicki, Frank J. TI Simulated 50 % radiation dose reduction in coronary CT angiography using adaptive iterative dose reduction in three-dimensions (AIDR3D) SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Coronary imaging; Computed tomography; Angiography; Image reconstruction; Radiation dose ID IMAGE QUALITY; RECONSTRUCTION TECHNIQUE; MYOCARDIAL-PERFUSION; COMPUTED-TOMOGRAPHY; DIAGNOSTIC PERFORMANCE; 320-MDCT ANGIOGRAPHY; CORE320 MULTICENTER; CARDIAC CT; CHEST CT; FEASIBILITY AB To compare the image quality of coronary CT angiography (CTA) studies between standard filtered back projection (FBP) and adaptive iterative dose reduction in three-dimensions (AIDR3D) reconstruction using CT noise additional software to simulate reduced radiation exposure. Images from 93 consecutive clinical coronary CTA studies were processed utilizing standard FBP, FBP with 50 % simulated dose reduction (FBP50 %), and AIDR3D with simulated 50 % dose reduction (AIDR50 %). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured within 5 regions-of-interest, and image quality for each reconstruction strategy was assessed by two independent readers using a 4-point scale. Compared to FBP, the SNR measured from the AIDR50 % images was similar or higher (airway: 38.3 +/- A 12.7 vs. 38.5 +/- A 14.5, p = 0.81, fat: 5.5 +/- A 1.9 vs. 5.4 +/- A 2.0, p = 0.20, muscle: 3.2 +/- A 1.2 vs. 3.1 +/- A 1.3, p = 0.38, aorta: 22.6 +/- A 9.4 vs. 20.2 +/- A 9.7, p < 0.0001, liver: 2.7 +/- A 1.0 vs. 2.3 +/- A 1.1, p < 0.0001), while the SNR of the FBP50 % images were all lower (p values < 0.0001). The CNR measured from AIDR50 % images was also higher than that from the FBP images for the aorta relative to muscle (20.5 +/- A 9.0 vs. 18.3 +/- A 9.2, p < 0.0001). The interobserver agreement in the image quality score was excellent (kappa = 0.82). The quality score was significantly higher for the AIDR50 % images compared to the FBP images (3.6 +/- A 0.6 vs. 3.3 +/- A 0.7, p = 0.004). Simulated radiation dose reduction applied to clinical coronary CTA images suggests that a 50 % reduction in radiation dose can be achieved with adaptive iterative dose reduction software with image quality that is at least comparable to images acquired at standard radiation exposure and reconstructed with filtered back projection. C1 [Chen, Marcus Y.; Leung, Steve W.; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Steigner, Michael L.; Kumamaru, Kanako K.; Rybicki, Frank J.] Harvard Univ, Brigham & Womens Hosp, Appl Imaging Sci Lab, Dept Radiol,Med Sch, Boston, MA 02115 USA. [Schultz, Kurt; Mather, Richard T.] Toshiba Med Res Inst, Vernon Hills, IL USA. RP Rybicki, FJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Appl Imaging Sci Lab, Dept Radiol,Med Sch, Boston, MA 02115 USA. EM frybicki@partners.org RI Leung, Steve/E-5624-2011 OI Leung, Steve/0000-0003-2832-2258 NR 38 TC 40 Z9 40 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JUN PY 2013 VL 29 IS 5 BP 1167 EP 1175 DI 10.1007/s10554-013-0190-1 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 177OO UT WOS:000321384900025 PM 23404384 ER PT J AU Chung, J Pao, M AF Chung, Joyce Pao, Maryland TI Stepping stones for psychiatry residents who pursue scientific research careers SO INTERNATIONAL REVIEW OF PSYCHIATRY LA English DT Article ID PHYSICIAN-SCIENTISTS; CLINICAL NEUROSCIENCE; EDUCATION; INSTITUTE; PROJECT; FUTURE; MODEL AB Advances in areas of neuroscience are highly relevant to psychiatric disorders but there exists a gap between discoveries in neuroscience and the practice of clinical psychiatry. Psychiatry is a field in need of high impact research conducted by physician-scientists who have first-hand experience treating patients with mental illness and who use this clinical knowledge to improve and discover better or novel interventions. This paper focuses primarily on the training of psychiatry residents for successful scientific research careers and what residency programmes and others can do to help them succeed. Changes also need to be made at a regulatory level to enhance the research training and literacy of psychiatry residents. The shortage of psychiatrists who are well trained in basic and translational research can only be remedied if the path to becoming an independent investigator is lined with stepping stones that support success, including during the residency years. Partnerships among funding agencies, professional societies and training institutions can lay the groundwork for our psychiatric trainees to stay on the path to rewarding scientific research careers. C1 [Chung, Joyce; Pao, Maryland] NIH, NIMH, Div Intramural Res Programs, Off Clin Director, Bethesda, MD 20892 USA. RP Chung, J (reprint author), NIH, NIMH, Div Intramural Res Programs, Off Clin Director, 10 Ctr Dr MSC 1276, Bethesda, MD 20892 USA. EM chungj@mail.nih.gov NR 37 TC 3 Z9 3 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0954-0261 J9 INT REV PSYCHIATR JI Int. Rev. Psych. PD JUN PY 2013 VL 25 IS 3 BP 284 EP 290 DI 10.3109/09540261.2013.800027 PG 7 WC Psychiatry SC Psychiatry GA 184RI UT WOS:000321910600005 PM 23859091 ER PT J AU Gao, S Ren, DB Peng, DX Zhang, WH Muszynski, A Carlson, RW Gu, XX AF Gao, Song Ren, Dabin Peng, Daxin Zhang, Wenhong Muszynski, Artur Carlson, Russell W. Gu, Xin-Xing TI Late acyltransferase genes IpxX and IpxL jointly contribute to the biological activities of Moraxella catarrhalis SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID BRANHAMELLA-CATARRHALIS; LIPID-A; LIPOPOLYSACCHARIDE; LIPOOLIGOSACCHARIDE; BIOSYNTHESIS; ENDOTOXIN; STRAINS AB Lipo-oligosaccharide (LOS) is a major surface component and virulence factor of the human respiratory pathogen Moraxella catarrhalis. Two late acyltransferase genes, IpxX and IpxL, have been identified involved in the incorporation of acyloxyacyl-linked secondary acyl chains into lipid A during M. catarrhalis LOS biosynthesis. In this study, a double mutant with a deletion of both the IpxX and IpxL genes in M. catarrhalis strain O35E was constructed and named O35ElpxXL. Structural analysis of lipid A showed that the O35ElpxXL mutant lacked two decanoic acids (10 : 0) and one dodecanoic (lauric) acid (12 : 0). In comparison with the O35E parental strain and the single mutants O35ElpxX and O35ElpxL, the double mutant O35ElpxXL displayed prominently decreased endotoxin content, reduced resistance to normal human serum and accelerated bacterial clearance at 0, 3 and 6 h after an aerosol challenge in a mouse model of bacterial pulmonary clearance. These results indicate that these two genes encoding late acyltransferases responsible for lipid A biosynthesis jointly contribute to the biological activities and pathogenicity of M. catarrhalis. The double mutant O35ElpxXL with dramatically reduced toxicity is proposed as a potential vaccine candidate against M. catarrhalis infections for further investigation. C1 [Gao, Song; Ren, Dabin; Peng, Daxin; Zhang, Wenhong; Gu, Xin-Xing] Natl Inst Deafness Other Commun Disorders, Natl Inst Hlth, Vaccine Res Sect, Rockville, MD 20850 USA. [Muszynski, Artur; Carlson, Russell W.] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. RP Ren, DB (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dabin.ren@rochestergeneral.org; guxx@mail.nih.gov RI Ren, Dabin/H-6263-2013 FU Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, USA [NIH0010103632]; Department of Energy [DE-FG09-93-ER20097] FX We thank Dr Eric J. Hansen (University of Texas, Dallas, TX, USA) for providing strain O35E and plasmid pWW115. We also thank Shengqing Yu for advice in the pulmonary clearance assay, Robert Morell for help with DNA sequencing, Yandan Yang for help with Southern blotting and Qingqing Gao for help with manuscript preparation. This research was supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, USA (NIH0010103632) and a Department of Energy grant (DE-FG09-93-ER20097) to the Complex Carbohydrate Research Center (CCRC), University of Georgia, USA. NR 16 TC 1 Z9 1 U1 1 U2 11 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD JUN PY 2013 VL 62 BP 807 EP 812 DI 10.1099/jmm.0.056846-0 PN 6 PG 6 WC Microbiology SC Microbiology GA 174IP UT WOS:000321149200001 PM 23475908 ER PT J AU Martin, WJ Glass, RI Araj, H Balbus, J Collins, FS Curtis, S Diette, GB Elwood, WN Falk, H Hibberd, PL Keown, SEJ Mehta, S Patrick, E Rosenbaum, J Sapkota, A Tolunay, HE Bruce, NG AF Martin, William J., II Glass, Roger I. Araj, Houmam Balbus, John Collins, Francis S. Curtis, Sian Diette, Gregory B. Elwood, William N. Falk, Henry Hibberd, Patricia L. Keown, Susan E. J. Mehta, Sumi Patrick, Erin Rosenbaum, Julia Sapkota, Amir Tolunay, H. Eser Bruce, Nigel G. TI Household Air Pollution in Low- and Middle-Income Countries: Health Risks and Research Priorities SO PLOS MEDICINE LA English DT Editorial Material ID RETROSPECTIVE COHORT; STOVE IMPROVEMENT; CARBON-MONOXIDE; EXPOSURE; GUATEMALA; CHILDREN; CHINA; DISEASE; XUANWEI; SMOKE C1 [Martin, William J., II] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Bethesda, MD USA. [Glass, Roger I.] Natl Inst Hlth, John E Fogarty Int Ctr, Bethesda, MD USA. [Araj, Houmam] NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Balbus, John] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Res Triangle Pk, NC USA. [Collins, Francis S.] Natl Inst Hlth, Bethesda, MD USA. [Curtis, Sian] Univ N Carolina, Carolina Populat Ctr, MEASURE Evaluat Project, Chapel Hill, NC USA. [Curtis, Sian] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Diette, Gregory B.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Elwood, William N.] Natl Inst Hlth, Off Behav & Social Sci Res, Bethesda, MD USA. [Falk, Henry] Ctr Dis Control & Prevent, Off Noncommunicable Dis Injury & Environm Hlth, Atlanta, GA USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Div Global Hlth, Boston, MA 02114 USA. [Keown, Susan E. J.] Palladian Partners, Silver Spring, MD USA. [Mehta, Sumi] Global Alliance Clean Cookstoves, Washington, DC USA. [Patrick, Erin] Womens Refugee Commiss, New York, NY USA. [Rosenbaum, Julia] FHI 360, Washington, DC USA. [Sapkota, Amir] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Tolunay, H. Eser] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Div Cardiovasc Sci, Bethesda, MD USA. [Bruce, Nigel G.] Univ Liverpool, Dept Publ Hlth & Policy, Liverpool L69 3BX, Merseyside, England. [Bruce, Nigel G.] WHO, Dept Publ Hlth & Environm, CH-1211 Geneva, Switzerland. RP Martin, WJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Bethesda, MD USA. EM wjmartin@mail.nih.gov RI Sapkota, Amir/A-5968-2011 FU NICHD NIH HHS [R24 HD041041, R24 HD050924, U01 HD058322, U10 HD078439] NR 48 TC 16 Z9 16 U1 2 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JUN PY 2013 VL 10 IS 6 AR e1001455 DI 10.1371/journal.pmed.1001455 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 172WB UT WOS:000321034800001 PM 23750119 ER PT J AU Pichler, I Del Greco, F Gogele, M Lill, CM Bertram, L Do, CB Eriksson, N Foroud, T Myers, RH Nalls, M Keller, MF Benyamin, B Whitfield, JB Pramstaller, PP Hicks, AA Thompson, JR Minelli, C AF Pichler, Irene Del Greco, Fabiola Goegele, Martin Lill, Christina M. Bertram, Lars Do, Chuong B. Eriksson, Nicholas Foroud, Tatiana Myers, Richard H. Nalls, Michael Keller, Margaux F. Benyamin, Beben Whitfield, John B. Pramstaller, Peter P. Hicks, Andrew A. Thompson, John R. Minelli, Cosetta CA PD GWAS Consortium Int Parkinsons Dis Genomics Consor Wellcome Trust Case Control Consor Genetics Iron Status Consortium TI Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study SO PLOS MEDICINE LA English DT Article ID MULTIPLE GENETIC-VARIANTS; GENOME-WIDE ASSOCIATION; CELL-SURFACE EXPRESSION; HEREDITARY HEMOCHROMATOSIS; SUBSTANTIA-NIGRA; HFE GENE; IN-VITRO; MUTATIONS; METAANALYSIS; TMPRSS6 AB Background: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genomewide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p=0.001) per 10 mu g/dl increase in serum iron. Conclusions: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. C1 [Pichler, Irene; Del Greco, Fabiola; Goegele, Martin; Pramstaller, Peter P.; Hicks, Andrew A.; Minelli, Cosetta] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Lill, Christina M.; Bertram, Lars] Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, Dept Vertebrate Genom, D-14195 Berlin, Germany. [Lill, Christina M.] Johannes Gutenberg Univ Mainz, Dept Neurol, Med Ctr, D-55122 Mainz, Germany. [Do, Chuong B.; Eriksson, Nicholas] 23andMe Inc, Mountain View, CA USA. [Foroud, Tatiana] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Nalls, Michael; Keller, Margaux F.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Keller, Margaux F.] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Benyamin, Beben; Whitfield, John B.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Benyamin, Beben] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. RP Pichler, I (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. EM irene.pichler@eurac.edu; cosetta.minelli@imperial.ac.uk RI Martinez, Maria/B-3111-2013; Vermeulen, H.H.M./L-4716-2015; corvol, jean-christophe/I-6387-2012; Hicks, Andrew/E-9518-2017; Trabzuni, Daniah/C-4034-2012; Traynor, Bryan/G-5690-2010; Bertram, Lars/K-3889-2015; Benyamin, Beben/D-9195-2012; O'Sullivan, Sean/C-9333-2012; Cooper, J Mark/D-5826-2013; Pramstaller, Peter/C-2357-2008; Swinkels, D.W./H-8098-2014; Deuschl, Gunther/A-7986-2010; lambert, jean-charles/F-8787-2013; LICEND, CEMND/F-1296-2015; Blackwell, Jenefer/H-3015-2015; Lill, Christina/J-9449-2015; Meitinger, Thomas/O-1318-2015; van de Warrenburg, Bart/D-1935-2010 OI Ouwehand, Willem/0000-0002-7744-1790; Chen, Honglei/0000-0003-3446-7779; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Hicks, Andrew/0000-0001-6320-0411; Myers, Richard/0000-0002-8365-2674; Trabzuni, Daniah/0000-0003-4826-9570; Pichler, Irene/0000-0001-8251-0757; Esko, Tonu/0000-0003-1982-6569; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Bhatia, Kailash/0000-0001-8185-286X; Bertram, Lars/0000-0002-0108-124X; Benyamin, Beben/0000-0001-5608-2293; O'Sullivan, Sean/0000-0002-0583-7956; Cooper, J Mark/0000-0002-3007-3054; Lill, Christina/0000-0002-2805-1307; FU Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; Cure Alzheimer's Fund (CAF); Fidelity Biosciences Research Initiative; Prize4Life; National Alliance for Research on Schizophrenia and Depression (NARSAD); EMD Serono; Robert P. & Judith N. Goldberg Foundation; Cogan Family Foundation [R01-NS076843]; Karyopharm Therapuetics Inc.; NIH; MJFF for Parkinson's Research; Susan G. Komen Foundation; Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences; National Human Genome Research Institute of the US National Institutes of Health (NIH), Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986, 2003-077]; US Department of Defense [W81XWH-09-2-0128]; NIH [NS057105, RR024992]; American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St. Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; section of medical genomics, the Prinses Beatrix Fonds; Forschungszentrum fur Umwelt und Gesundheit; German Federal Ministry of Education, Science, Research, and Technology; State of Bavaria; German National Genome Network (NGFNplus) [01GS08134]; German Federal Ministry of Education and Research [NGFN 01GR0468]; ERA-NET NEURON [01EW0908]; Helmholtz Alliance Mental Health in an Ageing Society [HA-215]; Initiative and Networking Fund of the Helmholtz Association; French National Agency of Research [ANR-08-MNP-012]; European Community; IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD) [PIAP-GA-2008-230596 MarkMD]; Wellcome Trust [083948/Z/07/Z]; Medical Research Council; Wellcome Trust disease centre [WT089698/Z/09/Z]; Parkinson's UK [8047, J-0804]; Medical Research Council [G0700943]; Department of Health's National Institute for Health Research Biomedical Research Centres; Wellcome Trust/Medical Research Council [WT089698] FX This study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation. The PDGene database has been made possible by the kind support of the Michael J. Fox Foundation (MJFF) for Parkinson's Research, with additional support from Cure Alzheimer's Fund (CAF), the Fidelity Biosciences Research Initiative, Prize4Life, the National Alliance for Research on Schizophrenia and Depression (NARSAD), and EMD Serono. RHM received grants from the Robert P. & Judith N. Goldberg Foundation, the Cogan Family Foundation and R01-NS076843, Characterization of the Role of cyclin G-Associated Kinase in Parkinson disease and an unrestricted grant from the Karyopharm Therapuetics Inc. TF has received research grants from NIH, MJFF for Parkinson's Research, and the Susan G. Komen Foundation. IPDGC was supported by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, and National Human Genome Research Institute of the US National Institutes of Health (NIH), Department of Health and Human Services (project numbers Z01-AG000949-02 and Z01-ES101986), human subjects protocol 2003-077. IPDGC was also supported by the US Department of Defense (award number W81XWH-09-2-0128); NIH (grants NS057105 and RR024992); American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St. Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum fur Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. It was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). It was also sponsored by the European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to HP and JHu). The WTCCC2 project was funded by the Wellcome Trust (083948/Z/07/Z). WTCCC1 study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to NW, JHa, and ASc). This study was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). DNA extraction work that was done in the UK at University College London Hospitals, University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding.; This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson's Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield, and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 35 Z9 35 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JUN PY 2013 VL 10 IS 6 AR e1001462 DI 10.1371/journal.pmed.1001462 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 172WB UT WOS:000321034800006 PM 23750121 ER PT J AU Sandel, ME Jette, AM Appelman, J Terdiman, J TeSelle, M Delmonico, RL Wang, H Camicia, M Rasch, EK Brandt, DE Chan, L AF Sandel, M. Elizabeth Jette, Alan M. Appelman, Jed Terdiman, Joseph TeSelle, Marian Delmonico, Richard L. Wang, Hua Camicia, Michelle Rasch, Elizabeth K. Brandt, Diane E. Chan, Leighton TI Designing and Implementing a System for Tracking Functional Status After Stroke: A Feasibility Study SO PM&R LA English DT Article ID POSTACUTE CARE; COPENHAGEN STROKE; TIME-COURSE; RECOVERY; REHABILITATION; OUTPATIENT; PATIENT; SCALE AB Objective: To determine the feasibility of tracking stroke patients' functional outcomes in an integrated health system across a care continuum using the computer version of the Activity Measure of Post-Acute Care (AM-PAC). Setting: A large integrated health care system in northern California. Participants: A total of 222 stroke patients (aged >= 18 years) who were hospitalized after an acute cerebrovascular accident. Methods: An AM-PAC assessment was made at discharge from sites of care, including acute hospital, inpatient rehabilitation hospital, skilled nursing facility, home during home care, and outpatient settings. Assessments also were completed in the patient's home at 6 months. Data from the AM-PAC program were integrated with the health care system's databases. Main Outcome Measurements: (1) AM-PAC administration time at the various sites of care; (2) assessment of a floor or a ceiling effect; and (3) administrative burden of tracking participants. Results: AM-PAC assessment sessions averaged 7.9 minutes for data acquisition in 3 domains: Basic Mobility, Activities of Daily Living, and Applied Cognition. Participants answered, on average, 27 AM-PAC questions per session. A small ceiling effect was observed at 6 months, and there was a larger ceiling effect when the instrument was administered in an institution, ie, when the AM-PAC institutional item bank was used rather than the community item bank. It was feasible to, track patients and to assess their function using the AM-PAC instrument from institutional to community settings. Implementation of the AM-PAC in clinical environments, and the success of the project, were influenced by instrumental, technological, operational, resource, and cultural factors. Conclusions: This study demonstrates the feasibility of implementing a single functional outcome instrument in clinical and community settings to measure rehabilitation functional outcomes of stroke patients. Integrating the AM-PAC measurement system into clinical workflows and the electronic medical record could provide assistance to clinicians for medical decision making, functional prognostication, and discharge planning. C1 [Sandel, M. Elizabeth] Kaiser Fdn Rehabil Ctr, Napa Solano Serv Area, Vallejo, CA 94589 USA. [Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02215 USA. [Appelman, Jed; Delmonico, Richard L.; Wang, Hua; Camicia, Michelle] Kaiser Fdn Rehabil Ctr, Vallejo, CA USA. [Terdiman, Joseph] Kaiser Permanente No Calif, Permanente Med Grp, Div Res, Oakland, CA USA. [TeSelle, Marian] Capital Serv Area, Sacramento, CA USA. [Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton] NIH, Dept Rehabil Med, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Sandel, ME (reprint author), Kaiser Fdn Rehabil Ctr, Napa Solano Serv Area, 975 Sereno Dr, Vallejo, CA 94589 USA. EM bsandel2@gmail.com OI Jette, Alan/0000-0002-2117-9973 FU NIH Intramural Research Program; National Institute of Neurological Diseases and Stroke [5RC1NS068397] FX Supported by the NIH Intramural Research Program and the National Institute of Neurological Diseases and Stroke (5RC1NS068397). NR 22 TC 3 Z9 3 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD JUN PY 2013 VL 5 IS 6 BP 481 EP 490 DI 10.1016/j.pmrj.2012.09.579 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 174LH UT WOS:000321156400005 PM 23159241 ER PT J AU Zhen, ZP Tang, W Chen, HM Lin, X Todd, T Wang, G Cowger, T Chen, XY Xie, J AF Zhen, Zipeng Tang, Wei Chen, Hongmin Lin, Xin Todd, Trever Wang, Geoffrey Cowger, Taku Chen, Xiaoyuan Xie, Jin TI RGD-Modified Apoferritin Nanoparticles for Efficient Drug Delivery to Tumors SO ACS NANO LA English DT Article DE ferritin; drug delivery; integrin alpha(v)beta(3); nanocarrier; doxorubicin ID FERRITIN; ADRIAMYCIN; CANCER; COMPLEXATION; DOXORUBICIN; TOXICITY; CAGE AB Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each ferritin is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD-integrin alpha(v)beta(3) interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein, we showed that after being precomplexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49 wt %). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation. C1 [Zhen, Zipeng; Tang, Wei; Chen, Hongmin; Todd, Trever; Wang, Geoffrey; Cowger, Taku; Xie, Jin] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Zhen, Zipeng; Tang, Wei; Chen, Hongmin; Todd, Trever; Wang, Geoffrey; Cowger, Taku; Xie, Jin] Univ Georgia, Bioimaging Res Ctr, Athens, GA 30602 USA. [Lin, Xin; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20852 USA. RP Xie, J (reprint author), Univ Georgia, Dept Chem, Athens, GA 30602 USA. EM jinxie@uga.edu RI Chen, Hongmin/B-9555-2011 FU NCI/NIH [5R00CA153772]; UGA; NIBIB, NIH; Philbrook scholarship FX This work was supported by an NCI/NIH R00 grant (5R00CA153772), a UGA startup grant, and the Intramural Research Program of NIBIB, NIH. T. Todd was supported by a Philbrook scholarship. We thank Prof. J. Frangioni at Harvard Medical School for generously providing the ZW800 dye. We thank Dr. C. Guo and Prof. B. Xu at UGA for helping with the AFM analysis. NR 29 TC 97 Z9 101 U1 14 U2 184 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUN PY 2013 VL 7 IS 6 BP 4830 EP 4837 DI 10.1021/nn305791q PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 173QK UT WOS:000321093800015 PM 23718215 ER PT J AU Lin, J Wang, SJ Huang, P Wang, Z Chen, SH Niu, G Li, WW He, J Cui, DX Lu, GM Chen, XY Nie, ZH AF Lin, Jing Wang, Shouju Huang, Peng Wang, Zhe Chen, Shouhui Niu, Gang Li, Wanwan He, Jie Cui, Daxiang Lu, Guangming Chen, Xiaoyuan Nie, Zhihong TI Photosensitizer-Loaded Gold Vesicles with Strong Plasmonic Coupling Effect for Imaging-Guided Photothermal/Photodynamic Therapy SO ACS NANO LA English DT Article DE gold vesicles; plasmonic coupling effect; photoacoustic imaging; photothermal therapy; photodynamic therapy; synergistic therapy ID TARGETING PHOTODYNAMIC THERAPY; INTRACELLULAR DRUG-DELIVERY; THERANOSTIC AGENTS; CANCER-THERAPY; FLUENCE RATE; NANOPARTICLES; NANORODS; PORPHYRIN AB A multifunctional theranostic platform based on photosensitizer-loaded plasmonic vesicular assemblies of gold nanoparticles (GNPs) is developed for effective cancer Imaging and treatment. The gold vesicles (GVs) composed of a monolayer of assembled GNPs show strong absorbance in the near-Infrared (NIR) range of 650-800 nm, as a result of the plasmonic coupling effect between neighboring GNPs in the vesicular membranes. The strong NIR absorption and the capability of encapsulating photosensitizer Ce6 in GVs enable trimodality NIR fluorescence/thermal/photoacoustic Imaging-guided synergistic photothermal/photodynamic therapy (PTT/PDT) with improved efficacy. The Ce6-loaded GVs (GV-Ce6) have the following characteristics: (i) high Ce6 loading efficiency (up to similar to 18.4 wt %; (ii) enhanced cellular uptake efficiency of Ce6; (iii) simultaneous trimodality NIR fluorescence/thermal/photoacoustic imaging; (iv) synergistic PTT/PDT treatment with improved efficacy using single wavelength continuous wave laser irradiation. C1 [Lin, Jing; He, Jie; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Wang, Shouju; Huang, Peng; Wang, Zhe; Chen, Shouhui; Niu, Gang; Li, Wanwan; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Lin, Jing; Huang, Peng; Chen, Shouhui; Cui, Daxiang] Shanghai Jiao Tong Univ, Inst Micronano Sci & Technol, Shanghai 200240, Peoples R China. [Wang, Shouju; Lu, Guangming] Nanjing Univ, Coll Med, Sch Clin, Jinling Hosp, Nanjing 210000, Jiangsu, Peoples R China. [Wang, Zhe] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov; znie@umd.edu RI Huang, Peng/H-9985-2013; Nie, Zhihong/D-7495-2011; Huang, Peng/R-2480-2016; OI Nie, Zhihong/0000-0001-9639-905X; Huang, Peng/0000-0003-3651-7813; He, Jie/0000-0003-0252-3094 FU University of Maryland; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Key Basic Research Program (973 Project) [2010CB-933901, 2013CB733802]; National Science Foundation of China [81272987, 31170961, 51102258]; Zhejiang Province Foundation [LY12H11011]; Chinese Academy of Sciences [2011T2J06] FX This work was supported by the startup funds from the University of Maryland, the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), the National Key Basic Research Program (973 Project) (2010CB-933901 and 2013CB733802), the National Science Foundation of China (81272987, 31170961, 51102258), Zhejiang Province Foundation (LY12H11011), and the Chinese Academy of Sciences professorship for Senior International Scientists (2011T2J06). NR 45 TC 221 Z9 224 U1 54 U2 476 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUN PY 2013 VL 7 IS 6 BP 5320 EP 5329 DI 10.1021/nn4011686 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 173QK UT WOS:000321093800068 PM 23721576 ER PT J AU Liu, DB Huang, XL Wang, ZT Jin, A Sun, XL Zhu, L Wang, F Ma, Y Niu, G Walker, ARH Chen, XY AF Liu, Dingbin Huang, Xinglu Wang, Zhantong Jin, Albert Sun, Xiaolian Zhu, Lei Wang, Fu Ma, Ying Niu, Gang Walker, Angela R. Hight Chen, Xiaoyuan TI Gold Nanoparticle-Based Activatable Probe for Sensing Ultra low Levels of Prostate-Specific Antigen SO ACS NANO LA English DT Article DE fluorescence-activatable probe; gold nanoparticle; prostate-specific antigen (PSA); rhodamine B isothiocyanate (RBITC) ID ENERGY-TRANSFER; ULTRASENSITIVE DETECTION; PROTEIN MICROARRAYS; ASSAY; CANCER; SENSITIVITY; BIOMARKERS; SERUM; FLUORESCENCE; BIOMOLECULES AB It Is still in high demand to develop extremely sensitive and accurate clinical tools for biomarkers of interest for early diagnosis and monitoring of diseases. In this report, we present a highly sensitive and compatible gold nanoparticle (AuNP)-based fluorescence-activatable probe for sensing ultralow levels of prostate-specific antigen (PSA) in patient serum samples. The limit of detection of the newly developed probe for PSA was pushed down to 0.032 pg/mL, which is more than 2 orders of magnitude lower than that of the conventional fluorescence probe. The ultrahigh sensitivity of this probe was attributed to the high loading efficiency of the dyes on AuNP surfaces and high fluorescence quenching-unquenching abilities of the dye-AuNP pairs. The efficiency and robustness of this probe were investigated In patient serum samples, demonstrating the great potential of this probe in real-world applications. C1 [Liu, Dingbin; Huang, Xinglu; Sun, Xiaolian; Zhu, Lei; Wang, Fu; Ma, Ying; Niu, Gang] Natl Inst Biomed Imaging & Bioengn, NIH, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. [Wang, Zhantong; Zhu, Lei; Chen, Xiaoyuan] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. [Jin, Albert] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20982 USA. [Walker, Angela R. Hight] Natl Inst Stand & Technol, Opt Tech Div, Phys Lab, Gaithersburg, MD 20899 USA. RP Chen, XY (reprint author), Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. EM shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016; Hight Walker, Angela/C-3373-2009; OI Zhu, Lei/0000-0002-1820-4795; Hight Walker, Angela/0000-0003-1385-0672; Jin, Albert/0000-0003-3826-1081; Wang, Fu/0000-0001-9222-0833 FU Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); NIH-NIBIB/NIST NRC FX This work was supported, in part, by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), D.L was supported by a postdoctoral fellowship from NIH-NIBIB/NIST NRC. NR 32 TC 58 Z9 60 U1 13 U2 169 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUN PY 2013 VL 7 IS 6 BP 5568 EP 5576 DI 10.1021/nn401837q PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 173QK UT WOS:000321093800096 PM 23683064 ER PT J AU Cook, MB AF Cook, Michael B. TI Optimization and Expansion of Predictive Models for Barrett's Esophagus and Esophageal Adenocarcinoma: Could a Life-Course Exposure History Be Beneficial? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID GASTROESOPHAGEAL-REFLUX DISEASE; LOW-GRADE DYSPLASIA; RISK-FACTORS; ENDOSCOPIC FINDINGS; GENERAL-POPULATION; SYMPTOMS; COLONOSCOPY; GERD; QUESTIONNAIRE; CONCLUSIONS AB Thrift et al. provide preliminary evidence that younger age of symptomatic gastroesophageal reflux disease exposure is associated with increased risk of Barrett's esophagus. If these findings are confirmed in other studies, the next logical steps are to test whether this, and other age-specific exposures, can help optimize predictive models of Barrett's esophagus and progression to esophageal adenocarcinoma. Expansion of these models to the general population and the greater Barrett's esophagus population, respectively, will be required for a screening and surveillance approach to be clinically successful and cost-effective. C1 NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. RP Cook, MB (reprint author), NCI, NIH, DHHS, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Suite 550 Room 5012, Bethesda, MD 20852 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural NIH HHS NR 32 TC 2 Z9 2 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUN PY 2013 VL 108 IS 6 BP 923 EP 925 DI 10.1038/ajg.2013.83 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 176KY UT WOS:000321304400008 PM 23735915 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI Relationship of Non-alcoholic Fatty Liver Disease With Cholecystectomy in the US Population SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID SERUM ALANINE AMINOTRANSFERASE; GALLSTONE-DISEASE; GALLBLADDER-DISEASE; RISK-FACTORS; INSULIN-RESISTANCE; UNITED-STATES; BILE-ACIDS; LAPAROSCOPIC CHOLECYSTECTOMY; PREVALENCE; ASSOCIATION AB OBJECTIVES: Other than weight-related conditions, risk factors for non-alcoholic fatty liver disease (NAFLD) are not well defined. We investigated the association of gallstones and cholecystectomy with NAFLD in a large, national, population-based study. METHODS: Among adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, ultrasonography for gallstone disease was performed, and videotapes were subsequently evaluated for NAFLD. Odds ratios (ORs) for the association of gallstone disease with NAFLD were calculated using logistic regression analysis to adjust for common associated factors. RESULTS: Among 12,232 participants without viral hepatitis or significant alcohol intake, the prevalence of gallstones was 7.4%, cholecystectomy 5.6%, and NAFLD 20.0%. Participants with cholecystectomy had higher age-sex-adjusted prevalence of NAFLD (48.4%) than those with gallstones (34.4%) or without gallstone disease (17.9%) (P<0.01 for all comparisons). Controlling for numerous factors associated with both NAFLD and gallstone disease, multivariate-adjusted analysis confirmed the association of NAFLD with cholecystectomy (OR = 2.4; 95% confidence interval (CI): 1.8-3.3), but not with gallstones (OR = 1.1; 95% CI: 0.84-1.4). CONCLUSIONS: The association of NAFLD with cholecystectomy, but not with gallstones, indicates that cholecystectomy may itself be a risk factor for NAFLD. C1 [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Everhart, James E.] Natl Inst Diabet & Digest & Kidney Dis, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cruhl@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN267200700001G, HHSN276201200161U] FX This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN267200700001G and HHSN276201200161U). NR 40 TC 26 Z9 26 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUN PY 2013 VL 108 IS 6 BP 952 EP 958 DI 10.1038/ajg.2013.70 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 176KY UT WOS:000321304400013 PM 23545713 ER PT J AU Romero, R Stanczyk, FZ AF Romero, Roberto Stanczyk, Frank Z. TI Progesterone is not the same as 17 alpha-hydroxyprogesterone caproate: implications for obstetrical practice SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID RECURRENT PRETERM DELIVERY; PLACEBO-CONTROLLED TRIAL; LABOR INDUCTION; EARLY-PREGNANCY; UTERINE CERVIX; DOUBLE-BLIND; VAGINAL PROGESTERONE; ANTI-PROGESTERONE; GUINEA-PIG; BIRTH AB Progestogen and progestins: what is the difference? A progestogen is a compound with progesterone-like action (natural or synthetic). This has been defined as the ability of a chemical agent to transform a proliferative into a secretory endometrium to support pregnancy. The term progestins refers to synthetic progestogens and, for the sake of clarity, should not be applied to natural progesterone (examples of progestins include medroxyprogesterone acetate, norethindrone, and levonorgestrel, which have been used as agents for contraception and hormone replacement). C1 [Romero, Roberto] NICHD NIH DHHS, Perinatol Res Branch, Detroit, MI USA. [Romero, Roberto] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. [Stanczyk, Frank Z.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. RP Romero, R (reprint author), NICHD NIH DHHS, Perinatol Res Branch, Detroit, MI USA. EM romeror@mail.nih.gov 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 FX 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. NR 79 TC 18 Z9 18 U1 0 U2 2 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 JUN PY 2013 VL 208 IS 6 BP 421 EP 426 DI 10.1016/j.ajog.2013.04.027 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 166YH UT WOS:000320596600004 PM 23643669 ER PT J AU D'Alton, ME Bonanno, CA Berkowitz, RL Brown, HL Copel, JA Cunningham, FG Garite, TJ Gilstrap, LC Grobman, WA Hankins, GDV Hauth, JC Iriye, BK Macones, GA Martin, JN Martin, SR Menard, K O'Keefe, DF Pacheco, LD Riley, LE Saade, GR Spong, CY AF D'Alton, Mary E. Bonanno, Clarissa A. Berkowitz, Richard L. Brown, Haywood L. Copel, Joshua A. Cunningham, F. Gary Garite, Thomas J. Gilstrap, Larry C., III Grobman, William A. Hankins, Gary D. V. Hauth, John C. Iriye, Brian K. Macones, George A. Martin, James N., Jr. Martin, Stephanie R. Menard, Kathryn O'Keefe, Daniel F. Pacheco, Luis D. Riley, Laura E. Saade, George R. Spong, Catherine Y. TI Putting the "M" back in maternal-fetal medicine SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material DE maternal-fetal medicine; maternal-fetal medicine education; maternal-fetal medicine research; maternal morbidity; maternal mortality ID UNITED-STATES; MORTALITY; DELIVERY; PREGNANCY; MORBIDITY; HEALTH; LABOR AB Although maternal death remains rare in the United States, the rate has not decreased for 3 decades. The rate of severe maternal morbidity, a more prevalent problem, is also rising. Rise in maternal age, in rates of obesity, and in cesarean deliveries as well as more pregnant women with chronic medical conditions all contribute to maternal mortality and morbidity in the United States. We believe it is the responsibility of maternal-fetal medicine (MFM) subspecialists to lead a national effort to decrease maternal mortality and morbidity. In doing so, we hope to reestablish the vital role of MFM subspecialists to take the lead in the performance and coordination of care in complicated obstetrical cases. This article will summarize our initial recommendations to enhance MFM education and training, to establish national standards to improve maternal care and management, and to address critical research gaps in maternal medicine. C1 [D'Alton, Mary E.; Bonanno, Clarissa A.; Berkowitz, Richard L.] Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY 10032 USA. [Brown, Haywood L.] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. [Copel, Joshua A.] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. [Cunningham, F. Gary] Univ Texas Southwestern Med Sch, Dept Obstet & Gynecol, Dallas, TX USA. [Garite, Thomas J.] Univ Calif Irvine, Sch Med, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Gilstrap, Larry C., III] Univ Texas Houston, Sch Med, Dept Obstet Gynecol & Reprod Sci, Houston, TX USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Hankins, Gary D. V.; Pacheco, Luis D.; Saade, George R.] Univ Texas Med Branch, Sch Med, Dept Obstet Gynecol, Galveston, TX 77555 USA. [Hankins, Gary D. V.; Pacheco, Luis D.; Saade, George R.] Univ Texas Med Branch, Sch Med, Dept Anesthesiol, Galveston, TX 77555 USA. [Hauth, John C.] Univ Alabama Birmingham, Sch Med, Dept Obstet & Gynecol, Birmingham, AL USA. [Iriye, Brian K.] High Risk Pregnancy Ctr, Las Vegas, NV USA. [Macones, George A.] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Martin, James N., Jr.] Univ Mississippi, Sch Med, Dept Obstet & Gynecol, Jackson, MS USA. [Martin, Stephanie R.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Menard, Kathryn] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [O'Keefe, Daniel F.] Soc Maternal Fetal Med, Washington, DC USA. [Riley, Laura E.] Harvard Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP D'Alton, ME (reprint author), Columbia Univ, Coll Phys & Surg, Dept Obstet & Gynecol, Div Maternal Fetal Med, 622 W 168 St,16th Floor, New York, NY 10032 USA. EM md511@columbia.edu FU American Board of Obstetrician Gynecologists FX Dr D'Alton delivered the keynote address, "Putting the 'M' Back in Maternal-Fetal Medicine," at the 2012 annual meeting of the American Gynecological and Obstetrical Society. Her address had the same title and content as this manuscript. Dr Spong, as a federal employee, cannot assign copyright. Dr Gilstrap is the executive director of the American Board of Obstetrician Gynecologists, which accredits the maternal-fetal medicine fellowships. No other author reports a conflict of interest. NR 22 TC 39 Z9 39 U1 0 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 JUN PY 2013 VL 208 IS 6 BP 442 EP 448 DI 10.1016/j.ajog.2012.11.041 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 166YH UT WOS:000320596600008 PM 23211544 ER PT J AU Guttmacher, AE AF Guttmacher, Alan E. TI Framework for preventing preterm birth must include contraception REPLY SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Guttmacher, AE (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 31 Ctr Dr, Bethesda, MD 20892 USA. EM guttmach@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2013 VL 208 IS 6 BP 509 EP 509 DI 10.1016/j.ajog.2013.01.035 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 166YH UT WOS:000320596600039 PM 23352988 ER PT J AU Peterson, CM Johnstone, EB Hammoud, AO Stanford, JB Varner, MW Kennedy, A Chen, Z Sun, LP Fujimoto, VY Hediger, ML Louis, GMB AF Peterson, C. Matthew Johnstone, Erica B. Hammoud, Ahmad O. Stanford, Joseph B. Varner, Michael W. Kennedy, Anne Chen, Zhen Sun, Liping Fujimoto, Victor Y. Hediger, Mary L. Louis, Germaine M. Buck CA ENDO Study Working Grp TI Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE Body mass index; dysmenorrhea; endometriosis; epidemiology; infertility; laparoscopy; magnetic resonance imaging; risk factors ID DEEP INFILTRATING ENDOMETRIOSIS; MENSTRUAL CHARACTERISTICS; INFERTILE WOMEN; PELVIC PAIN; PREVALENCE; DIAGNOSIS; STERILIZATION AB OBJECTIVE: We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study. STUDY DESIGN: In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age-and residence-matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. RESULTS: The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. CONCLUSION: An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized. C1 [Peterson, C. Matthew; Johnstone, Erica B.; Hammoud, Ahmad O.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Salt Lake City, UT 84132 USA. [Varner, Michael W.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. [Stanford, Joseph B.] Univ Utah, Sch Med, Dept Family & Prevent Med, Salt Lake City, UT 84132 USA. [Kennedy, Anne] Univ Utah, Sch Med, Dept Radiol, Salt Lake City, UT 84132 USA. [Chen, Zhen; Sun, Liping; Hediger, Mary L.; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Fujimoto, Victor Y.] Univ Calif San Francisco, Sch Med, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. RP Peterson, CM (reprint author), Univ Utah, Dept Obstet & Gynecol, 50 NMed Dr,Suite 2B200, Salt Lake City, UT 84132 USA. EM c.matthew.peterson@hsc.utah.edu RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health [N01-DK-6-3428, N01-DK-6-3427, 10001406-02] FX Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (contract numbers N01-DK-6-3428, N01-DK-6-3427, and 10001406-02). Ethicon Endo-Surgery LLC donated shears and scalpel blades through a signed Materials Transfer Agreement with the University of Utah and the NICHD. Partial support for all datasets within the Utah Population Database was provided by the Huntsman Cancer Institute. NR 31 TC 6 Z9 6 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2013 VL 208 IS 6 AR 451.e1 DI 10.1016/j.ajog.2013.02.040 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 166YH UT WOS:000320596600010 PM 23454253 ER PT J AU Lavoue, J Friesen, MC Burstyn, I AF Lavoue, J. Friesen, M. C. Burstyn, I. TI Workplace measurements by the U.S. Occupational Safety and Health Administration since 1979: Descriptive analysis and potential uses for exposure assessment (vol 57, pg 77, 2013) SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Correction AB This letter summarizes modifications to the results presented in Lavou et al. (2012): Lavou, J., Burstyn, I., Friesen, M. (2012) Workplace Measurements by the US Occupational Safety and Health Administration since 1979: Descriptive Analysis and Potential Uses for Exposure Assessment. Annals of occupational hygiene 57(1):7797. Although several results were altered, the conclusions were not affected by the changes. C1 [Lavoue, J.] Univ Montreal Hosp Res Ctr, Montreal, PQ, Canada. [Friesen, M. C.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, North Bethesda, MD USA. [Burstyn, I.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. RP Lavoue, J (reprint author), Univ Montreal Hosp Res Ctr, Montreal, PQ, Canada. RI Friesen, Melissa/A-5362-2009 NR 2 TC 4 Z9 4 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JUN PY 2013 VL 57 IS 5 BP 681 EP 683 DI 10.1093/annhyg/met027 PG 3 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 173GJ UT WOS:000321066100016 PM 23946941 ER PT J AU Metlay, G AF Metlay, Grischa TI Biomedical Computing: Digitizing Life in the United States. SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Book Review C1 [Metlay, Grischa] NIH, Bethesda, MD 20892 USA. RP Metlay, G (reprint author), NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 EI 1086-3176 J9 B HIST MED JI Bull. Hist. Med. PD SUM PY 2013 VL 87 IS 2 BP 296 EP 297 PG 2 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 172SA UT WOS:000321024000015 ER PT J AU Reilly, KM AF Reilly, Karlyne M. TI Extending the Convergence of Canonical WNT Signaling and Classic Cancer Pathways for Treatment of Malignant Peripheral Nerve Sheath Tumors SO CANCER DISCOVERY LA English DT Editorial Material ID GROWTH-FACTOR RECEPTOR; BETA-CATENIN; PROGRESSION AB Malignant peripheral nerve sheath tumors (MPNST) are incurable tumors of the Schwann cell lineage that progress unpredictably from benign plexiform neurofibromas. In this issue of Cancer Discovery, Watson and colleagues use an insertional mutagenesis screen combined with network analysis to identify the canonical WNT signaling pathway as an important potential biomarker of tumor progression and target for combination therapy in MPNSTs. C1 [Reilly, Karlyne M.] NCI, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Reilly, KM (reprint author), NCI, West 7th St,Ft Detrick,POB B, Frederick, MD 21702 USA. EM ReillyK@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 11 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUN PY 2013 VL 3 IS 6 BP 610 EP 612 DI 10.1158/2159-8290.CD-13-0192 PG 3 WC Oncology SC Oncology GA 180RV UT WOS:000321614100017 PM 23749527 ER PT J AU Killian, JK Kim, SY Miettinen, M Smith, C Merino, M Tsokos, M Quezado, M Smith, WI Jahromi, MS Xekouki, P Szarek, E Walker, RL Lasota, J Raffeld, M Klotzle, B Wang, ZF Jones, L Zhu, YL Wang, YH Waterfall, JJ O'Sullivan, MJ Bibikova, M Pacak, K Stratakis, C Janeway, KA Schiffman, JD Fan, JB Helman, L Meltzer, PS AF Killian, J. Keith Kim, Su Young Miettinen, Markku Smith, Carly Merino, Maria Tsokos, Maria Quezado, Martha Smith, William I., Jr. Jahromi, Mona S. Xekouki, Paraskevi Szarek, Eva Walker, Robert L. Lasota, Jerzy Raffeld, Mark Klotzle, Brandy Wang, Zengfeng Jones, Laura Zhu, Yuelin Wang, Yonghong Waterfall, Joshua J. O'Sullivan, Maureen J. Bibikova, Marina Pacak, Karel Stratakis, Constantine Janeway, Katherine A. Schiffman, Joshua D. Fan, Jian-Bing Helman, Lee Meltzer, Paul S. TI Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor SO CANCER DISCOVERY LA English DT Article ID OF-FUNCTION MUTATIONS; IDH2 MUTATIONS; COPY-NUMBER; KIT; SUPPRESSORS; INHIBITION; HISTONE; UPDATE; ASSAY; SDHA AB Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway-mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle-defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance. SIGNIFICANCE: This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction. (c) 2013 AACR. C1 [Killian, J. Keith; Kim, Su Young; Miettinen, Markku; Smith, Carly; Merino, Maria; Tsokos, Maria; Quezado, Martha; Walker, Robert L.; Lasota, Jerzy; Raffeld, Mark; Wang, Zengfeng; Jones, Laura; Zhu, Yuelin; Wang, Yonghong; Waterfall, Joshua J.; Helman, Lee; Meltzer, Paul S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Smith, William I., Jr.] Suburban Hosp, Bethesda, MD USA. [Xekouki, Paraskevi; Szarek, Eva; Pacak, Karel; Stratakis, Constantine] Eunice Kennedy Shriver NICHD, Bethesda, MD USA. [Jahromi, Mona S.; Schiffman, Joshua D.] Univ Utah, Salt Lake City, UT USA. [Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Janeway, Katherine A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [O'Sullivan, Maureen J.] Our Ladys Childrens Hosp, Dublin, Ireland. RP Meltzer, PS (reprint author), NCI, Genet Branch, 37 Convent Dr MSC 4265, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov FU Intramural Research Program of NIH; National Cancer Institute; Center for Cancer Research FX This work was supported by grants from the Intramural Research Program of NIH, the National Cancer Institute, and the Center for Cancer Research. NR 26 TC 105 Z9 109 U1 1 U2 24 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUN PY 2013 VL 3 IS 6 BP 648 EP 657 DI 10.1158/2159-8290.CD-13-0092 PG 10 WC Oncology SC Oncology GA 180RV UT WOS:000321614100022 PM 23550148 ER PT J AU Olson, MT Breaud, A Harlan, R Emezienna, N Schools, S Yergey, AL Clarke, W AF Olson, Matthew T. Breaud, Autumn Harlan, Robert Emezienna, Nkechinyere Schools, Sabitha Yergey, Alfred L. Clarke, William TI Alternative Calibration Strategies for the Clinical Laboratory: Application to Nortriptyline Therapeutic Drug Monitoring SO CLINICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; INFECTIOUS-DISEASES-SOCIETY; PERFORMANCE LIQUID-CHROMATOGRAPHY; PRACTICE GUIDELINES; AMERICA; PHARMACOKINETICS; ANTIDEPRESSANTS; QUANTIFICATION; IMMUNOASSAYS; IONIZATION AB BACKGROUND: The addition of a calibration curve with every run is both time-consuming and expensive for clinical mass spectrometry assays. We present alternative calibration strategies that eliminate the need for a calibration curve except as required by laboratory regulations. METHODS: We measured serum nortriptyline concentrations prospectively in 68 patients on 16 days over a 2-month period using a method employing calibration schemes that relied on the measurement of the response ratio (RR) corrected by the response factor (RF), i.e., a measurement of the RR for an equimolar mixture of the analyte and internal standard. Measurements were taken with contemporaneous RF (cRF) measurements as well as sporadic RF (sRF) measurements. The measurements with these alternative calibration schemes were compared against the clinical results obtained by interpolation on a calibration curve, and those differences were evaluated for analytical and clinical significance. RESULTS: The differences between the values measured by cRF and sRF calibration and interpolation on a calibration curve were not significant (P = 0.088 and P = 0.091, respectively). Both the cRF- and sRF-based calibration results demonstrated a low mean bias against the calibration curve interpolations of 3.69% (95% CI, -15.8% to 23.2%) and 3.11% (95% CI, -16.4% to 22.6%), respectively. When these results were classified as subtherapeutic, therapeutic, or supratherapeutic, there was categorical agreement in 95.6% of the cRF calibration results and 94.1% of the sRF results. CONCLUSIONS: cRF and sRF calibration in a clinically validated liquid chromatography-tandem mass spectrometry assay yields results that are analytically and clinically commensurate to those produced by interpolation with a calibration curve. (C) 2013 American Association for Clinical Chemistry C1 [Olson, Matthew T.; Breaud, Autumn; Harlan, Robert; Emezienna, Nkechinyere; Schools, Sabitha; Clarke, William] Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. [Yergey, Alfred L.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Clarke, W (reprint author), Sheikh Zayed Tower,B-1020F,1800 Orleans St, Baltimore, MD 21287 USA. EM wclarke@jhmi.edu FU S. Schools, Johns Hopkins University; Thermo Fisher Scientific FX Research Funding: S. Schools, Johns Hopkins University; W. Clarke, Thermo Fisher Scientific. NR 23 TC 13 Z9 13 U1 0 U2 8 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2013 VL 59 IS 6 BP 920 EP 927 DI 10.1373/clinchem.2012.194639 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 179VC UT WOS:000321548500011 PM 23426427 ER PT J AU Roukos, V Burman, B Misteli, T AF Roukos, Vassilis Burman, Bharat Misteli, Tom TI The cellular etiology of chromosome translocations SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; CLASS SWITCH RECOMBINATION; V(D)J RECOMBINATION; MAMMALIAN-CELLS; FRAGILE SITES; C-MYC; SPATIAL-ORGANIZATION; GENOMIC INSTABILITY; CHROMATIN-STRUCTURE; SEQUENCING REVEALS AB Chromosome translocations are the most severe form of genome defect. Trans locations represent the end product of a series of cellular mistakes and they form after cells suffer multiple DNA double strand breaks (DSBs), which evade the surveillance mechanisms that usually eliminate them. Rather than being accurately repaired, translocating DSBs are misjoined to form aberrant fusion chromosomes. Although translocations have been extensively characterized using cytological methods and their pathological relevance in cancer and numerous other diseases is well established, how translocations form in the context of the intact cell nucleus is poorly understood. A combination of imaging approaches and biochemical methods to probe genome architecture and chromatin structure suggest that the spatial organization of the genome and features of chromatin, including sequence properties, higher order chromatin structure and histone modifications, are key determinants of translocation formation. C1 [Roukos, Vassilis; Burman, Bharat; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Burman, Bharat] Tufts Univ, Sackler Sch Biomed Sci, Program Cell Mol & Dev Biol, Boston, MA 02111 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI Roukos, Vassilis/K-6248-2012 FU Intramural NIH HHS [ZIA BC010309-13] NR 79 TC 12 Z9 12 U1 0 U2 10 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2013 VL 25 IS 3 BP 357 EP 364 DI 10.1016/j.ceb.2013.02.015 PG 8 WC Cell Biology SC Cell Biology GA 177ZF UT WOS:000321413200012 PM 23498663 ER PT J AU Hammer, JA Burkhardt, JK AF Hammer, John A., III Burkhardt, Janis K. TI Controversy and consensus regarding myosin II function at the immunological synapse SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID T-CELL-ACTIVATION; RETROGRADE FLOW; ACTIN POLYMERIZATION; IMMUNE SYNAPSE; F-ACTIN; ADHESION MOLECULES; ANTIGEN RECEPTOR; MICROCLUSTERS; MOTILITY; COMPLEX AB Regulated actin dynamics play a central role in modulating signaling events at the immunological synapse (IS). Polymerization of actin filaments at the periphery of the IS, coupled to depolymerization near the center, generates a centripetal flow of the actin network and associated movement of signaling molecules. A recent flurry of papers addresses the role of myosin II in facilitating these events. Investigators agree that myosin II is present at the IS, where it forms actomyosin arcs within the peripheral supramolecular activation cluster, a region corresponding to the lamellum of migrating cells. However, there is substantial disagreement about the extent to which myosin II drives IS formation and signaling events leading to T cell activation. C1 [Hammer, John A., III] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Burkhardt, Janis K.] Univ Penn, Dept Pathol & Lab Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Burkhardt, Janis K.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Burkhardt, JK (reprint author), Univ Penn, Dept Pathol & Lab Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. EM jburkhar@mail.med.upenn.edu FU National Institutes of Health [R01AI065644, P01CA093615]; Division of Intramural Research, National Heart, Lung and Blood Institute FX We apologize to colleagues whose works were not cited due to space constraints. We thank Alexander Babich and Jason Yi for thoughtful insights and assistance with preparation of the manuscript. This work was supported by National Institutes of Health Grant R01AI065644 and P01CA093615 to JKB and funding from the Division of Intramural Research, National Heart, Lung and Blood Institute to JAH. NR 53 TC 19 Z9 19 U1 0 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD JUN PY 2013 VL 25 IS 3 BP 300 EP 306 DI 10.1016/j.coi.2013.03.010 PG 7 WC Immunology SC Immunology GA 183ID UT WOS:000321807100002 PM 23623641 ER PT J AU Thaventhiran, JED Fearon, DT Gattinoni, L AF Thaventhiran, James E. D. Fearon, Douglas T. Gattinoni, Luca TI Transcriptional regulation of effector and memory CD8(+) T cell fates SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID CUTTING EDGE; BETA-CATENIN; RECALL RESPONSES; VIRAL-INFECTION; STEM-CELLS; DIFFERENTIATION; GENERATION; EXPRESSION; WNT; PATHWAY AB Immunity to intracellular pathogens and cancer relies on the generation of robust CD8(+) T cell effector responses as well as the establishment of immunological memory. During a primary immune response CD8(+) T cells experience diverse extracellular environmental cues and cell-cell interactions that trigger downstream transcriptional programs ultimately guiding a CD8(+) T cell to undertake either an effector or a memory cell fate. Here, we discuss our current understanding of the signaling pathways and transcriptional networks that regulate effector and memory commitment in CD8(+) T lymphocytes. C1 [Thaventhiran, James E. D.] Papworth Hosp NHS Fdn Trust, Ctr Lung Infect, Cambridge CB23 3RE, England. [Fearon, Douglas T.] Univ Cambridge, Dept Med, Sch Clin Med, Cambridge CB2 2QH, England. [Fearon, Douglas T.] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge CB2 0RE, England. [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Thaventhiran, JED (reprint author), Papworth Hosp NHS Fdn Trust, Ctr Lung Infect, Cambridge CB23 3RE, England. EM jedt2@cam.ac.uk; gattinol@mail.nih.gov RI Gattinoni, Luca/A-2281-2008 OI Gattinoni, Luca/0000-0003-2239-3282 FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research; Ludwig Institute for Cancer Research; NIHR Cambridge Biomedical Research Centre and the Wellcome Trust FX This work was supported by the Intramural Research Programs of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Cambridge Biomedical Research Centre and the Wellcome Trust. The authors would like to thank Y. Ji, C.A. Klebanoff and J. Crompton for helpful discussion. NR 66 TC 13 Z9 13 U1 0 U2 15 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD JUN PY 2013 VL 25 IS 3 BP 321 EP 328 DI 10.1016/j.coi.2013.05.010 PG 8 WC Immunology SC Immunology GA 183ID UT WOS:000321807100005 PM 23747000 ER PT J AU He, K Xun, PC Liu, K Morris, S Reis, J Guallar, E AF He, Ka Xun, Pengcheng Liu, Kiang Morris, Steve Reis, Jared Guallar, Eliseo TI Mercury Exposure in Young Adulthood and Incidence of Diabetes Later in Life The CARDIA Trace Element Study SO DIABETES CARE LA English DT Article ID INSULIN-RESISTANCE; FISH-OIL; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; FATTY-ACIDS; RISK; GLUCOSE; METAANALYSIS; METHYLMERCURY; CONSUMPTION AB OBJECTIVE-Laboratory studies suggest that exposure to methylmercury at a level similar to those found in fish may induce pancreatic islet beta-cell dysfunction. Few, if any, human studies have examined the association between mercury exposure and diabetes incidence. We examined whether toenail mercury levels are associated with incidence of diabetes in a large prospective cohort. RESEACH DESIGN AND METHODS-A prospective cohort of 3,875 American young adults, aged 20-32 years, free of diabetes in 1987 (baseline), were enrolled and followed six times until 2005. Baseline toenail mercury levels were measured with instrumental neutron-activation analysis. Incident diabetes was identified by plasma glucose levels, oral glucose tolerance tests, hemoglobin AlC levels, and/or antidiabetes medications. RESULTS-A total of 288 incident cases of diabetes occurred over 18 years of follow-up. In multivariate analyses adjusted for age, sex, ethnicity, study center, education, smoking status, alcohol consumption, physical activity, family history of diabetes, intakes of long-chain n-3 fatty acids and magnesium, and toenail selenium, toenail mercury levels were positively associated with the incidence of diabetes. The hazard ratio (95% CI) of incident diabetes compared the highest to the lowest quintiles of mercury exposure was 1.65 (1.07-2.56; P for trend = 0.02). Higher mercury exposure at baseline was also significantly associated with decreased homeostasis model assessment of beta-cell function index (P for trend < 0.01). CONCLUSIONS-Our results are consistent with findings from laboratory studies and provide longitudinal human data suggesting that people with high mercury exposure in young adulthood may have elevated risk of diabetes later in life. C1 [He, Ka; Xun, Pengcheng] Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Bloomington, IN 47405 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Morris, Steve] Univ Missouri, Res Reactor Ctr, Columbia, MO USA. [Morris, Steve] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. [Reis, Jared] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Guallar, Eliseo] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Guallar, Eliseo] Johns Hopkins Univ, Dept Med, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Guallar, Eliseo] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. RP He, K (reprint author), Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Bloomington, IN 47405 USA. EM kahe@indiana.edu RI Xun, Pengcheng/D-3411-2013; Guallar, Eliseo/D-3807-2014 OI Guallar, Eliseo/0000-0002-4471-9565 FU National Heart, Lung, and Blood Institute [N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095]; [R01-HL-081572] FX This study was supported by grant R01-HL-081572. CARDIA was supported by grants N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, and N01-HC-95095 from the National Heart, Lung, and Blood Institute. NR 37 TC 31 Z9 31 U1 2 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2013 VL 36 IS 6 BP 1584 EP 1589 DI 10.2337/dc12-1842 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178UJ UT WOS:000321472600023 PM 23423697 ER PT J AU Preis, SR Pencina, MJ Mann, DM D'Agostino, RB Savage, PJ Fox, CS AF Preis, Sarah Rosner Pencina, Michael J. Mann, Devin M. D'Agostino, Ralph B., Sr. Savage, Peter J. Fox, Caroline S. TI Early-Adulthood Cardiovascular Disease Risk Factor Profiles Among Individuals With and Without Diabetes in the Framingham Heart Study SO DIABETES CARE LA English DT Article ID CORONARY-ARTERY CALCIFICATION; BLOOD-PRESSURE; YOUNG-ADULTS; MELLITUS; CHOLESTEROL; PREVENTION; COMMUNITY; DIAGNOSIS; COMMITTEE; DESIGN AB OBJECTIVE-Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis. RESEARCH DESIGN AND METHODS-Among participants free of CVD, incident diabetes cases (fasting plasma glucose >= 126 mg/dL or treatment) occurring at examinations 2 through 8 (1979-2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls. RESULTS-We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant. CONCLUSIONS-CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes. C1 [Preis, Sarah Rosner; Fox, Caroline S.] NHLBI, Framingham, MA USA. [Preis, Sarah Rosner; Fox, Caroline S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Preis, Sarah Rosner; Pencina, Michael J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Pencina, Michael J.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Mann, Devin M.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Savage, Peter J.; Fox, Caroline S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Preis, SR (reprint author), NHLBI, Framingham, MA USA. EM srpreis@bu.edu OI Preis, Sarah/0000-0002-9360-4166; Mann, Devin/0000-0002-2099-0852 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195). NR 22 TC 15 Z9 16 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2013 VL 36 IS 6 BP 1590 EP 1596 DI 10.2337/dc12-1121 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178UJ UT WOS:000321472600024 PM 23340887 ER PT J AU Linder, BL Fradkin, JE Rodgers, GP AF Linder, Barbara L. Fradkin, Judith E. Rodgers, Griffin P. TI The TODAY Study: An NIH Perspective on Its Implications for Research SO DIABETES CARE LA English DT Editorial Material ID YOUTH; INTERVENTION; ADOLESCENTS; REDUCTION; LIFE C1 [Linder, Barbara L.; Fradkin, Judith E.; Rodgers, Griffin P.] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. RP Linder, BL (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. EM linderb@mail.nih.gov NR 17 TC 13 Z9 13 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2013 VL 36 IS 6 BP 1775 EP 1776 DI 10.2337/dc13-0707 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178UJ UT WOS:000321472600053 PM 23704678 ER PT J AU Tang, JY van Panhuys, N Kastenmuller, W Germain, RN AF Tang, Jianyong van Panhuys, Nicolas Kastenmueller, Wolfgang Germain, Ronald N. TI The future of immunoimaging - Deeper, bigger, more precise, and definitively more colorful SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; LIGHT-SHEET MICROSCOPY; FOLLICULAR DENDRITIC CELLS; RED FLUORESCENT PROTEINS; NODE B-CELLS; IN-VIVO; LYMPH-NODES; MULTIPHOTON MICROSCOPY; IMAGING REVEALS; STRUCTURED ILLUMINATION AB Immune cells are thoroughbreds, moving farther and faster and surveying more diverse tissue space than their nonhematopoietic brethren. Intravital 2-photon microscopy has provided insights into the movements and interactions of many immune cell types in diverse tissues, but more information is needed to link such analyses of dynamic cell behavior to function. Here, we describe additional methods whose application promises to extend our vision, allowing more complete, multi-scale dissection of how immune cell positioning and movement are linked to system state, host defense, and disease. C1 [Tang, Jianyong; van Panhuys, Nicolas; Kastenmueller, Wolfgang; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lab Syst Biol, NIH, Bldg 4,Rm 126A MSC 0421,10 Ctr Dr, Bethesda, MD 20892 USA. EM rgermain@nih.gov RI van Panhuys, Nicholas/E-1812-2011; OI van Panhuys, Nicholas/0000-0003-2199-852X FU Intramural Research Program of NIAID, NIH FX This work was supported by the Intramural Research Program of NIAID, NIH. We apologize to all colleagues whose primary work could not be directly cited due to editorial length and reference limitations. NR 112 TC 15 Z9 15 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2013 VL 43 IS 6 BP 1407 EP 1412 DI 10.1002/eji.201243119 PG 6 WC Immunology SC Immunology GA 169MZ UT WOS:000320785700004 PM 23568494 ER PT J AU Yang, D Wei, F Tewary, P Howard, OMZ Oppenheim, JJ AF Yang, De Wei, Feng Tewary, Poonam Howard, O. M. Zack Oppenheim, Joost J. TI Alarmin-induced cell migration SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID EOSINOPHIL-DERIVED NEUROTOXIN; ANTIMICROBIAL PEPTIDE LL-37; GLYCATION END-PRODUCTS; GROWTH-FACTOR RECEPTOR; GROUP BOX-1 PROTEIN; ENDOTHELIAL PROGENITOR CELLS; IMMATURE DENDRITIC CELLS; INDUCED IMMUNE-RESPONSES; MESENCHYMAL STEM-CELLS; KAPPA-B ACTIVATION AB Alarmins are endogenous, constitutively available, damage-associated molecular patterns that upon release can mobilize and activate various leukocytes for the induction of innate and adaptive immune responses. For our immune system to function appropriately, it relies on navigating various leukocytes to distinct places at the right time. The direction of cell migration is determined by chemotactic factors that include classical chemoattractants, chemokines, certain growth factors, and alarmins. This viewpoint provides an overview of alarmin-induced cell migration. Alarmins are capable of inducing the migration of diverse types of leukocytes and nonleukocytes either directly by triggering specific receptors or indirectly by inducing production of chemokines through the activation of various leukocytes via pattern recognition receptors. The receptors used by alarmins to directly induce cell migration can either be G alpha i protein-coupled receptors or receptors such as the receptor for advanced glycation end products; however, the intracellular signaling events responsible for the direct chemotactic activities of alarmins are, to date, only partially elucidated. Given that alarmins act in concert with chemokines to regulate the recruitment and trafficking of leukocytes, these damage-associated molecular patterns are potentially involved in diverse biological processes as discussed in this viewpoint. C1 [Yang, De] Sci Application & Int Corp Frederick Inc, Basic Res Program, Frederick, MD USA. [Yang, De; Wei, Feng; Tewary, Poonam; Howard, O. M. Zack; Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick Natl Labs Canc Res, Frederick, MD 21701 USA. [Yang, De; Wei, Feng] Tianjin Med Univ, Res Ctr Basic Med Sci, Tianjin, Peoples R China. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Frederick Natl Labs Canc Res, Frederick, MD 21701 USA. EM yangd@mail.nih.gov; oppenhei@ncifcrf.gov RI Howard, O M Zack/B-6117-2012; Wei, Feng/E-2806-2015 OI Howard, O M Zack/0000-0002-0505-7052; Wei, Feng/0000-0002-4797-449X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute; 973 grant from the National Key Basic Research Program of China [2012CB932503] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. This work was also supported in part by a 973 grant (2012CB932503) from the National Key Basic Research Program of China. NR 108 TC 12 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2013 VL 43 IS 6 BP 1412 EP 1418 DI 10.1002/eji.201243138 PG 7 WC Immunology SC Immunology GA 169MZ UT WOS:000320785700005 PM 23619968 ER PT J AU Tjomsland, V Ellegard, R Burgener, A Mogk, K Che, KF Westmacott, G Hinkula, J Lifson, JD Larsson, M AF Tjomsland, Veronica Ellegard, Rada Burgener, Adam Mogk, Kenzie Che, Karlhans F. Westmacott, Garrett Hinkula, Jorma Lifson, Jeffrey D. Larsson, Marie TI Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Antigen presentation; Antigen processing; Complement opsonization; Dendritic cells; HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELLS; ANTIGEN PRESENTATION; DC-SIGN; INTEGRIN ALPHA(4)BETA(7); LECTIN RECEPTORS; TRANS-INFECTION; VIRAL TRANSFER; ENDOSOMES; PATHOGENESIS AB Induction of optimal HIV-1-specific T-cell responses, which can contribute to controlling viral infection in vivo, depends on antigen processing and presentation processes occurring in DCs. Opsonization can influence the routing of antigen processing and pathways used for presentation. We studied antigen proteolysis and the role of endocytic receptors in MHC class I (MHCI) and II (MHCII) presentation of antigens derived from HIV-1 in human monocyte-derived immature DCs (IDCs) and mature DCs, comparing free and complement opsonized HIV-1 particles. Opsonization of virions promoted MHCI presentation by DCs, indicating that complement opsonization routes more virions toward the MHCI presentation pathway. Blockade of macrophage mannose receptor (MMR) and beta 7-integrin enhanced MHCI and MHCII presentation by IDCs and mature DCs, whereas the block of complement receptor 3 decreased MHCI and MHCII presentation. In addition, we found that IDC and MDC proteolytic activities were modulated by HIV-1 exposure; complement-opsonized HIV-1 induced an increased proteasome activity in IDCs. Taken together, these findings indicate that endocytic receptors such as MMR, complement receptor 3, and beta 7-integrin can promote or disfavor antigen presentation probably by routing HIV-1 into different endosomal compartments with distinct efficiencies for degradation of viral antigens and MHCI and MHCII presentation, and that HIV-1 affects the antigen-processing machinery. C1 [Tjomsland, Veronica; Ellegard, Rada; Che, Karlhans F.; Hinkula, Jorma; Larsson, Marie] Linkoping Univ, Div Mol Virol, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. [Burgener, Adam; Mogk, Kenzie] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Westmacott, Garrett] Natl Microbiol Lab, Winnipeg, MB, Canada. [Lifson, Jeffrey D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Larsson, M (reprint author), Linkoping Univ, Div Mol Virol, Dept Clin & Expt Med, S-58185 Linkoping, Sweden. EM marie.larsson@liu.se OI Hinkula, Jorma/0000-0003-1908-5609 FU Swedish Research Council; Swedish, Physicians against AIDS research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; C ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [AI52731] FX We want to thank the Biological Products Core of the AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, MD, USA for providing infectious HIV-1. This work has been supported by grants through: ML: AI52731, The Swedish Research Council, The Swedish, Physicians against AIDS research Foundation, The Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linkoping University Hospital Research Fund, C ALF, and the Swedish Society of Medicine and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E (JDL) NR 47 TC 7 Z9 7 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2013 VL 43 IS 6 BP 1470 EP 1483 DI 10.1002/eji.201242935 PG 14 WC Immunology SC Immunology GA 169MZ UT WOS:000320785700015 PM 23526630 ER PT J AU Thorat, SA Kang, DW Ryu, H Kim, MS Kim, HS Ann, J Ha, T Kim, SE Son, K Choi, S Blumberg, PM Frank, R Bahrenberg, G Schiene, K Christoph, T Lee, J AF Thorat, Shivaji A. Kang, Dong Wook Ryu, HyungChul Kim, Myeong Seop Kim, Ho Shin Ann, Jihyae Ha, Taehwan Kim, Sung-Eun Son, Karam Choi, Sun Blumberg, Peter M. Frank, Robert Bahrenberg, Gregor Schiene, Klaus Christoph, Thomas Lee, Jeewoo TI 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE TRPV1 antagonists; Analgesic; Molecular modeling; Capsaicin ID CAPSAICIN RECEPTORS; PAIN; ANALGESICS; TARGET AB The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethylpyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 535 using our hTRPV1 homology model indicated that the A- and B-region 2-(3fluoro-4-methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Thorat, Shivaji A.; Kang, Dong Wook; Ryu, HyungChul; Kim, Myeong Seop; Kim, Ho Shin; Ann, Jihyae; Ha, Taehwan; Kim, Sung-Eun; Lee, Jeewoo] Seoul Natl Univ, Med Chem Lab, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. [Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Leading Res Lab NLRL Mol Modeling & Drug Des, Div Life & Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea. [Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank, Robert; Bahrenberg, Gregor; Schiene, Klaus; Christoph, Thomas] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. [Kang, Dong Wook] Catholic Univ Daegu, Dept Pharmaceut Sci & Technol, Coll Hlth & Med Sci, Gyongsan 712702, Gyeongsangbuk D, South Korea. RP Lee, J (reprint author), Seoul Natl Univ, Med Chem Lab, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Grunenthal; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Leading Research Lab (NLRL) program [2011-0028885]; Ewha Global Top 5 Grant; Intramural Research Program of NIH; Center for Cancer Research, NCI [Z1A BC 005270] FX This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), Grants from the National Leading Research Lab (NLRL) program (2011-0028885), the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). NR 22 TC 13 Z9 13 U1 1 U2 8 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD JUN PY 2013 VL 64 BP 589 EP 602 DI 10.1016/j.ejmech.2013.04.003 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 175KT UT WOS:000321230300057 PM 23685943 ER PT J AU Andreani, A Granaiola, M Locatelli, A Morigi, R Rambaldi, M Varoli, L Dalla Sega, FV Prata, C Nguyen, TL Bai, RL Hamel, E AF Andreani, Aldo Granaiola, Massimiliano Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Dalla Sega, Francesco Vieceli Prata, Cecilia Nguyen, Tam L. Bai, Ruoli Hamel, Ernest TI Cytotoxic activities of substituted 3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones and studies on their mechanisms of action SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Oxindole; Knoevenagel reaction; Antiproliferative activity; NADPH oxidase 4; Tubulin assembly ID NADPH OXIDASE 4; ANTITUMOR-ACTIVITY; 3-SUBSTITUTED INDOLIN-2-ONES; CANCER-CELLS; APOPTOSIS; OXINDOLE; TUBULIN; ANGIOGENESIS; DERIVATIVES; INHIBITORS AB The synthesis of new trimethoxybenzylidene-indolinones is reported. Their cytotoxic activity was evaluated according to Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, drug screen protocols. The study of the mechanism of action suggests that inhibition of Nox4 in B1647 cells (acute myeloid leukemia) could contribute to the antiproliferative effect of some compounds. Moreover, inhibition of tubulin assembly was observed for the most cytotoxic compound, and the structural basis for this activity was delineated by binding models. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Andreani, Aldo; Granaiola, Massimiliano; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla; Dalla Sega, Francesco Vieceli; Prata, Cecilia] Univ Bologna, Dipartimento Farm & Biotecnol FaBiT, I-40126 Bologna, Italy. [Nguyen, Tam L.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. [Bai, Ruoli; Hamel, Ernest] Frederick Natl Lab Canc Res, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Rambaldi, M (reprint author), Univ Bologna, Dipartimento Farm & Biotecnol FaBiT, Via Belmeloro 6, I-40126 Bologna, Italy. EM mirella.rambaldi@unibo.it FU University of Bologna, Italy (RFO); MIUR (PRIN) FX This work has been supported by a grant from the University of Bologna, Italy (RFO), and from MIUR (PRIN 2009). We are grateful to the National Cancer Institute (Bethesda, MD) for the anticancer tests. We are grateful to Prof. Laura Landi for her scientific suggestions and comments, which have contributed to the performance of this study. NR 35 TC 1 Z9 1 U1 0 U2 11 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD JUN PY 2013 VL 64 BP 603 EP 612 DI 10.1016/j.ejmech.2013.03.033 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 175KT UT WOS:000321230300058 PM 23685944 ER PT J AU Ballew, BJ Savage, SA AF Ballew, Bari J. Savage, Sharon A. TI Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE aplastic anemia; cerebroretinal microangiopathy with calcification and cyst; Coats plus; congenital; dyskeratosis; Hoyeraal-Hreidarsson syndrome; inherited bone marrow failure syndrome; pulmonary fibrosis; Revesz syndrome; shelterin; telomerase; telomere; telomere biology disorder ID BONE-MARROW FAILURE; STEM-CELL TRANSPLANTATION; IDIOPATHIC PULMONARY-FIBROSIS; HOYERAAL-HREIDARSSON-SYNDROME; REVERSE-TRANSCRIPTASE; APLASTIC-ANEMIA; ANTITHYMOCYTE GLOBULIN; CEREBELLAR HYPOPLASIA; CONDITIONING REGIMEN; MUTATIONS AB Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by aberrant telomere biology. The mucocutaneous triad of nail dysplasia, abnormal skin pigmentation and oral leukoplakia is diagnostic, but is not always present; DC can also be diagnosed by the presence of very short leukocyte telomeres. Patients with DC are at high risk of bone marrow failure, pulmonary fibrosis, liver disease, cancer and other medical problems. Germline mutations in one of nine genes associated with telomere maintenance are present in approximately 60% of patients. DC is one among the group of clinically and biologically related telomere biology disorders, including Hoyeraal-Hreidarsson syndrome, Revesz syndrome, Coats plus (also known as cranioretinal microangiopathy with calcifications and cysts) and subsets of aplastic anemia, pulmonary fibrosis, nonalcoholic and noninfectious liver disease and leukemia. The authors review the pathobiology that connects DC and the related telomere biology disorders, methods of diagnosis and management modalities. C1 [Ballew, Bari J.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS 7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 94 TC 40 Z9 45 U1 3 U2 21 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD JUN PY 2013 VL 6 IS 3 BP 327 EP 337 DI 10.1586/EHM.13.23 PG 11 WC Hematology SC Hematology GA 168LG UT WOS:000320706600018 PM 23782086 ER PT J AU Staudt, LM AF Staudt, Louis M. TI Therapy of DLBCL based on genomics SO HEMATOLOGICAL ONCOLOGY LA English DT Article DE B-cell receptor (BCR); lenalidomide; ibrutinib; NFkB; MYD88; bortezomib ID B-CELL LYMPHOMA; MOLECULAR SUBTYPES; PATHOGENESIS C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, Bldg 10-4N114 NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov NR 15 TC 9 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0278-0232 J9 HEMATOL ONCOL JI Hematol. Oncol. PD JUN PY 2013 VL 31 SU 1 SI SI BP 26 EP 28 DI 10.1002/hon.2062 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 165GX UT WOS:000320472600002 PM 23775644 ER PT J AU Subbarao, K AF Subbarao, K. TI Pandemic influenza: Lessons from 2009 and future challenges SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Meeting Abstract CT 28th International Congress of Chemotherapy and Infection Incorporating / 14th Asia-Pacific Congress of Clinical Microbiology and Infection CY JUN 05-08, 2013 CL Yokohama, JAPAN SP Int Soc Chemotherapy C1 [Subbarao, K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD JUN PY 2013 VL 42 SU 2 BP S8 EP S8 PG 1 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 178KS UT WOS:000321447400023 ER PT J AU Martin, R Safaee, SD Somsamouth, K Mounivong, B Sinclair, R Bansal, S Singh, PN AF Martin, Robyn Safaee, Sahar D. Somsamouth, Khamphithoun Mounivong, Boualoy Sinclair, Ryan Bansal, Shweta Singh, Pramil N. TI Mixed Methods Pilot Study of Sharing Behaviors among Waterpipe Smokers of Rural Lao PDR: Implications for Infectious Disease Transmission SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE infectious disease; waterpipe; mode of transmission; person-to-person; communicable ID TOBACCO SMOKING; NARGHILE SMOKING; BIRTH-WEIGHT; HEALTH; PIPE; TUBERCULOSIS; MARIJUANA; EPIDEMIC; NICOTINE; OUTCOMES AB To date, the sharing behaviors associated with the homemade tobacco waterpipe used in rural areas of the Western Pacific Region have not been studied. Evidence from studies of manufactured waterpipes raises the possibility of infectious disease transmission due to waterpipe sharing. The objective of our pilot study in rural Lao People's Democratic Republic (PDR) was to identify and measure the prevalence of waterpipe sharing behaviors. We first conducted ethnographic studies to investigate waterpipe-smoking behaviors. These findings were then used to develop an interviewer-administered household survey that was used in a sampling of waterpipe smokers from three villages of the Luang Namtha province of Lao PDR (n = 43). Sampled waterpipe smokers were predominantly male (90.7%), older (mean age 49, SD 13.79), married (95.4%), farmers (78.6%), and had completed no primary education. Pipes were primarily made from bamboo (92.9%). Almost all (97.6%) smokers were willing to share their pipe with others. At the last time they smoked, smokers shared a pipe with at least one other person (1.2 +/- 0.5 persons). During the past week, they had shared a pipe with five other persons (5.2 +/- 3.8 persons). The high prevalence of sharing behaviors among waterpipe smokers in rural Southeast Asia raises the possibility that this behavior provides important and unmeasured social network pathways for the transmission of infectious agents. C1 [Martin, Robyn; Safaee, Sahar D.; Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Loma Linda, CA 92350 USA. [Martin, Robyn; Safaee, Sahar D.; Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Dept Global Hlth, Loma Linda, CA 92350 USA. [Somsamouth, Khamphithoun; Mounivong, Boualoy] Minist Hlth, Ctr Informat & Educ Hlth, Viangchan, Laos. [Sinclair, Ryan] Loma Linda Univ, Sch Publ Hlth, Dept Environm Hlth, Loma Linda, CA 92350 USA. [Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. RP Singh, PN (reprint author), Loma Linda Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Loma Linda, CA 92350 USA. EM robmartin@llu.edu; sdsafaee@gmail.com; ksomsamut@hotmail.com; mounivong_99@hotmail.com; rsinclair@llu.edu; shweta@sbansal.com; psingh@llu.edu OI Bansal, Shweta/0000-0002-1740-5421 FU Fogarty/NIH [R03 TWOO7345-01] FX The authors are grateful for the assistance of Scott Rawson of the Adventist Development and Relief Agency in Lao. We are also grateful to the people of Luang Nam Tha district for their time and willingness to participate in our study. Funding: This study was supported by grant R03 TWOO7345-01 from Fogarty/NIH (PI: Pramil Singh). Ethic Approval: Ethics review and approval was obtained by the Institutional Review Board of Loma Linda University and the Ethics Committee on Research, Ministry of Health, Vientiane Capital, Lao PDR. Participant Consent: Obtained. NR 37 TC 7 Z9 7 U1 1 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUN PY 2013 VL 10 IS 6 BP 2120 EP 2132 DI 10.3390/ijerph10062120 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 169IE UT WOS:000320772800002 PM 23708049 ER PT J AU McDermott, MM Carroll, TJ Kibbe, M Kramer, CM Liu, K Guralnik, JM Keeling, AN Criqui, MH Ferrucci, L Yuan, C Tian, L Liao, YH Berry, J Zhao, LH Carr, J AF McDermott, Mary M. Carroll, Timothy J. Kibbe, Melina Kramer, Christopher M. Liu, Kiang Guralnik, Jack M. Keeling, Aoife N. Criqui, Michael H. Ferrucci, Luigi Yuan, Chun Tian, Lu Liao, Yihua Berry, Jarret Zhao, Lihui Carr, James TI Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerotic plaque; intermittent claudication; peripheral arterial disease; physical functioning ID MR-ANGIOGRAPHY; CLASSIFICATION; OSTEOARTHRITIS; ISCHEMIA; HINDLIMB; CRITERIA; INDEX; SIZE AB OBJECTIVES We studied associations of magnetic resonance imaging (MRI)-measured superficial femoral artery (SFA) occlusions with functional performance, leg symptoms, and collateral vessel number in peripheral artery disease (PAD). We studied associations of collateral vessel number with functional performance in PAD. BACKGROUND Associations of MRI-detected SFA occlusion and collateral vessel number with functional performance among individuals with PAD have not been reported. METHODS A total of 457 participants with an ankle brachial index (ABI) <1.00 had MRI measurement of the proximal SFA with 12 consecutive 2.5-mu m cross-sectional images. An occluded SFA was defined as an SFA in which at least 1 segment was occluded. A nonoccluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography. Lower extremity functional performance was measured with the 6-min walk, 4-m walking velocity at usual and fastest pace, and the Short Physical Performance Battery (SPPB) (0 to 12 scale, 12 = best). RESULTS Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer 6-min walk performance (1,031 vs. 1,169 feet, p = 0.006), slower fast-paced walking velocity (1.15 vs. 1.22 m/s, p = 0.042), and lower SPPB score (9.07 vs. 9.75, p = 0.038) compared with the absence of an SFA occlusion. More numerous collateral vessels were associated with better 6-min walk performance (0 to 3 collaterals-1,064 feet, 4 to 7 collaterals-1,165 feet, >= 8 collaterals-1,246 feet, p trend = 0.007), faster usual-paced walking speed (0 to 3 collaterals-0.84 m/s, 4 to 7 collaterals-0.88 m/s, >= 8 collaterals-0.91 m/s, p trend = 0.029), and faster rapid-paced walking speed (0 to 3 collaterals-1.17 m/s, 4 to 7 collaterals-1.22 m/s, >= 8 collaterals-1.29 m/s, p trend = 0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders. CONCLUSIONS Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, whereas more numerous collaterals are associated with better functional performance. (Magnetic Resonance Imaging to Identify Characteristics of Plaque Build-Up in People With Peripheral Arterial Disease; NCT00520312) (c) 2013 by the American College of Cardiology Foundation C1 [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Liao, Yihua; Zhao, Lihui] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Carroll, Timothy J.; Carr, James] Northwestern Univ, Feinberg Sch Med, Dept Radiol, Chicago, IL 60611 USA. [Carroll, Timothy J.] Northwestern Univ, Dept Biomed Engn & Radiol, Chicago, IL 60611 USA. [Kibbe, Melina] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Kibbe, Melina] Jesse Brown VA Med Ctr, Div Vasc Surg, Chicago, IL USA. [Kramer, Christopher M.] Univ Virginia, Dept Med, Div Cardiol, Charlottesville, VA USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Keeling, Aoife N.] Beaumont Hosp, Dept Radiol, Dublin 9, Ireland. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Yuan, Chun] Univ Washington, Dept Radiol Elect Engn & Bioengn, Seattle, WA 98195 USA. [Yuan, Chun] Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. [Tian, Lu] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Berry, Jarret] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Med, Dallas, TX 75390 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu RI Carroll, Timothy/B-6934-2009 FU National Heart Lung and Blood Institute [R01-HL083064, R01-HL109244]; Intramural Research Program of the National Institute on Aging; Jesse Brown VA Medical Center; Siemens Healthcare; VP Diagnostics; Philips Healthcare; Siemens; Lantheus Medical Imaging FX From the *Department of Medicine, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; dagger Department of Preventive Medicine, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; double dagger Department of Radiology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois; Department of Biomedical Engineering and Radiology, Northwestern University, Chicago, Illinois; parallel to Department of Surgery, Northwestern University, Chicago, Illinois; Division of Vascular Surgery, Jesse Brown VA Medical Center, Chicago, Illinois; #Division of Cardiology, Department of Medicine, University of Virginia, Charlottesville, Virginia; **Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; dagger dagger Department of Radiology, Beaumont Hospital, Dublin, Ireland; double dagger double dagger Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California; Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland; parallel to parallel to Department of Radiology, Electrical Engineering, and Bioengineering, University of Washington, Seattle, Washington; Department of Radiology, University of Washington School of Medicine, Seattle, Washington; ##Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; and the ***Division of Cardiology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Supported by the National Heart Lung and Blood Institute (R01-HL083064) and (R01-HL109244), the Intramural Research Program of the National Institute on Aging, and the Jesse Brown VA Medical Center. Dr. Kramer receives research support from Siemens Healthcare. Dr. Yuan receives research support from VP Diagnostics and from Philips Healthcare; and is a consultant for ImagePace. Dr. Berry is on the Speakers' Bureau of Merck. Dr. Carr receives research support from Siemens and Lantheus Medical Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUN PY 2013 VL 6 IS 6 BP 687 EP 694 DI 10.1016/j.jcmg.2012.10.024 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 172CI UT WOS:000320977200008 PM 23647796 ER PT J AU Shechner, T Wakschlag, N Britton, JC Jarcho, J Ernst, M Pine, DS AF Shechner, Tomer Wakschlag, Naomi Britton, Jennifer C. Jarcho, Johanna Ernst, Monique Pine, Daniel S. TI Empirical Examination of the Potential Adverse Psychological Effects Associated with Pediatric fMRI Scanning SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID CHILDHOOD BEHAVIORAL-INHIBITION; RESONANCE-IMAGING EXAMINATIONS; MAGNETIC-RESONANCE; ANXIETY DISORDERS; CLAUSTROPHOBIA; POPULATIONS; SEDATION; BENEFIT; BRAIN AB Background: Over the past decade, the number of functional magnetic resonance imaging (fMRI) studies has increased dramatically. As MRI scans may be anxiety provoking, performing them in a research setting, particularly with children already prone to anxiety, raises questions about ethics as well as methodological feasibility. It is essential to address these questions before expanding the use of this technique to clinical settings, or more widely in the context of pediatric psychopharmacology and biological psychiatry research. The current study investigates the psychological reactions of anxious and non-anxious children and non-anxious adults to an fMRI scan. Methods: Eighty-seven anxious children, 140 non-anxious children, and 98 non-anxious adults rated their emotional reactions to an fMRI scan. Results: Results indicated that anxious and non-anxious children reported no greater anxiety after fMRI scanning than did adults. In addition, no age-related differences in distress were observed. These data demonstrate that anxious children, healthy children, and healthy adults have similar emotional reactions to fMRI scanning. Conclusions: The observed findings suggest that the potential for fMRI to produce anxiety should not impede its widespread use in clinical research, psychopharmacology, and biological psychiatry. C1 [Shechner, Tomer; Wakschlag, Naomi; Jarcho, Johanna; Ernst, Monique; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. [Britton, Jennifer C.] Univ Miami, Dept Psychol, Miami, FL USA. RP Shechner, T (reprint author), NIMH, Sect Dev Affect Neurosci, 9000 Rockville Pike,Bldg 15K,Rm 208, Bethesda, MD 20892 USA. EM shechnert@mail.nih.gov RI Britton, Jennifer/J-4501-2013; OI Jarcho, Johanna/0000-0001-9075-6968 FU Intramural Research Program of the National Institute of Mental Health (NIMH) FX This research was supported in part by the Intramural Research Program of the National Institute of Mental Health (NIMH). NR 27 TC 1 Z9 1 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD JUN PY 2013 VL 23 IS 5 BP 357 EP 362 DI 10.1089/cap.2012.0076 PG 6 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 168LJ UT WOS:000320707000008 PM 23738869 ER PT J AU Shah, SK AF Shah, Seema K. TI Outsourcing Ethical Obligations: Should the Revised Common Rule Address the Responsibilities of Investigators and Sponsors? SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID BOARDS AB The Common Rule creates a division of moral labor in research. It implies that investigators and sponsors can outsource their ethical obligations to IRBs and participants, thereby fostering a culture of compliance, rather than one of responsibility. The proposed revisions to the Common Rule are likely to exacerbate this problem. To harness the expressive power of the law, I propose the Common Rule be revised to include the ethical responsibilities of investigators and sponsors. C1 NIH, Div Aids, Bethesda, MD USA. RP Shah, SK (reprint author), NIH, Div Aids, Bethesda, MD USA. FU Intramural Research Program of the NIH in the Warren G. Magnussen Clinical Center; University of Maryland Carey Law School's Law & Health Care Program; Johns Hopkins Berman Institute of Bioethics FX This research was supported by the Intramural Research Program of the NIH, in the Warren G. Magnussen Clinical Center. The opinions expressed here are the views of the author. They do not represent any position or policy of the U.S. National Institutes of Health, the Public Health Service, or the Department of Health and Human Services. The author would like to thank Alan Wertheimer, Govind Persad, Annette Rid, Harry Surden, Diane Hoffmann, Leslie Meltzer Henry, Holly Fernandez Lynch, an anonymous peer reviewer, the participants in the 2012 Health Law and Bioethics Roundtable (co-sponsored by University of Maryland Carey Law School's Law & Health Care Program and the Johns Hopkins Berman Institute of Bioethics), and the participants in the "The Future of Human Subjects Research Regulation" conference at the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics at Harvard Law School for their helpful comments and suggestions. NR 51 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SUM PY 2013 VL 41 IS 2 SI SI BP 397 EP 410 DI 10.1111/jlme.12051 PG 14 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 171MR UT WOS:000320934000003 PM 23802893 ER PT J AU Eggly, S Meert, KL Berger, J Zimmerman, J Anand, KJS Newth, CJL Harrison, R Carcillo, J Dean, JM Willson, DF Nicholson, C AF Eggly, Susan Meert, Kathleen L. Berger, John Zimmerman, Jerry Anand, K. J. S. Newth, Christopher J. L. Harrison, Rick Carcillo, Joseph Dean, J. Michael Willson, Douglas F. Nicholson, Carol CA Eunice Kennedy Shriver Natl Inst C TI Physicians' Conceptualization of "Closure" as a Benefit of Physician-Parent Follow-up Meetings after a Child's Death in the Pediatric Intensive Care Unit SO JOURNAL OF PALLIATIVE CARE LA English DT Article ID BEREAVED PARENTS; GRIEF; LIFE; PERSPECTIVES; RESILIENCE; CAREGIVER; PROVIDERS; RECOVERY; EVENTS; SENSE AB We examined physicians' conceptualization of closure as a benefit of follow-up meetings with bereaved parents. The frequency of use and the meaning of the word "closure" were analyzed in transcripts of interviews with 67 critical care physicians affiliated with the Collaborative Pediatric Critical Care Research Network. In all, 38 physicians (57 percent) used the word "closure" at least once (median: 2; range: 1 to 7), for a total of 86 times. Physicians indicated that closure is a process or trajectory rather than an achievable goal. They also indicated that parents and physicians can move toward closure by gaining a better understanding of the causes and circumstances of the death and by reconnecting with, or resolving relationships between, parents and health professionals. Physicians suggested that a primary reason to conduct follow-up meetings is that such meetings offer parents and physicians an opportunity to move toward closure. Future research should attempt to determine whether followup meetings reduce the negative effects of bereavement for parents and physicians. C1 [Meert, Kathleen L.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Berger, John] Childrens Natl Med Ctr, Crit Care Unit, Washington, DC 20010 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Anand, K. J. S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Anand, K. J. S.] Le Bonheur Childrens Hosp, Memphis, TN USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, Rick] Childrens Hosp Los Angeles, Mattel Childrens Hosp, Los Angeles, CA 90027 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Dean, J. Michael] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Willson, Douglas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] Natl Inst Child Hlth & Human Dev, Pediat Crit Care & Rehabil Program, Bethesda, MD USA. RP Eggly, S (reprint author), Wayne State Univ, Dept Oncol, 4100 John R St,MMO3CB, Detroit, MI 48201 USA. EM egglys@karmanos.org OI Anand, Kanwaljeet/0000-0001-6498-1483 FU National Institute of Child Health and Human Development; US Department of Health and Human Services [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10-HD050012, U01HD049934] FX This study was funded through cooperative agreements of the National Institute of Child Health and Human Development and the US Department of Health and Human Services (U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10-HD050012, and U01HD049934). The authors have no other financial relationships to disclose in relation to this manuscript. NR 38 TC 5 Z9 5 U1 0 U2 9 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD SUM PY 2013 VL 29 IS 2 BP 69 EP 75 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 177YU UT WOS:000321412100002 PM 23923469 ER PT J AU Cohen, L AF Cohen, Leonardo TI Off-line motor memory processing from mechanism to rehabilitation-Mechanisms of post stroke neuroplasticity SO JOURNAL OF SPORT & EXERCISE PSYCHOLOGY LA English DT Meeting Abstract C1 [Cohen, Leonardo] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 0895-2779 J9 J SPORT EXERCISE PSY JI J. Sport Exerc. Psychol. PD JUN PY 2013 VL 35 SU S BP S11 EP S11 PG 1 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 186PI UT WOS:000322056200028 ER PT J AU Meltzer, JA Wagage, S Ryder, J Solomon, B Braun, AR AF Meltzer, Jed A. Wagage, Suraji Ryder, Jennifer Solomon, Beth Braun, Allen R. TI Adaptive significance of right hemisphere activation in aphasic language comprehension SO NEUROPSYCHOLOGIA LA English DT Article DE Language; Aphasia; Magnetoencephalography; Stroke; Syntax ID POSITRON-EMISSION-TOMOGRAPHY; VERBAL WORKING-MEMORY; SENTENCE COMPREHENSION; POSTSTROKE APHASIA; SYNTACTIC COMPREHENSION; BROCAS APHASIA; PET ACTIVATION; FRONTAL-CORTEX; BOLD RESPONSE; NEURAL BASIS AB Aphasic patients often exhibit increased right hemisphere activity during language tasks. This may represent takeover of function by regions homologous to the left-hemisphere language networks, maladaptive interference, or adaptation of alternate compensatory strategies. To distinguish between these accounts, we tested language comprehension in 25 aphasic patients using an online sentence-picture matching paradigm while measuring brain activation with MEG. Linguistic conditions included semantically irreversible ("The boy is eating the apple") and reversible ("The boy is pushing the girl") sentences at three levels of syntactic complexity. As expected, patients performed well above chance on irreversible sentences, and at chance on reversible sentences of high complexity. Comprehension of reversible non-complex sentences ranged from nearly perfect to chance, and was highly correlated with offline measures of language comprehension. Lesion analysis revealed that comprehension deficits for reversible sentences were predicted by damage to the left temporal lobe. Although aphasic patients activated homologous areas in the right temporal lobe, such activation was not correlated with comprehension performance. Rather, patients with better comprehension exhibited increased activity in dorsal fronto-parietal regions. Correlations between performance and dorsal network activity occurred bilaterally during perception of sentences, and in the right hemisphere during a post-sentence memory delay. These results suggest that effortful reprocessing of perceived sentences in short-term memory can support improved comprehension in aphasia, and that strategic recruitment of alternative networks, rather than homologous takeover, may account for some findings of right hemisphere language activation in aphasia. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Meltzer, Jed A.] Baycrest Ctr Geriatr Care, Rotman Res Inst, Toronto, ON, Canada. [Meltzer, Jed A.; Wagage, Suraji; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD USA. [Ryder, Jennifer; Solomon, Beth] NIH, Speech Language Pathol Sect, Dept Rehabil Med, MO Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Meltzer, JA (reprint author), Baycrest Ctr Geriatr Care, Rotman Res Inst, 3560 Bathurst St, Toronto, ON, Canada. EM jmeltzer@research.baycrest.org OI Meltzer, Jed/0000-0002-4301-1901 FU National Institute on Deafness and Other Communication Disorders FX This research was supported by the Intramural Program of the National Institute on Deafness and Other Communication Disorders. NR 66 TC 8 Z9 8 U1 6 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUN PY 2013 VL 51 IS 7 BP 1248 EP 1259 DI 10.1016/j.neuropsychologia.2013.03.007 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 179RQ UT WOS:000321539400013 PM 23566891 ER PT J AU Doroshow, JH Sleijfer, S Stupp, R Anderson, K AF Doroshow, James H. Sleijfer, Stefan Stupp, Roger Anderson, Kenneth TI Cancer Clinical Trials-Do We Need a New Algorithm in the Age of Stratified Medicine? SO ONCOLOGIST LA English DT Editorial Material C1 [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Sleijfer, Stefan] Erasmus Univ, Med Ctr, Inst Canc, Rotterdam, Netherlands. [Sleijfer, Stefan] Netherlands Ctr, Rotterdam, Netherlands. [Stupp, Roger] Univ Lausanne, Dept Clin Neurosci, Lausanne, Switzerland. [Stupp, Roger] Univ Zurich Hosp, Ctr Canc, CH-8091 Zurich, Switzerland. [Stupp, Roger] EORTC, Brussels, Belgium. [Anderson, Kenneth] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Anderson, Kenneth] Dana Farber Canc Inst, Kraft Family Blood Ctr, Boston, MA 02115 USA. RP Doroshow, JH (reprint author), NCI, NIH, Bldg 31,Room 3A-44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov NR 5 TC 4 Z9 4 U1 0 U2 3 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD JUN PY 2013 VL 18 IS 6 BP 651 EP 652 DI 10.1634/theoncologist.2013-0190 PG 2 WC Oncology SC Oncology GA 172YL UT WOS:000321043200006 PM 23814160 ER PT J AU Ballard-Barbash, R George, SM Alfano, CM Schmitz, K AF Ballard-Barbash, Rachel George, Stephanie M. Alfano, Catherine M. Schmitz, Kathryn TI Physical Activity Across the Cancer Continuum THE LEMANNE/CASSILETH/GUBILI ARTICLE REVIEWED SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 [Ballard-Barbash, Rachel; George, Stephanie M.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schmitz, Kathryn] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 1 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 2013 VL 27 IS 6 BP 589 EP + PG 2 WC Oncology SC Oncology GA 174MH UT WOS:000321159200016 PM 23909075 ER PT J AU Indzhykulian, AA Stepanyan, R Nelina, A Spinelli, KJ Ahmed, ZM Belyantseva, IA Friedman, TB Barr-Gillespie, PG Frolenkov, GI AF Indzhykulian, Artur A. Stepanyan, Ruben Nelina, Anastasiia Spinelli, Kateri J. Ahmed, Zubair M. Belyantseva, Inna A. Friedman, Thomas B. Barr-Gillespie, Peter G. Frolenkov, Gregory I. TI Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells SO PLOS BIOLOGY LA English DT Article ID SYNDROME TYPE 1D; MOUSE INNER-EAR; SENSORY TRANSDUCTION; FAST ADAPTATION; GUINEA-PIG; DEVELOPMENTAL ACQUISITION; MECHANICAL TRANSDUCTION; PROTOCADHERIN GENE; KINOCILIAL LINKS; COHERENT MOTION AB Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca2+-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery. C1 [Indzhykulian, Artur A.; Stepanyan, Ruben; Nelina, Anastasiia; Frolenkov, Gregory I.] Univ Kentucky, Dept Physiol, Lexington, KY USA. [Spinelli, Kateri J.; Barr-Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97201 USA. [Ahmed, Zubair M.] Cincinnati Childrens Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH USA. [Friedman, Thomas B.] NIDCD, Mol Genet Lab, NIH, Rockville, MD USA. RP Indzhykulian, AA (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. EM Gregory.Frolenkov@uky.edu OI Indzhykulian, Artur/0000-0002-2076-6818; Spinelli, Kateri/0000-0002-6290-0886; Frolenkov, Gregory/0000-0002-9810-5024; Barr-Gillespie, Peter/0000-0002-9787-5860 FU NIDCD/NIH [R01 DC008861, R01 DC002368, P30 DC005983, DC000048-15, R01 DC012564] FX This study was supported by NIDCD/NIH grants: R01 DC008861 to G.I.F.; R01 DC002368 and P30 DC005983 to P.G.B-G.; NIDCD/NIH intramural funds DC000048-15 to T.B.F.; and R01 DC012564 to Z.M.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 37 Z9 39 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JUN PY 2013 VL 11 IS 6 AR e1001583 DI 10.1371/journal.pbio.1001583 PG 15 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 172YJ UT WOS:000321042900010 PM 23776407 ER PT J AU Andrus, J Bottazzi, ME Chow, J Goraleski, KA Fisher-Hoch, SP Lambuth, JK Lee, BY Margolis, HS McCormick, JB Melby, P Murray, KO Rico-Hesse, R Valenzuela, JG Hotez, PJ AF Andrus, Jon Bottazzi, Maria Elena Chow, Jennifer Goraleski, Karen A. Fisher-Hoch, Susan P. Lambuth, Jocelyn K. Lee, Bruce Y. Margolis, Harold S. McCormick, Joseph B. Melby, Peter Murray, Kristy O. Rico-Hesse, Rebeca Valenzuela, Jesus G. Hotez, Peter J. TI Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Editorial Material ID WEST-NILE-VIRUS; TROPICAL DISEASES; CHAGAS-DISEASE; UNITED-STATES; RISK-FACTORS; VISCERAL LEISHMANIASIS; TRYPANOSOMA-CRUZI; EPIDEMIC DENGUE; NORTH-AMERICA; MEXICO BORDER C1 [Andrus, Jon] WHO, Pan Amer Hlth Org, Washington, DC USA. [Bottazzi, Maria Elena; Lambuth, Jocelyn K.; Murray, Kristy O.; Rico-Hesse, Rebeca; Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Houston, TX 77030 USA. [Bottazzi, Maria Elena; Hotez, Peter J.] Sabin Vaccine Inst, Houston, TX USA. [Bottazzi, Maria Elena; Hotez, Peter J.] Texas Childrens Hosp Ctr Vaccine Dev, Houston, TX USA. [Chow, Jennifer] Res Amer, Alexandria, VA USA. [Goraleski, Karen A.] Amer Soc Trop Med & Hyg, Deerfield, IL USA. [Fisher-Hoch, Susan P.; McCormick, Joseph B.] Univ Texas Brownsville, Sch Publ Hlth, Brownsville, TX 78520 USA. [Lee, Bruce Y.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Margolis, Harold S.] Ctr Dis Control & Prevent, Dengue Branch, San Juan, PR USA. [Melby, Peter] Univ Texas Med Branch, Galveston, TX 77555 USA. [Valenzuela, Jesus G.] NIAID, NIH, Rockville, MD USA. [Hotez, Peter J.] Rice Univ, James A Baker III Inst Publ Policy, Houston, TX USA. RP Andrus, J (reprint author), WHO, Pan Amer Hlth Org, Washington, DC USA. EM hotez@bcm.edu OI Hotez, Peter/0000-0001-8770-1042 FU NIAID NIH HHS [R01 AI099483] NR 70 TC 6 Z9 6 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUN PY 2013 VL 7 IS 6 AR e2021 DI 10.1371/journal.pntd.0002021 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 175AL UT WOS:000321201300001 PM 23826397 ER PT J AU Harding-Esch, EM Sillah, A Edwards, T Burr, SE Hart, JD Joof, H Laye, M Makalo, P Manjang, A Molina, S Sarr-Sissoho, I Quinn, TC Lietman, T Holland, MJ Mabey, D West, SK Bailey, R AF Harding-Esch, Emma M. Sillah, Ansumana Edwards, Tansy Burr, Sarah E. Hart, John D. Joof, Hassan Laye, Mass Makalo, Pateh Manjang, Ahmed Molina, Sandra Sarr-Sissoho, Isatou Quinn, Thomas C. Lietman, Tom Holland, Martin J. Mabey, David West, Sheila K. Bailey, Robin CA Partnership Rapid Elimination Trac TI Mass Treatment with Azithromycin for Trachoma: When Is One Round Enough? Results from the PRET Trial in The Gambia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID OCULAR CHLAMYDIA-TRACHOMATIS; ACTIVE TRACHOMA; ANTIBIOTIC-TREATMENT; INFECTIOUS TRACHOMA; RISK-FACTORS; COMMUNITY; PREVALENCE; TANZANIA; ELIMINATION; STRATEGIES AB Background: The World Health Organization has recommended three rounds of mass drug administration (MDA) with antibiotics in districts where the prevalence of follicular trachoma (TF) is >= 10% in children aged 1-9 years, with treatment coverage of at least 80%. For districts at 5-10% TF prevalence it was recommended that TF be assessed in 1-9 year olds in each community within the district, with three rounds of MDA provided to any community where TF >= 10%. Worldwide, over 40 million people live in districts whose TF prevalence is estimated to be between 5 and 10%. The best way to treat these districts, and the optimum role of testing for infection in deciding whether to initiate or discontinue MDA, are unknown. Methods: In a community randomized trial with a factorial design, we randomly assigned 48 communities in four Gambian districts, in which the prevalence of trachoma was known or suspected to be above 10%, to receive annual mass treatment with expected coverage of 80-89% ("Standard"), or to receive an additional visit in an attempt to achieve coverage of 90% or more ("Enhanced"). The same 48 communities were randomised to receive mass treatment annually for three years ("3x"), or to have treatment discontinued if Chlamydia trachomatis (Ct) infection was not detected in a sample of children in the community after mass treatment (stopping rule("SR")). Primary outcomes were the prevalence of TF and of Ct infection in 0-5 year olds at 36 months. Results: The baseline prevalence of TF and of Ct infection in the target communities was 6.5% and 0.8% respectively. At 36 months the prevalence of TF was 2.8%, and that of Ct infection was 0.5%. No differences were found between the arms in TF or Ct infection prevalence either at baseline (Standard-3x: TF 5.6%, Ct 0.7%; Standard-SR: TF 6.1%, Ct 0.2%; Enhanced-3x: TF 7.4%, Ct 0.9%; and Enhanced-SR: TF 6.2%, Ct 1.2%); or at 36 months (Standard-3x: TF 2.3%, Ct 1.0%; Standard-SR TF 2.5%, Ct 0.2%; Enhanced-3x TF 3.0%, Ct 0.2%; and Enhanced-SR TF 3.2%, Ct 0.7%). The implementation of the stopping rule led to treatment stopping after one round of MDA in all communities in both SR arms. Mean treatment coverage of children aged 0-9 in communities randomised to standard treatment was 87.7% at baseline and 84.8% and 88.8% at one and two years, respectively. Mean coverage of children in communities randomized to enhanced treatment was 90.0% at baseline and 94.2% and 93.8% at one and two years, respectively. There was no evidence of any difference in TF or Ct prevalence at 36 months resulting from enhanced coverage or from one round of MDA compared to three. Conclusions: The Gambia is close to the elimination target for active trachoma. In districts prioritised for three MDA rounds, one round of MDA reduced active trachoma to low levels and Ct infection was not detectable in any community. There was no additional benefit to giving two further rounds of MDA. Programmes could save scarce resources by determining when to initiate or to discontinue MDA based on testing for Ct infection, and one round of MDA may be all that is necessary in some settings to reduce TF below the elimination threshold. C1 [Harding-Esch, Emma M.; Edwards, Tansy; Burr, Sarah E.; Hart, John D.; Molina, Sandra; Holland, Martin J.; Mabey, David; Bailey, Robin] London Sch Hyg & Trop Med, London WC1, England. [Sillah, Ansumana; Laye, Mass] Natl Eye Hlth Programme Gambia, Kanifing, Gambia. [Burr, Sarah E.; Hart, John D.; Joof, Hassan; Makalo, Pateh; Manjang, Ahmed; Sarr-Sissoho, Isatou; Holland, Martin J.] MRC Unit, Fajara, Gambia. [Quinn, Thomas C.] NIAID, Bethesda, MD 20892 USA. [Lietman, Tom] Univ Calif San Francisco, San Francisco, CA 94143 USA. [West, Sheila K.] Johns Hopkins Univ, Dana Ctr Prevent Ophthalmol, Baltimore, MD USA. RP Harding-Esch, EM (reprint author), London Sch Hyg & Trop Med, London WC1, England. EM Robin.Bailey@lshtm.ac.uk OI Mabey, David/0000-0002-0031-8276 FU Bill and Melinda Gates Foundation FX This study was funded by a grant from the Bill and Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 16 Z9 16 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUN PY 2013 VL 7 IS 6 AR e2115 DI 10.1371/journal.pntd.0002115 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 175AL UT WOS:000321201300003 PM 23785525 ER PT J AU Hertz, T Ahmed, H Friedrich, DP Casimiro, DR Self, SG Corey, L McElrath, MJ Buchbinder, S Horton, H Frahm, N Robertson, MN Graham, BS Gilbert, P AF Hertz, Tomer Ahmed, Hasan Friedrich, David P. Casimiro, Danilo R. Self, Steven G. Corey, Lawrence McElrath, M. Juliana Buchbinder, Susan Horton, Helen Frahm, Nicole Robertson, Michael N. Graham, Barney S. Gilbert, Peter TI HIV-1 Vaccine-Induced T-Cell Reponses Cluster in Epitope Hotspots that Differ from Those Induced in Natural Infection with HIV-1 SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; I-PEPTIDE BINDING; ADENOVIRUS TYPE-5; RESPONSES; IMMUNITY; TRIALS; CANDIDATE; STEP; IMMUNOGENICITY; SAFETY AB Several recent large clinical trials evaluated HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5) vectors expressing HIV-derived antigens. These vaccines primarily elicited T-cell responses, which are known to be critical for controlling HIV infection. In the current study, we present a meta-analysis of epitope mapping data from 177 participants in three clinical trials that tested two different HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level epitope responses in these trials by generating population-based epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1) Are vaccine-induced responses randomly distributed across vaccine inserts, or do they cluster into immunodominant epitope hotspots? (2) Are the immunodominance patterns observed for these two vaccines in three vaccine trials different from one another? (3) Do vaccine-induced hotspots overlap with epitope hotspots induced by chronic natural infection with HIV-1? (4) Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5) Can epitope prediction methods be used to identify these hotspots? We found that vaccine responses clustered into epitope hotspots in all three vaccine trials and some of these hotspots were not observed in chronic natural infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same vaccine in different populations. Some of the vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5 HIV vaccine. Finally, we found that epitope prediction methods can partially predict the location of vaccine-induced epitope hotspots. Our findings have implications for vaccine design and suggest a framework by which different vaccine candidates can be compared in early phases of evaluation. C1 [Hertz, Tomer; Ahmed, Hasan; Friedrich, David P.; Self, Steven G.; Corey, Lawrence; McElrath, M. Juliana; Frahm, Nicole; Gilbert, Peter] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV Res & Prevent, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Hertz, Tomer; Ahmed, Hasan; Friedrich, David P.; Self, Steven G.; Corey, Lawrence; McElrath, M. Juliana; Frahm, Nicole; Gilbert, Peter] Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, Seattle, WA 98104 USA. [Casimiro, Danilo R.; Robertson, Michael N.] Merck Res Labs, West Point, PA USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, HIV Res Sect, San Francisco, CA USA. [Horton, Helen] Seattle Biomed Res Inst, Viral Vaccine Program, Seattle, WA 98109 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hertz, T (reprint author), Fred Hutchinson Canc Res Ctr, Stat Ctr HIV Res & Prevent, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM thertz@fhcrc.org RI Hertz, Tomer/S-5744-2016 OI Hertz, Tomer/0000-0002-0561-1578 FU NIH K25 award [K25 AI087397-01] FX The study was funded by an NIH K25 award K25 AI087397-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 11 Z9 11 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2013 VL 9 IS 6 AR e1003404 DI 10.1371/journal.ppat.1003404 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 175CG UT WOS:000321206600016 PM 23818843 ER PT J AU Josefsson, L Palmer, S Faria, NR Lemey, P Casazza, J Ambrozak, D Kearney, M Shao, W Kottilil, S Sneller, M Mellors, J Coffin, JM Maldarelli, F AF Josefsson, Lina Palmer, Sarah Faria, Nuno R. Lemey, Philippe Casazza, Joseph Ambrozak, David Kearney, Mary Shao, Wei Kottilil, Shyamasundaran Sneller, Michael Mellors, John Coffin, John M. Maldarelli, Frank TI Single Cell Analysis of Lymph Node Tissue from HIV-1 Infected Patients Reveals that the Majority of CD4(+) T-cells Contain One HIV-1 DNA Molecule SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VIVO; ANTIRETROVIRAL THERAPY; PERIPHERAL-BLOOD; REVERSE-TRANSCRIPTASE; INFECTED INDIVIDUALS; TYPE-1; RECOMBINATION; LYMPHOCYTES; MEMORY AB Genetic recombination contributes to the diversity of human immunodeficiency virus (HIV-1). Productive HIV-1 recombination is, however, dependent on both the number of HIV-1 genomes per infected cell and the genetic relationship between these viral genomes. A detailed analysis of the number of proviruses and their genetic relationship in infected cells isolated from peripheral blood and tissue compartments is therefore important for understanding HIV-1 recombination, genetic diversity and the dynamics of HIV-1 infection. To address these issues, we used a previously developed single-cell sequencing technique to quantify and genetically characterize individual HIV-1 DNA molecules from single cells in lymph node tissue and peripheral blood. Analysis of memory and naive CD4(+) T cells from paired lymph node and peripheral blood samples from five untreated chronically infected patients revealed that the majority of these HIV-1-infected cells (>90%) contain only one copy of HIV-1 DNA, implying a limited potential for productive recombination in virus produced by these cells in these two compartments. Phylogenetic analysis revealed genetic similarity of HIV-1 DNA in memory and naive CD4(+) T-cells from lymph node, peripheral blood and HIV-1 RNA from plasma, implying exchange of virus and/or infected cells between these compartments in untreated chronic infection. C1 [Josefsson, Lina; Palmer, Sarah] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Solna, Sweden. [Josefsson, Lina; Palmer, Sarah] Swedish Inst Communicable Dis Control, Dept Diagnost & Vaccinol, Solna, Sweden. [Josefsson, Lina; Palmer, Sarah; Kearney, Mary; Shao, Wei; Maldarelli, Frank] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Faria, Nuno R.; Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Louvain, Belgium. [Casazza, Joseph; Ambrozak, David] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kottilil, Shyamasundaran; Sneller, Michael] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Mellors, John] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Josefsson, L (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Solna, Sweden. EM Lina.josefsson@ki.se RI Faria, Nuno/I-2975-2012; OI Faria, Nuno/0000-0001-8839-2798; Rodrigues Faria, Nuno/0000-0002-9747-8822 FU NIH; National Cancer Institute, Center for Cancer Research, the National Institutes of Health; Swedish Research Council; Foundation for AIDS Research [amfAR: 107170-44-RGRL]; Erik and Edith Fernstrom Foundation for Medical Research; Sven Gard Foundation for Virology Research; Fundacao para a Ciencia e Tecnologia [SFRH/BD/64530/2009]; FM Kirby Foundation FX This study was supported by a NIH Bench to Bedside Award to FM in the HIV DRP, the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, the National Institutes of Health, the Swedish Research Council, and The Foundation for AIDS Research (amfAR: 107170-44-RGRL). LJ was supported by The Erik and Edith Fernstrom Foundation for Medical Research and Sven Gard Foundation for Virology Research. NRF was supported by Fundacao para a Ciencia e Tecnologia under grant agreement No. SFRH/BD/64530/2009. Logistical support was provided through PACT - MMC contract. JMC was a research Professor of the American Cancer Society with support from the FM Kirby Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 39 Z9 39 U1 4 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2013 VL 9 IS 6 AR e1003432 DI 10.1371/journal.ppat.1003432 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 175CG UT WOS:000321206600039 PM 23818847 ER PT J AU Kelada, S Sethupathy, P Okoye, IS Kistasis, E Czieso, S White, SD Chou, D Martens, C Ricklefs, SM Virtaneva, K Sturdevant, DE Porcella, SF Belkaid, Y Wynn, TA Wilson, MS AF Kelada, Samir Sethupathy, Praveen Okoye, Isobel S. Kistasis, Eleni Czieso, Stephanie White, Sandra D. Chou, David Martens, Craig Ricklefs, Stacy M. Virtaneva, Kimmo Sturdevant, Dan E. Porcella, Stephen F. Belkaid, Yasmine Wynn, Thomas A. Wilson, Mark S. TI miR-182 and miR-10a Are Key Regulators of Treg Specialisation and Stability during Schistosome and Leishmania-associated Inflammation SO PLOS PATHOGENS LA English DT Article ID T-CELL FUNCTION; PROTOONCOGENE C-MAF; TRANSCRIPTION FACTOR; FOXP3 GENE; IN-VITRO; TGF-BETA; EX-VIVO; DIFFERENTIATION; EXPRESSION; RESPONSES AB A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4(+)Foxp3(+) regulatory T cells (Treg) calibrate immune responses; however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA "regulatory hubs" miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFN gamma axis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFN gamma production. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4(+)Foxp3(+) cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function. C1 [Kelada, Samir; Sethupathy, Praveen] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Okoye, Isobel S.; Kistasis, Eleni; Czieso, Stephanie; Wilson, Mark S.] Natl Inst Med Res, MRC, Div Mol Immunol, London NW7 1AA, England. [White, Sandra D.; Chou, David; Belkaid, Yasmine; Wynn, Thomas A.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Martens, Craig; Ricklefs, Stacy M.; Virtaneva, Kimmo; Sturdevant, Dan E.; Porcella, Stephen F.] NIAID, Rocky Mt Labs, Res Technol Sect, Hamilton, MT 59840 USA. RP Kelada, S (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. EM mwilson@nimr.mrc.ac.uk OI Kelada, Samir/0000-0003-2676-9232 FU National Institute for Medical Research, MRC [MC_UP_A253_1028]; NIAID, NIH Intramural Programme FX This work was funded by NIAID, NIH Intramural Programme and National Institute for Medical Research, MRC (MRC File Reference number MC_UP_A253_1028). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 37 Z9 40 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2013 VL 9 IS 6 AR e1003451 DI 10.1371/journal.ppat.1003451 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 175CG UT WOS:000321206600050 PM 23825948 ER PT J AU Latorre-Margalef, N Grosbois, V Wahlgren, J Munster, VJ Tolf, C Fouchier, RAM Osterhaus, ADME Olsen, B Waldenstrom, J AF Latorre-Margalef, Neus Grosbois, Vladimir Wahlgren, John Munster, Vincent J. Tolf, Conny Fouchier, Ron A. M. Osterhaus, Albert D. M. E. Olsen, Bjorn Waldenstrom, Jonas TI Heterosubtypic Immunity to Influenza A Virus Infections in Mallards May Explain Existence of Multiple Virus Subtypes SO PLOS PATHOGENS LA English DT Article ID PATHOGENIC AVIAN INFLUENZA; HEMAGGLUTININ SUBTYPE; ANAS-PLATYRHYNCHOS; HETEROLOGOUS NEURAMINIDASE; WILD BIRDS; RT-PCR; H5N1; EVOLUTION; CHICKENS; VACCINES AB Wild birds, particularly duck species, are the main reservoir of influenza A virus (IAV) in nature. However, knowledge of IAV infection dynamics in the wild bird reservoir, and the development of immune responses, are essentially absent. Importantly, a detailed understanding of how subtype diversity is generated and maintained is lacking. To address this, 18,679 samples from 7728 Mallard ducks captured between 2002 and 2009 at a single stopover site in Sweden were screened for IAV infections, and the resulting 1081 virus isolates were analyzed for patterns of immunity. We found support for development of homosubtypic hemagglutinin (HA) immunity during the peak of IAV infections in the fall. Moreover, re-infections with the same HA subtype and related prevalent HA subtypes were uncommon, suggesting the development of natural homosubtypic and heterosubtypic immunity (p-value = 0.02). Heterosubtypic immunity followed phylogenetic relatedness of HA subtypes, both at the level of HA clades (p-value = 0.04) and the level of HA groups (p-value = 0.05). In contrast, infection patterns did not support specific immunity for neuraminidase (NA) subtypes. For the H1 and H3 Clades, heterosubtypic immunity showed a clear temporal pattern and we estimated within-clade immunity to last at least 30 days. The strength and duration of heterosubtypic immunity has important implications for transmission dynamics of IAV in the natural reservoir, where immune escape and disruptive selection may increase HA antigenic variation and explain IAV subtype diversity. C1 [Latorre-Margalef, Neus; Tolf, Conny; Waldenstrom, Jonas] Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, Kalmar, Sweden. [Grosbois, Vladimir] Int Res Ctr Agr Dev CIRAD UPR AGIRs, Montpellier, France. [Wahlgren, John] Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden. [Munster, Vincent J.; Fouchier, Ron A. M.; Osterhaus, Albert D. M. E.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Olsen, Bjorn] Uppsala Univ, Dept Med Sci, Infect Dis Sect, Uppsala, Sweden. RP Latorre-Margalef, N (reprint author), Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, Kalmar, Sweden. EM jonas.waldenstrom@lnu.se RI Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; Osterhaus, Albert/0000-0002-6074-1172; Olsen, Bjorn/0000-0002-4646-691X; Waldenstrom, Jonas/0000-0002-1152-4235; Munster, Vincent/0000-0002-2288-3196 FU Swedish Environmental Protection Agency [V-124-01, V-98-04]; Swedish Research Council [200858, 2010-3067, 2011-48]; Swedish Research Council Formas [2007-297, 2009-1220]; Sparbanksstiftelsen Kronan; Swedish Board of Agriculture; EU NP6; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported by grants from The Swedish Environmental Protection Agency (V-124-01 and V-98-04), The Swedish Research Council (200858, 2010-3067, 2011-48), The Swedish Research Council Formas (2007-297, 2009-1220) and the Sparbanksstiftelsen Kronan. The surveillance at Ottenby was part of the European Union wild bird surveillance and has received support from the Swedish Board of Agriculture and from the EU NP6-funded New Flubird project. V.J. Munster was partially funded by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 26 Z9 26 U1 4 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUN PY 2013 VL 9 IS 6 AR e1003443 DI 10.1371/journal.ppat.1003443 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 175CG UT WOS:000321206600043 PM 23818849 ER PT J AU Magnan, RE Koblitz, AR McCaul, KD Dillard, AJ AF Magnan, Renee E. Koeblitz, Amber R. McCaul, Kevin D. Dillard, Amanda J. TI Self-Monitoring Effects of Ecological Momentary Assessment on Smokers' Perceived Risk and Worry SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE ecological momentary assessment; EMA; smoking; reactivity; self-monitoring; risk; worry ID SMOKING-CESSATION; ASSESSMENT EMA; QUESTIONNAIRE; METAANALYSIS; ANTECEDENTS; VALIDATION; REACTIVITY; MOTIVATION; BEHAVIORS; EXAMPLE AB Using ecological momentary assessment (EMA), we sought to determine whether differences in reporting would exist for smokers who self-monitored their smoking-related negative thoughts five times daily in comparison to a non-EMA control group. One hundred seventeen smokers were randomly assigned to two conditions. Eighty-eight smokers carried personal digital assistants (PDAs) for 2 weeks and monitored negative thoughts each day, and 29 smokers did not self-monitor their negative thoughts. All smokers completed pretest and posttest assessments reporting their perceived risk and worry associated with smoking consequences. The data revealed evidence of self-monitoring effects, as smokers in the EMA condition reported less worry after 2 weeks of self-monitoring compared to smokers in the control condition. The two conditions did not differ in their reports of perceived risk of smoking consequences. These data suggest that EMA procedures asking respondents to self-monitor their thoughts about smoking may influence feelings about their smoking behavior. C1 [Magnan, Renee E.] Washington State Univ Vancouver, Dept Psychol, Vancouver, WA 98686 USA. [Koeblitz, Amber R.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [McCaul, Kevin D.] N Dakota State Univ, Dept Psychol, Fargo, ND 58105 USA. [Dillard, Amanda J.] Grand Valley State Univ, Dept Psychol, Allendale, MI 49401 USA. RP Magnan, RE (reprint author), Washington State Univ Vancouver, Dept Psychol, 14204 NE Salmon Creek Ave, Vancouver, WA 98686 USA. EM renee.magnan@vancouver.wsu.edu FU NCI NIH HHS [K05CA92633, R21 CA098962, K05 CA092633] NR 30 TC 2 Z9 2 U1 6 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD JUN PY 2013 VL 25 IS 2 BP 416 EP 423 DI 10.1037/a0031232 PG 8 WC Psychology, Clinical SC Psychology GA 173DR UT WOS:000321058800010 PM 23244640 ER PT J AU Boyce, CA Lynne-Landsman, SD AF Boyce, Cheryl Anne Lynne-Landsman, Sarah D. TI Integrating Translational Neuroscience to Improve Drug Abuse Treatment for Adolescents SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Editorial Material DE adolescence; drug abuse; treatment; neuroscience ID SUBSTANCE USE DISORDERS; BEHAVIOR; BRAIN; OUTCOMES AB Adolescence is an exciting and challenging period of maturation, rapid brain development, and developmental changes in neurobiological, neurocognitive, and neurobehavioral processes. Although behavioral therapies available for adolescent substance abuse have increased, effectiveness research in this area lags considerably behind that of clinical research on treatment for drug-abusing adults. Behavioral treatment approaches show significant promise for treating drug-abusing adolescents, but many have not incorporated innovations in neuroscience on brain development, cognitive processes, and neuroimaging. Linking developmental neuroscience with behavioral treatments can create novel drug abuse interventions and increase the effectiveness of existing interventions for substance-abusing adolescents. Contemporary research on brain development, cognition, and neuroscience is ripe for translation to inform developmentally sensitive drug abuse treatments for adolescents. Neuroscientists and interventionists are challenged to build mutual collaborations for integration of neuroscience and drug abuse treatment for adolescents. C1 [Boyce, Cheryl Anne] NIDA, Div Clin Neurosci & Behav Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lynne-Landsman, Sarah D.] Univ Florida, Dept Hlth Outcomes & Policy, Inst Child Hlth Policy, Gainesville, FL 32611 USA. RP Boyce, CA (reprint author), NIDA, NIH, DHHS, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM cboyce@mail.nih.gov NR 33 TC 1 Z9 1 U1 2 U2 12 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD JUN PY 2013 VL 27 IS 2 SI SI BP 547 EP 551 DI 10.1037/a0032434 PG 5 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 170HS UT WOS:000320841600022 PM 23815451 ER PT J AU Spain, LM Martey, L Akolkar, B Leschek, E Appel, M Fradkin, J AF Spain, Lisa M. Martey, Louis Akolkar, Beena Leschek, Ellen Appel, Michael Fradkin, Judith TI NIH Research To Prevent Type 1 Diabetes: George Eisenbarth's Legacy SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Editorial Material ID INSULIN C1 [Spain, Lisa M.; Martey, Louis; Akolkar, Beena; Leschek, Ellen; Appel, Michael; Fradkin, Judith] NIDDK, Div Diabet Endocrinol & Metab, NIH, Bethesda, MD 20817 USA. RP Spain, LM (reprint author), NIDDK, Div Diabet Endocrinol & Metab, NIH, 6707 Democracy Blvd, Bethesda, MD 20817 USA. EM spainl@niddk.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD JUN PY 2013 VL 15 SU 2 DI 10.1089/dia.2013.0096 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 169GE UT WOS:000320767000001 ER PT J AU Segars, JH Akopians, AL AF Segars, James H. Akopians, Alin L. TI The two health disparities of uterine fibroids SO FERTILITY AND STERILITY LA English DT Editorial Material C1 [Segars, James H.] Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Akopians, Alin L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. FU Intramural NIH HHS [ZIE HD008737-12] NR 5 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2013 VL 99 IS 7 BP 1851 EP 1852 DI 10.1016/j.fertnstert.2013.03.002 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 165TE UT WOS:000320505900017 PM 23541314 ER PT J AU Mendola, P AF Mendola, Pauline TI Epithelial ovarian tumors and fertility drugs-are we asking the right questions? SO FERTILITY AND STERILITY LA English DT Editorial Material ID RISK C1 Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD USA. OI Mendola, Pauline/0000-0001-5330-2844 FU Intramural NIH HHS [Z99 HD999999] NR 5 TC 0 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2013 VL 99 IS 7 BP 1853 EP 1854 DI 10.1016/j.fertnstert.2013.02.047 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 165TE UT WOS:000320505900018 PM 23541313 ER PT J AU Lewis, EI Chason, RJ DeCherney, AH Armstrong, A Elkas, J Venkatesan, AM AF Lewis, Erin I. Chason, Rebecca J. DeCherney, Alan H. Armstrong, Alicia Elkas, John Venkatesan, Aradhana M. TI Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review SO FERTILITY AND STERILITY LA English DT Article DE Benign metastasizing leiomyoma; uterine leiomyoma; hormone therapy; intravenous leiomyomatosis; leiomyomatosis peritonealis disseminata ID SMOOTH-MUSCLE TUMORS; OF-THE-LITERATURE; BILATERAL SALPINGO-OOPHORECTOMY; UTERINE LEIOMYOMA; UTERUS; MULTIPLE; GROWTH; LUNG; ESTROGEN; HYSTERECTOMY AB Objective: To evaluate novel hormonal therapies in patients with unresectable benign metastasizing leiomyoma (BML) disease. Design: Case series. Setting: National Institutes of Health (NIH). Patient(s): Five subjects with the diagnosis of BML based on imaging and/or histopathologic diagnosis. Intervention(s): Four patients were treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor. One patient was treated with an antiprogestin (CDB-2914). Main Outcome Measure(s): Response to therapy was measured by tumor burden on cross-sectional imaging employing RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 guidelines. Result(s): Four patients treated with single or combination therapy of leuprolide acetate and/or an aromatase inhibitor demonstrated stable disease with reduction in tumor burden. The fifth patient treated with antiprogestin (CDB-2914) had degeneration of her tumor, progression of its size, and an improvement in symptoms. Conclusion(s): Hormone treatment with GnRH agonist and/or aromatase inhibition may be a therapeutic option to reduce tumor burden in unresectable BML disease or for those patients who wish to avoid surgical intervention. RECIST 1.1 guidelines, while traditionally used to evaluate tumor response to cancer therapeutics, may be useful in evaluating BML tumor burden response to hormone therapy. (Fertil Steril (R) 2013; 99: 2017-24. (C) 2013 by American Society for Reproductive Medicine.) C1 [Lewis, Erin I.] Univ Calif Los Angeles, Dept Obstet & Gynecol, Med Ctr, Los Angeles, CA 90095 USA. [Chason, Rebecca J.; DeCherney, Alan H.; Armstrong, Alicia] Eunice Kennedy Shriver NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Elkas, John] Northern Virginia Pelv Surg Associates PC, Annandale, VA USA. [Venkatesan, Aradhana M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Lewis, EI (reprint author), Univ Calif Los Angeles, Dept Obstet & Gynecol, 10833 Le Conte Ave,CHS 24-126, Los Angeles, CA 90095 USA. EM elewis@mednet.ucla.edu FU Intramural Research Program of the National Institutes of Health; Program in Reproductive and Adult Endocrinology, the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health Clinical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health; the Program in Reproductive and Adult Endocrinology, the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the National Institutes of Health Clinical Center. NR 72 TC 12 Z9 14 U1 1 U2 7 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 JUN PY 2013 VL 99 IS 7 BP 2017 EP 2024 DI 10.1016/j.fertnstert.2013.01.147 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 165TE UT WOS:000320505900044 PM 23465706 ER PT J AU Kassim, SH Somerville, RPT AF Kassim, Sadik H. Somerville, Robert P. T. TI From Lipoproteins to Chondrocytes: A Brief Summary of the European Medicines Agency's Regulatory Guidelines for Advanced Therapy Medicinal Products SO HUMAN GENE THERAPY LA English DT Editorial Material C1 [Kassim, Sadik H.; Somerville, Robert P. T.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Kassim, SH (reprint author), NCI, NIH, Surg Branch, CRC, 10 Ctr Dr,Room 3-3808, Bethesda, MD 20892 USA. EM sadik.kassim@nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN PY 2013 VL 24 IS 6 BP 568 EP 570 DI 10.1089/hum.2013.101 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 166VW UT WOS:000320588300002 PM 23777464 ER PT J AU Purdue, MP AF Purdue, Mark P. TI Trichloroethylene and Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID EXPOSURE; RISK C1 [Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8114, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUN PY 2013 VL 105 IS 12 BP 844 EP 846 DI 10.1093/jnci/djt131 PG 3 WC Oncology SC Oncology GA 170MZ UT WOS:000320857800006 PM 23723421 ER PT J AU Ito, K Baudino, L Kihara, M Leroy, V Vyse, TJ Evans, LH Izui, S AF Ito, Kiyoaki Baudino, Lucie Kihara, Masao Leroy, Valerie Vyse, Timothy J. Evans, Leonard H. Izui, Shozo TI Three Sgp loci act independently as well as synergistically to elevate the expression of specific endogenous retroviruses implicated in murine lupus SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Systemic lupus erythematosus; Endogenous retrovirus; gp70 ID GP70 IMMUNE-COMPLEXES; NEW-ZEALAND MICE; EMBRYONIC STEM-CELLS; ZINC-FINGER GENES; SYSTEMIC-LUPUS; ENVELOPE GLYCOPROTEIN; LEUKEMIA-VIRUS; BXSB MICE; AUTOANTIBODY PRODUCTION; NZB MICE AB Endogenous retroviruses are implicated in murine lupus nephritis. They provide a source of nephritogenic retroviral gp70-anti-gp70 immune complexes through the production of serum gp70 protein and anti-gp70 autoantibodies as a result of the activation of TLR7. The Sgp (serum gp70 production) loci identified in lupus-prone mice play distinct roles for the expression of different classes of endogenous retroviruses, as Sgp3 regulates the transcription of xenotropic, polytropic and modified polytropic (mPT) viruses, and Sgp4 the transcription of only xenotropic viruses. In the present study, we extended these analyses to a third locus, Sgp5, using BALB/c mice congenic for the NZW-derived Sgp5 allele and also explored the possible interaction of Sgp3 and Sgp4 loci to promote the expression of endogenous retroviruses and serum gp70. The analysis of Sgp5 BALB/c congenic mice demonstrated that the Sgp5 locus enhanced the expression of xenotropic and mPT viruses, thereby upregulating the production of serum gp70. These data indicate a distinct action of the Sgp5 locus on the expression of endogenous retroviruses, as compared with two other Sgp loci. Moreover, comparative analysis of C57BL/6 double congenic mice for Sgp3 and Sgp4 loci with single congenic mice revealed that Sgp3 and Sgp4 acted synergistically to elevate the transcription of the potentially replication-competent Xmv18 provirus and the production of serum gp70. This indicates that the combined effect of three different Sgp loci markedly enhance the expression of endogenous retroviruses and their gene product, serum gp70, thereby contributing to the formation of nephritogenic gp70-anti-gp70 immune complexes in murine lupus. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ito, Kiyoaki; Baudino, Lucie; Kihara, Masao; Leroy, Valerie; Izui, Shozo] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. [Vyse, Timothy J.] Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England. [Evans, Leonard H.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Izui, S (reprint author), Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. EM Shozo.Izui@unige.ch FU Swiss National Foundation [310030_127644]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Swiss National Foundation for Scientific Research (grant 310030_127644). L.H.E. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Mr. Guy Brighouse and Ms Montserrat Alvarez for their excellent technical assistance. NR 41 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD JUN PY 2013 VL 43 BP 10 EP 17 DI 10.1016/j.jaut.2013.01.014 PG 8 WC Immunology SC Immunology GA 170CW UT WOS:000320828400002 PM 23465716 ER PT J AU Veltmaat, JM Ramsdell, AF Sterneck, E AF Veltmaat, Jacqueline M. Ramsdell, Ann F. Sterneck, Esta TI Positional Variations in Mammary Gland Development and Cancer SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Review DE Embryonic development; Body axis; Anterior-posterior; Asymmetry; Mammary gland; Breast cancer ID SKIN APPENDAGE PLACODES; LEFT-RIGHT ASYMMETRY; LEFT-RIGHT AXIS; BREAST-CANCER; SUPERNUMERARY NIPPLES; EMBRYONIC-DEVELOPMENT; EPITHELIAL-CELLS; TRANSGENIC MICE; MOUSE EMBRYO; MORPHOGENESIS AB Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and the same functional outcome as a milk-producing organ, the mammary glands are easily presumed to be mere copies of one another. Based on our analysis of published data with inclusion of new results related to mammary development and pathology in mice, we argue that this presumption is incorrect: Between and within pairs, mammary glands differ from one another, and tumor incidence and biology depend on the position along the anterior-posterior and the left-right axis as well. This insight has implications for experimental designs with mouse models and for data extrapolation between mammary glands within and between species. We suggest that improved documentation of location-specific mammary gland features will lead to more insights into the molecular mechanisms of mammary gland development and cancer biology in both mice and humans. C1 [Veltmaat, Jacqueline M.] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore. [Ramsdell, Ann F.] Univ S Carolina, Sch Med, Coll Arts & Sci, Dept Cell Biol & Anat, Columbia, SC 29208 USA. [Ramsdell, Ann F.] Univ S Carolina, Sch Med, Coll Arts & Sci, Program Womens & Gender Studies, Columbia, SC 29208 USA. [Ramsdell, Ann F.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Sterneck, Esta] NCI, Ctr Canc Res, Frederick, MD 21702 USA. RP Veltmaat, JM (reprint author), ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore. EM jveltmaat.sc@gmail.com; ramsdell@musc.edu; sternecg@mail.nih.gov RI ASTAR, IMCB/E-2320-2012; OI Ramsdell, Ann F/0000-0003-2469-7079 FU A*STAR; National Institute of Health (NIH) [HD068993]; Intramural Research Program of the NIH; Federal Funds [HHSN261200800001E] FX We are indebted to many colleagues for suggestions and discussion. We thank Glenn Summers, Robert Leighty, Thu Duong, May Yin Lee and Li Sun for expert assistance. Research was supported by A*STAR (J.M.V.), National Institute of Health (NIH) HD068993 (A. F. R.) and the Intramural Research Program of the NIH in part with Federal Funds under contract no.HHSN261200800001E (E.S). NR 83 TC 14 Z9 14 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD JUN PY 2013 VL 18 IS 2 SI SI BP 179 EP 188 DI 10.1007/s10911-013-9287-3 PG 10 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 170SY UT WOS:000320875100012 PM 23666389 ER PT J AU Haroon, N Inman, R Learch, T Weisman, M Ward, M Reveille, J Gensler, L AF Haroon, Nigil Inman, Robert Learch, Thomas Weisman, Michael Ward, Michael Reveille, John Gensler, Lianne TI TNF Inhibitors Slow Radiographic Progression of Ankylosing Spondylitis SO JOURNAL OF RHEUMATOLOGY LA English DT Meeting Abstract CT Canadian-Rheumatology-Association Meeting CY FEB 13-16, 2013 CL Ottawa, CANADA SP Canadian Rheumatol Assoc C1 [Haroon, Nigil] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Inman, Robert] Univ Toronto, Toronto, ON, Canada. [Learch, Thomas; Weisman, Michael] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Ward, Michael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Reveille, John] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Gensler, Lianne] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUN PY 2013 VL 40 IS 6 MA 3 BP 950 EP 951 PG 2 WC Rheumatology SC Rheumatology GA 158XX UT WOS:000320009600031 ER PT J AU Ceresini, G Ceda, GP Lauretani, F Maggio, M Usberti, E Marina, M Bandinelli, S Guralnik, JM Valenti, G Ferrucci, L AF Ceresini, Graziano Ceda, Gian Paolo Lauretani, Fulvio Maggio, Marcello Usberti, Elisa Marina, Michela Bandinelli, Stefania Guralnik, Jack M. Valenti, Giorgio Ferrucci, Luigi TI Thyroid Status and 6-Year Mortality in Elderly People Living in a Mildly Iodine-Deficient Area: The Aging in the Chianti Area Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE subclinical hyperthyroidism; aging; mortality ID CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; SUBCLINICAL HYPOTHYROIDISM; CARDIOVASCULAR MORTALITY; PHYSICAL FUNCTION; RISK-FACTOR; HORMONE CONCENTRATIONS; COGNITIVE FUNCTION; FOLLOW-UP; DYSFUNCTION AB Objectives To test the hypothesis that, in older adults, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with mortality independent of potential confounders. Design Longitudinal. Setting Community-based. Participants Nine hundred fifty-one individuals aged 65 and older. Measurements Plasma thyrotropin, free thyroxine, and free triiodothyronine concentrations and demographic features were evaluated in participants of the Invecchiare in Chianti Study aged 65 and older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis. Results Eight hundred nineteen participants were euthyroid, 83 had subclinical hyperthyroidism (SHyper), and 29 had subclinical hypothyroidism (SHypo). Overt hypo- and hyperthyroidism were found in five and 15 subjects, respectively. During a median of 6years of follow-up, 210 deaths occurred (22.1%), 98 (46.6%) of which were from cardiovascular causes. Kaplan-Meier analysis revealed higher overall mortality for SHyper (P=.04) than euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (hazard ratio (HR)=1.65, 95% confidence interval (CI)=1.02-2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality. In euthyroid subjects, thyrotropin was found to be predictive of lower risk of all-cause mortality (HR=0.76, 95% CI=0.57-0.99). Conclusion SHyper is an independent risk factor for all-cause mortality in older adults. Low to normal circulating thyrotropin should be carefully monitored in elderly euthyroid individuals. C1 [Ceresini, Graziano; Ceda, Gian Paolo; Maggio, Marcello; Usberti, Elisa; Marina, Michela; Valenti, Giorgio] Univ Hosp Parma, Geriatr Endocrine Unit, Dept Clin & Expt Med, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze Toscana, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] Lab Epidemiol Demog & Biometry, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Ceresini, G (reprint author), Dept Clin & Expt Med, Geriatr Endocrine Unit, Via Gramsci 14, I-43100 Parma, Italy. EM ceresini@unipr.it RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1\RS97.71]; U.S. National Institute on Aging [263_MD_9164_13, 263_MD_821336]; MURST, Rome [FIL0774249] FX This work was supported as a target project (ICS 110.1 vertical bar RS97.71) by the Italian Ministry of Health and, in part, by the U.S. National Institute on Aging (Contracts 263_MD_9164_13 and 263_MD_821336), and by Grant FIL0774249 from MURST, Rome (to GC). NR 43 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2013 VL 61 IS 6 BP 868 EP 874 DI 10.1111/jgs.12267 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 164KD UT WOS:000320407100002 PM 23647402 ER PT J AU Laudisio, A Bandinelli, S Gemma, A Ferrucci, L Incalzi, RA AF Laudisio, Alice Bandinelli, Stefania Gemma, Antonella Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Metabolic Syndrome and Hemoglobin Levels in Elderly Adults: The Invecchiare in Chianti Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE metabolic syndrome; hemoglobin; elderly; frailty; epidemiology ID DWELLING OLDER WOMEN; BODY-MASS INDEX; SERUM FERRITIN; HEART-FAILURE; RISK-FACTORS; ANEMIA; ASSOCIATION; MORTALITY; HEALTH; AGE AB Objectives To assess the association between metabolic syndrome (MetS) and hemoglobin levels in older adults. Design The Invecchiare in Chianti (InCHIANTI) Study, a cohort study with a 6-year follow-up. Setting Tuscany, Italy. Participants Adults aged 65 and older (N=1,036). Measurements MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The adjusted association between baseline hemoglobin and MetS was assessed using multivariable linear regression with hemoglobin as a continuous variable and using logistic regression with median hemoglobin level as the reference. Logistic regression was also performed with any incident decline in hemoglobin levels as the dependent variable. Results MetS was diagnosed in 263 (25%) participants. At baseline, MetS was associated with higher hemoglobin levels (B=0.18, 95% confidence interval (CI)=0.03-0.33, P=.02) and with hemoglobin levels above the median value (odds ratio (OR)=1.65, 95% CI=1.17-2.32, P=.004) after adjusting. After 6years, MetS was associated with lower adjusted probability of lower hemoglobin levels (OR=0.34, 95% CI=0.15-0.79, P=.012) but only in the oldest tertile of participants. Conclusion MetS is associated with higher hemoglobin levels in older subjects and with lower probability of hemoglobin loss over 6years in those in the oldest age group. C1 [Laudisio, Alice; Incalzi, Raffaele Antonelli] Campus Biomed Univ, Geriatr Sect, I-00128 Rome, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Gemma, Antonella] Azienda Sanit Locale Roma E, UOS Accesso & Presa Carico Assistenziale, Rome, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Laudisio, A (reprint author), Campus Biomed Univ, Via Alvaro del Portillo 200, I-00128 Rome, Italy. EM lavoralice@gmail.com OI Antonelli Incalzi, Raffaele/0000-0003-2100-2075 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002] 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 U.S. National Institute on Aging (Contracts 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-Up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-Up 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging (Contract N01-AG-5-0002). NR 30 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2013 VL 61 IS 6 BP 963 EP 968 DI 10.1111/jgs.12256 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 164KD UT WOS:000320407100014 PM 23647258 ER PT J AU Pierson, TM Markello, T Accardi, J Wolfe, L Adams, D Sincan, M Tarazi, NM Fajardo, KF Cherukuri, PF Bajraktari, I Meilleur, KG Donkervoort, S Jam, M Hub, Y Lehky, TJ Cruz, P Mullikin, JC Bonnemann, C Gahl, WA Boerkoel, CF Tifft, CJ AF Pierson, Tyler Mark Markello, Thomas Accardi, John Wolfe, Lynne Adams, David Sincan, Murat Tarazi, Noor M. Fajardo, Karin Fuentes Cherukuri, Praveen F. Bajraktari, Ilda Meilleur, Katy G. Donkervoort, Sandra Jam, Mina Hu, Ying Lehky, Tanya J. Cruz, Pedro Mullikin, James C. Bonnemann, Carsten Gahl, William A. Boerkoel, Cornelius F. Tifft, Cynthia J. TI Novel SNP array analysis and exome sequencing detect a homozygous exon 7 deletion of MEGF10 causing early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) SO NEUROMUSCULAR DISORDERS LA English DT Article DE EMARDD; MEGF10; SNP array; Exome sequencing; Deletion analysis; Myopathy ID CONGENITAL MYOPATHY; REARRANGEMENTS; MUTATIONS; SMARD1; GENE AB Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) is a myopathic disorder associated with mutations in MEGF10. By novel analysis of SNP array hybridization and exome sequence coverage, we diagnosed a 10-years old girl with EMARDD following identification of a novel homozygous deletion of exon 7 in MEGF10. In contrast to previously reported EMARDD patients, her weakness was more prominent proximally than distally, and involved her legs more than her arms. MRI of her pelvis and thighs showed muscle atrophy and fatty replacement. Ultrasound of several muscle groups revealed dense homogenous increases in echogenicity. Cloning and sequencing of the deletion breakpoint identified features suggesting the mutation arose by fork stalling and template switching. These findings constitute the first genomic deletion causing EMARDD, expand the clinical phenotype, and provide new insight into the pattern and histology of its muscular pathology. Published by Elsevier B.V. C1 [Pierson, Tyler Mark; Markello, Thomas; Wolfe, Lynne; Adams, David; Tarazi, Noor M.; Fajardo, Karin Fuentes; Cherukuri, Praveen F.; Gahl, William A.; Boerkoel, Cornelius F.; Tifft, Cynthia J.] NIH Off Rare Dis Res, NIH Undiagnosed Dis Program, Bethesda, MD USA. [Pierson, Tyler Mark; Markello, Thomas; Accardi, John; Wolfe, Lynne; Adams, David; Tarazi, Noor M.; Fajardo, Karin Fuentes; Cherukuri, Praveen F.; Gahl, William A.; Boerkoel, Cornelius F.; Tifft, Cynthia J.] NHGRI, Bethesda, MD 20892 USA. [Pierson, Tyler Mark; Bajraktari, Ilda; Meilleur, Katy G.; Donkervoort, Sandra; Jam, Mina; Hu, Ying; Bonnemann, Carsten] NINDS, Neyrogenet Branch, NIH, Bethesda, MD 20892 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Pediat & Neurol, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Regenerat Med Inst, Los Angeles, CA 90048 USA. [Markello, Thomas; Gahl, William A.; Tifft, Cynthia J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Adams, David; Sincan, Murat] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Wolfe, Lynne; Lehky, Tanya J.] NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. [Cruz, Pedro; Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Pierson, TM (reprint author), Cedars Sinai Med Ctr, Dept Pediat & Neurol, 8700 Beverly Blvd,NT Suite 4221, Los Angeles, CA 90048 USA. EM tyler.pierson@cshs.org FU Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health; Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases FX During this work TMP, DA, TM, KFF, CFB, and CT were supported by the NTH Undiagnosed Diseases Program; TM, GG, MS, NFH, PFC, PC, JKT, JCM, and WAG were supported by The Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health. CGB, SD, YH, TB, and KM were supported by The Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. TMP was also supported by The Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. NR 14 TC 8 Z9 8 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUN PY 2013 VL 23 IS 6 BP 483 EP 488 DI 10.1016/j.nmd.2013.01.013 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 178AG UT WOS:000321415900007 PM 23453856 ER PT J AU Evangelista, AM Deschamps, AM Liu, DL Raghavachari, N Murphy, E AF Evangelista, Alicia M. Deschamps, Anne M. Liu, Delong Raghavachari, Nalini Murphy, Elizabeth TI miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1 SO PHYSIOLOGICAL GENOMICS LA English DT Article DE sexual dimorphism; cardiac; nitric oxide synthase; ets-1; miR-222 ID ESTROGEN-RECEPTOR-ALPHA; NITRIC-OXIDE SYNTHASE; ISCHEMIA-REPERFUSION INJURY; S-NITROSYLATION; MYOCARDIAL-INFARCTION; GENE-EXPRESSION; ISCHEMIA/REPERFUSION INJURY; ADRENERGIC-STIMULATION; BREAST-CANCER; NO SYNTHASE AB It is well recognized that there is sex-dimorphic expression of mRNA and protein in the heart; however, the underlying mechanism is poorly understood. Endothelial nitric oxide synthase (eNOS) is an important regulator of cardiac function, and the expression levels of eNOS differ between male and female hearts. The aim of this study was to examine whether expression of specific microRNA (miRNA, miR) in males and females contributes to changes in the expression of eNOS. miRNA was extracted from the myocardium of male and female C57BL/6 mice and subjected to an Affymetrix miRNA array. Decreased expression of miR-222 was discovered in females and confirmed by qRT-PCR from whole heart or isolated cardiomyocytes. The transcription factor V-ets erythroblastosis virus E26 oncogene homolog-1 (ets-1) was identified as a potential target of miR-222 using TargetScan, and fivefold increased ets-1 protein expression in females was confirmed by Western blot. Targeting of ets-1 by miR-222 was determined in HEK293 cells overexpressing luciferase under regulation of either the ets-1 3'-UTR, a null 3'-UTR control, or a scrambled ets-1 3'-UTR and treated with a small molecule miR-222 mimic or inhibitor. Additionally qRT-PCR confirmed that mRNA levels of the ets-1 transcriptional target, eNOS, were 25% higher in females. Compared with untreated myocyte controls, 50% inhibition of eNOS expression was achieved by treatment with a miR-222 mimic, compared with a 25% increase due to miR-222 inhibitor. Our findings indicate that sex-dependent miR-222 regulation alters the expression of the cardiac regulatory protein eNOS. C1 [Evangelista, Alicia M.; Deschamps, Anne M.; Murphy, Elizabeth] NHLBI, Dept Syst Biol, NIH, Bethesda, MD 20892 USA. [Raghavachari, Nalini] NHLBI, DNA Sequencing & Genom Core, NIH, Bethesda, MD 20892 USA. [Liu, Delong] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, NIH, Bldg 10,Rm 8N204,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov OI Deschamps, Anne/0000-0001-7415-1408 FU NHLBI Intramural [Z01HL-006059, Z01HL-002066] FX This work was supported, in whole or in part, by NHLBI Intramural Grants Z01HL-006059 and Z01HL-002066. NR 40 TC 10 Z9 10 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUN PY 2013 VL 45 IS 12 BP 493 EP 498 DI 10.1152/physiolgenomics.00008.2013 PG 6 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 165TN UT WOS:000320507100005 PM 23632416 ER PT J AU Nurmi, EL Spilman, SL Whelan, F Scahill, LL Aman, MG McDougle, CJ Arnold, LE Handen, B Johnson, C Sukhodolsky, DG Posey, DJ Lecavalier, L Stigler, KA Ritz, L Tierney, E Vitiello, B McCracken, JT AF Nurmi, E. L. Spilman, S. L. Whelan, F. Scahill, L. L. Aman, M. G. McDougle, C. J. Arnold, L. E. Handen, B. Johnson, C. Sukhodolsky, D. G. Posey, D. J. Lecavalier, L. Stigler, K. A. Ritz, L. Tierney, E. Vitiello, B. McCracken, J. T. CA Res Units Pediat TI Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE autistic disorder; children; CNR1; leptin; risperidone; weight gain ID BODY-MASS INDEX; CB1 RECEPTOR ANTAGONIST; LEPTIN PROMOTER REGION; WHITE ADIPOSE-TISSUE; FOOD-INTAKE; HUMAN OBESITY; FTO GENE; ENDOCANNABINOID SYSTEM; SCHIZOPHRENIC-PATIENTS; LEPR POLYMORPHISMS AB Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N = 225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P = 1.0 x 10(-6)), CNR1 (P = 9.6 x 10(-5)) and the leptin (LEP) promoter (P = 1.4 x 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P = 1.3 x 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event. C1 [Nurmi, E. L.; Spilman, S. L.; Whelan, F.; McCracken, J. T.] UCLA Semel Inst, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Scahill, L. L.; Sukhodolsky, D. G.] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Aman, M. G.; Lecavalier, L.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [McDougle, C. J.] Massachusetts Gen Hosp, Dept Psychiat, Lurie Autism Ctr, Boston, MA 02114 USA. [Arnold, L. E.] Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. [Handen, B.; Johnson, C.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Posey, D. J.; Stigler, K. A.] Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA. [Ritz, L.] NINDS, NIH, Bethesda, MD 20892 USA. [Tierney, E.] Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD USA. [Vitiello, B.] NIMH, NIH, Bethesda, MD 20892 USA. RP McCracken, JT (reprint author), UCLA Semel Inst, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza, Los Angeles, CA 90024 USA. EM jmccracken@mednet.ucla.edu RI Nurmi, Erika/P-4627-2014; OI Nurmi, Erika/0000-0003-4893-8957; Sukhodolsky, Denis/0000-0002-5401-792X FU NIMH [T32MH073517, K23 MH094613, K24 MH010805, N01MH70010, N01MH80011, U10MH66768, N01MH70001, U10MH66766, N01MH70009, U10MH66764]; Korczak Foundation FX This work was partially supported by the following sources: NIMH grants T32MH073517 (ELN), K23 MH094613 (ELN), K24 MH010805 (JTM) and N01MH70010 (JTM), N01MH80011 and U10MH66768 (MGA), N01MH70001 and U10MH66766 (CJM), N01MH70009 and U10MH66764 (LLS) and a grant from the Korczak Foundation (LLS). Study medications were donated by Janssen Pharmaceutica. NR 87 TC 17 Z9 18 U1 2 U2 13 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 JUN PY 2013 VL 3 AR e274 DI 10.1038/tp.2013.26 PG 8 WC Psychiatry SC Psychiatry GA 174VL UT WOS:000321184600008 PM 23799528 ER PT J AU Kortum, RL Rouquette-Jazdanian, AK Samelson, LE AF Kortum, Robert L. Rouquette-Jazdanian, Alexandre K. Samelson, Lawrence E. TI Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells SO TRENDS IN IMMUNOLOGY LA English DT Review DE Ras; extracellular signal-regulated kinase; PAK; Bam32; Sos; phospholipase C-gamma 1 ID NUCLEOTIDE EXCHANGE FACTOR; ANTIGEN RECEPTOR; NEGATIVE SELECTION; ERK ACTIVATION; LYMPHOPROLIFERATIVE DISEASE; POSITIVE SELECTION; DELETION REVEALS; THYMIC SELECTION; PROTEIN-KINASES; CANCER-THERAPY AB Extracellular signal-regulated kinase (ERK) activation is important for both thymocyte development and T cell function. Classically, signal transduction from the T cell antigen receptor (TCR) to ERK is thought to be regulated by signaling from Ras guanine nucleotide exchange factors (GEFs), through the small G protein Ras, to the three-tiered Raf-MAPK/ERK kinase (MEK)-ERK kinase cascade. Developing and mature T cells express four members of two RasGEF families, RasGRP1, RasGRP4, son of sevenless 1 (Sos1), and Sos2, and several models describing combined signaling from these RasGEFs have been proposed. However, recent studies suggest that existing models need revision to include both distinct and overlapping roles of multiple RasGEFs during thymocyte development and novel, Ras-independent signals to ERK that have been identified in peripheral T cells. C1 [Kortum, Robert L.; Rouquette-Jazdanian, Alexandre K.; Samelson, Lawrence E.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov FU Intramural Research Program of the NIH, CCR, NCI FX We would like to thank Connie Sommers and Lakshmi Balagopalan for helpful suggestions and careful reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, CCR, NCI. NR 80 TC 35 Z9 35 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2013 VL 34 IS 6 BP 259 EP 268 DI 10.1016/j.it.2013.02.004 PG 10 WC Immunology SC Immunology GA 174LY UT WOS:000321158200003 PM 23506953 ER PT J AU Belkaid, Y Bouladoux, N Hand, TW AF Belkaid, Yasmine Bouladoux, Nicolas Hand, Timothy W. TI Effector and memory T cell responses to commensal bacteria SO TRENDS IN IMMUNOLOGY LA English DT Review ID INFLAMMATORY-BOWEL-DISEASE; SEGMENTED FILAMENTOUS BACTERIA; INTESTINAL DENDRITIC CELLS; HEPATICUS-INDUCED COLITIS; RETINOIC-ACID; GUT MICROBIOTA; CROHNS-DISEASE; TGF-BETA; SUSCEPTIBILITY LOCI; ULCERATIVE-COLITIS AB Barrier surfaces are home to a vast population of commensal organisms that together encode millions of proteins; each of them possessing several potential foreign antigens. Regulation of immune responses to this enormous antigenic load represents a tremendous challenge for the immune system. Tissues exposed to commensals have developed elaborate systems of regulation including specialized populations of resident lymphocytes that maintain barrier function and limit potential responses to commensal antigens. However, in settings of infection and inflammation these regulatory mechanisms are compromised and specific effector responses against commensal bacteria can develop. This review discusses the circumstances controlling the fate of commensal specific T cells and how dysregulation of these responses could lead to severe pathological outcomes. C1 [Belkaid, Yasmine; Bouladoux, Nicolas; Hand, Timothy W.] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov; timothy.hand@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We would like to thank the members of the Belkaid laboratory for helpful discussions and in particular Drs. A. Poholek, E. Wohlfert, and S. Naik for critical reading. NR 122 TC 18 Z9 18 U1 1 U2 19 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2013 VL 34 IS 6 BP 299 EP 306 DI 10.1016/j.it.2013.03.003 PG 8 WC Immunology SC Immunology GA 174LY UT WOS:000321158200007 PM 23643444 ER PT J AU McBride, AA Jang, MK AF McBride, Alison A. Jang, Moon Kyoo TI Current Understanding of the Role of the Brd4 Protein in the Papillomavirus Lifecycle SO VIRUSES-BASEL LA English DT Review DE Brd4; BET protein; HPV; papillomavirus; transcription; chromatin; replication; tethering; partitioning; bromodomain ID BET BROMODOMAIN INHIBITION; DNA-DAMAGE RESPONSE; VIRAL E2 PROTEIN; RISK HUMAN-PAPILLOMAVIRUS; HOST MITOTIC CHROMOSOMES; HPV18 REGULATORY REGION; NUT MIDLINE CARCINOMA; BOVINE PAPILLOMAVIRUS; TRANSCRIPTIONAL ACTIVATION; E6 PROMOTER AB The Brd4 protein is an epigenetic reader that is central to regulation of cellular transcription and mitotic bookmarking. The transcription and replication proteins of many viruses interact with Brd4. We describe the multiple roles of Brd4 in the papillomavirus lifecycle. C1 [McBride, Alison A.; Jang, Moon Kyoo] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM amcbride@nih.gov; jangmk@niaid.nih.gov OI McBride, Alison/0000-0001-5607-5157 FU Intramural Research Program of the NIAID; NIH FX This work was funded by the Intramural Research Program of the NIAID, NIH. NR 143 TC 16 Z9 16 U1 0 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUN PY 2013 VL 5 IS 6 BP 1374 EP 1394 DI 10.3390/v5061374 PG 21 WC Virology SC Virology GA 169HE UT WOS:000320769900001 PM 23722886 ER PT J AU Choudhary, A Galvin, TA Williams, DK Beren, J Bryant, MA Khan, AS AF Choudhary, Anil Galvin, Teresa A. Williams, Dhanya K. Beren, Joel Bryant, Mark A. Khan, Arifa S. TI Influence of Naturally Occurring Simian Foamy Viruses (SFVs) on SIV Disease Progression in the Rhesus Macaque (Macaca mulatta) Model SO VIRUSES-BASEL LA English DT Article DE Indian rhesus macaques; simian immunodeficiency virus; simian foamy virus; SIV pathogenesis; preclinical AIDS model; dual retrovirus infections ID CLASS-I ALLELES; IMMUNODEFICIENCY-VIRUS; PERSISTENT INFECTION; NONHUMAN-PRIMATES; VIRAL LOAD; REPLICATION; EXPRESSION; MONKEYS; NEUTRALIZATION; RETROVIRUSES AB We have investigated the influence of naturally occurring simian foamy viruses (SFVs) on simian immunodeficiency virus (SIV) infection and disease in Indian rhesus macaques. Animals were divided into two groups based upon presence or absence of SFV; in each group, eight monkeys were injected with SIVmac239 virus obtained from a molecular clone and four were injected with medium. Blood was collected every two weeks for evaluation of SIV infection based upon T cell-subsets, plasma viral load, development and persistence of virus-specific antibodies, and clinical changes by physical examination and hematology. Comparative analysis of SFV+/SIV+ and SFV-/SIV+ monkey groups indicated statistically significant differences in the plasma viral load between 6-28 weeks, particularly after reaching plateau at 20-28 weeks, in the CD4(+) and CD8(+) T-cell numbers over the entire study period (2-43 weeks), and in the survival rates evaluated at 49 weeks. There was an increase in the plasma viral load, a decreasing trend in the CD4(+) T cells, and a greater number of animal deaths in the SFV+/SIV+ group. The results, although based upon a small number of animals, indicated that pre-existing SFV infection can influence SIV infection and disease outcome in the rhesus macaque model. The study highlights consideration of the SFV status in evaluating results from SIV pathogenesis and vaccine challenge studies in monkeys and indicates the potential use of the SFV/SIV monkey model to study the dynamics of SFV and HIV-1 dual infections, recently reported in humans. C1 [Choudhary, Anil; Galvin, Teresa A.; Williams, Dhanya K.; Khan, Arifa S.] US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Beren, Joel] US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Bryant, Mark A.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Khan, AS (reprint author), US FDA, Lab Retroviruses, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM anil.choudhary@fda.hhs.gov; teresa.galvin@fda.hhs.gov; dhanya.williams@fda.hhs.gov; joel.beren@fda.hhs.gov; bryantm@ors.od.nih.gov; arifa.khan@fda.hhs.gov FU Biomedical Advanced Research and Development Authority (BARDA) FX We thank the assistance of Ernest Madison, Shelly Lower, Lewis Shankle, and Brianna Skinner-Harris with animal bleeds and care, and David C. Montefiori for providing the SIV neutralizing antibody data. The study was initiated by funding from Biomedical Advanced Research and Development Authority (BARDA; previously ORDC/OPHEMC). The following reagent was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: 174xCEM from Peter Cresswell. We are grateful to Ronald Desrosiers and Eliosa Yuste for the cloned SIVmac239 DNA, protocols for virus preparation, and to Ronald Desrosiers and Mark Lewis for discussions regarding the SIV study. NR 41 TC 12 Z9 12 U1 1 U2 4 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUN PY 2013 VL 5 IS 6 BP 1414 EP 1430 DI 10.3390/v5061414 PG 17 WC Virology SC Virology GA 169HE UT WOS:000320769900003 PM 23744104 ER PT J AU Hennekam, RCM Allanson, JE Biesecker, LG Carey, JC Opitz, JM Vilain, E AF Hennekam, Raoul C. M. Allanson, Judith E. Biesecker, Leslie G. Carey, John C. Opitz, John M. Vilain, Eric TI Elements of Morphology: Standard Terminology for the External Genitalia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE nomenclature; definitions; ontology; genitalia; male genitalia; female genitalia; anatomy; anthropometry; morphology; dysmorphology ID CLITORAL SIZE; LENGTH; PENIS; CIRCUMFERENCE; HYPOSPADIAS; EPISPADIAS; MANAGEMENT; APHALLIA; INFANTS; CHORDEE AB An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the male and female genitalia, and define and illustrate the terms that describe the major characteristics of these body regions. Published 2013. This article is a U. S. Government work and is in the public domain in the USA. C1 [Hennekam, Raoul C. M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat & Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Allanson, Judith E.] Univ Ottawa, Dept Pediat, Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1N 6N5, Canada. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Carey, John C.; Opitz, John M.] Univ Utah, Div Med Genet Human Genet Pathol Obstet & Gynecol, Salt Lake City, UT USA. [Vilain, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Vilain, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Vilain, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. RP Hennekam, RCM (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Pediat, Floor H7-236,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM r.c.hennekam@amc.uva.nl FU NIH [1 R01 HD068138]; National Human Genome Research Institute FX Grant sponsor: NIH; Grant number: # 1 R01 HD068138; Grant sponsor: Intramural Research Program of the National Human Genome Research Institute. NR 52 TC 7 Z9 8 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN PY 2013 VL 161A IS 6 BP 1238 EP 1263 DI 10.1002/ajmg.a.35934 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA 167RD UT WOS:000320649700004 PM 23650202 ER PT J AU Speksnijder, L Cohen-Overbeek, TE Knapen, MFCM Lunshof, SM Hoogeboom, AJM van den Ouwenland, AM de Coo, IFM Lequin, MH Bolz, HJ Bergmann, C Biesecker, LG Willems, PJ Wessels, MW AF Speksnijder, Leonie Cohen-Overbeek, Titia E. Knapen, Maarten F. C. M. Lunshof, Simone M. Hoogeboom, A. Jeannette M. van den Ouwenland, Ans M. de Coo, Irenaneus F. M. Lequin, Maarten H. Bolz, Hanno J. Bergmann, Carsten Biesecker, Leslie G. Willems, Patrick J. Wessels, Marja W. TI A De Novo GLI3 Mutation in a Patient With Acrocallosal Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE acrocallosal syndrome; GLI3 mutation; greig cephalopolysyndactyly syndrome; prenatal diagnosis ID PHENOTYPIC SPECTRUM; POINT MUTATIONS; GREIG SYNDROME; CORPUS-CALLOSUM; DELINEATION; GENE; HYDROLETHALUS; ASSOCIATION; PREDICTION; POSITION AB Acrocallosal syndrome is characterized by postaxial polydactyly, macrocephaly, agenesis of the corpus callosum, and severe developmental delay. In a few patients with this disorder, a mutation in the KIF7 gene has been reported, which was associated with impaired GLI3 processing and dysregulaton of GLI3 transcription factors. A single patient with acrocallosal syndrome and a de novo p. Ala934Pro mutation in GLI3 has been reported, whereas diverse and numerous GLI3 mutations have also been described in syndromes with overlapping clinical manifestations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, trigonocephaly with craniosynostosis and polydactyly, oral-facial-digital syndrome, and non-syndromic polydactyly. Here, we describe a second patient with acrocallosal syndrome, who has a de novo, novel c.2786T>C mutation in GLI3, which predicts p. Leu929Pro. This mutation is in the same domain as the mutation in the previously reported patient. These data confirm that mutations in GLI3 are a cause of the acrocallosal phenotype. (C) 2013 Wiley Periodicals, Inc. C1 [Speksnijder, Leonie; Cohen-Overbeek, Titia E.; Knapen, Maarten F. C. M.] Erasmus MC Univ Med Ctr, Dept Obstet & Gynecol, NL-3015 GE Rotterdam, Netherlands. [Lunshof, Simone M.] Amphia Hosp, Dept Obstet & Gynecol, Breda, Netherlands. [Hoogeboom, A. Jeannette M.; van den Ouwenland, Ans M.] Erasmus MC Univ Med Ctr, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands. [de Coo, Irenaneus F. M.] Erasmus MC Univ Med Ctr, Dept Pediat Neurol, NL-3015 GE Rotterdam, Netherlands. [Lequin, Maarten H.] Erasmus MC Univ Med Ctr, Dept Pediat Radiol, NL-3015 GE Rotterdam, Netherlands. [Bolz, Hanno J.; Bergmann, Carsten] Bioscientia, Ctr Human Genet, Ingelheim, Germany. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Willems, Patrick J.] GENDIA Genet Diagnost Network, B-2020 Antwerp, Belgium. RP Wessels, MW (reprint author), Erasmus MC Univ Med Ctr, Dept Clin Genet, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM m.w.wessels@erasmusmc.nl NR 33 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUN PY 2013 VL 161A IS 6 BP 1394 EP 1400 DI 10.1002/ajmg.a.35874 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 167RD UT WOS:000320649700023 PM 23633388 ER PT J AU Luo, XH Huang, CY Wang, L AF Luo, Xianghua Huang, Chiung-Yu Wang, Lan TI Quantile Regression for Recurrent Gap Time Data SO BIOMETRICS LA English DT Article DE Clustered survival data; Data perturbation; Gap times; Quantile regression; Recurrent events; Within-cluster resampling ID SURVIVAL ANALYSIS; MARGINAL REGRESSION; RESAMPLING METHOD; FAILURE TIME; MODELS; EVENTS AB Evaluating covariate effects on gap times between successive recurrent events is of interest in many medical and public health studies. While most existing methods for recurrent gap time analysis focus on modeling the hazard function of gap times, a direct interpretation of the covariate effects on the gap times is not available through these methods. In this article, we consider quantile regression that can provide direct assessment of covariate effects on the quantiles of the gap time distribution. Following the spirit of the weighted risk-set method by Luo and Huang (2011, Statistics in Medicine 30, 301-311), we extend the martingale-based estimating equation method considered by Peng and Huang (2008, Journal of the American Statistical Association 103, 637-649) for univariate survival data to analyze recurrent gap time data. The proposed estimation procedure can be easily implemented in existing software for univariate censored quantile regression. Uniform consistency and weak convergence of the proposed estimators are established. Monte Carlo studies demonstrate the effectiveness of the proposed method. An application to data from the Danish Psychiatric Central Register is presented to illustrate the methods developed in this article. C1 [Luo, Xianghua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Huang, Chiung-Yu] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Wang, Lan] Univ Minnesota, Sch Stat, Minneapolis, MN 55455 USA. RP Luo, XH (reprint author), Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. EM luox0054@umn.edu FU University of Minnesota [22281]; NSF [DMS-1007603] FX We thank the Associate Editor and reviewer for their valuable comments, Drs Preben Bo Mortensen and William Eaton for providing schizophrenia data, Mr Todd DeFor for editing manuscript drafts, and University of Minnesota Supercomputing Institute for providing computing resources for this research. This research was supported by University of Minnesota Grant-in-Aid 22281 to XL and by grant NSF DMS-1007603 to LW. NR 27 TC 1 Z9 1 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD JUN PY 2013 VL 69 IS 2 BP 375 EP 385 DI 10.1111/biom.12010 PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 171LV UT WOS:000320931300011 PM 23489055 ER PT J AU Wu, CO Zheng, G Kwak, M AF Wu, Colin O. Zheng, Gang Kwak, Minjung TI A Joint Regression Analysis for Genetic Association Studies with Outcome Stratified Samples SO BIOMETRICS LA English DT Article DE Genetic association study; Joint regression model; Pleiotropic analysis; Qualitative trait; Quantitative trait; Stratified sample ID RHEUMATOID-ARTHRITIS; ENVIRONMENT INTERACTIONS; MIXED DISCRETE; TRAITS; BINARY; MODELS; LINKAGE; VALUES AB Genetic association studies in practice often involve multiple traits resulting from a common disease mechanism, and samples for such studies are often stratified based on some trait outcomes. In such situations, statistical methods using only one of these traits may be inadequate and lead to under-powered tests for detecting genetic associations. We propose in this article an estimation and testing procedure for evaluating the shared-association of a genetic marker on the joint distribution of multiple traits of a common disease. Specifically, we assume that the disease mechanism involves both quantitative and qualitative traits, and our samples could be stratified based on the qualitative trait. Through a joint likelihood function, we derive a class of estimators and test statistics for evaluating the shared genetic association on both the quantitative and qualitative traits. Our simulation study shows that the joint likelihood test procedure is potentially more powerful than association tests based on separate traits. Application of our proposed procedure is demonstrated through the rheumatoid arthritis data provided by the Genetic Analysis Workshop 16 (GAW16). C1 [Wu, Colin O.; Zheng, Gang; Kwak, Minjung] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. EM wuc@nhlbi.nih.gov FU National Institutes of Health [NO1-AR-2-2263, RO1-AR-44422]; National Arthritis Foundation FX This work is based on the GAW16 data gathered with the support of grants from the National Institutes of Health (NO1-AR-2-2263 and RO1-AR-44422, Peter K. Gregersen, PI) and the National Arthritis Foundation. We would like to thank Dr. Neal Jeffereis for helping us organizing the GAW16 data. We would also like to thank Dr. James Troendle, Dr. Xin Tian, and the reviewers for many insightful suggestions and comments on the manuscript. NR 31 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2013 VL 69 IS 2 BP 417 EP 426 DI 10.1111/biom.12012 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 171LV UT WOS:000320931300015 PM 23489105 ER PT J AU Andaya, AA Enewold, L Zahm, SH Shriver, CD Stojadinovic, A McGlynn, KA Zhu, KM AF Andaya, Abegail A. Enewold, Lindsey Zahm, Shelia H. Shriver, Craig D. Stojadinovic, Alexander McGlynn, Katherine A. Zhu, Kangmin TI Race and Colon Cancer Survival in an Equal-Access Health Care System SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COLORECTAL-CANCER; RACIAL DISPARITIES; SOCIOECONOMIC-STATUS; ETHNIC DISPARITIES; UNITED-STATES; MORTALITY; ASSOCIATION; OUTCOMES; WHITES; CARCINOMA AB Studies have shown that Whites have a higher colorectal cancer survival rate than Blacks. However, it is unclear whether racial disparities result from unequal access to medical care or factors other than health care access or both. This study assessed whether non-Hispanic Whites (NHW) and non-Hispanic Blacks (NHB) differ in colon cancer survival in an equal-access health care system and examined whether racial differences varied by demographic and tumor characteristics. The study included 2,537 Military Health System patients diagnosed with colon cancer between 1998 and 2007. Median follow-up time was 31.4 months. Cox models estimated HRs and 95% confidence intervals (CI) for race, overall and stratified by age at diagnosis, sex, and tumor stage. No difference in overall survival (OS) between NHWs and NHBs was observed in general. However, among patients younger than 50 years old, NHBs experienced significantly worse OS than NHWs (HR: 2.03, 95% CI: 1.30-3.19). Furthermore, stratification by sex and tumor stage showed that this racial disparity was confined to women(HR: 2.87; 95% CI: 1.35-6.11) and patients with distant stage disease (HR: 2.45; 95% CI: 1.15-5.22) in this age group. When medical care is equally available When medical NHBs, similar overall colon cancer survival was observed; however, evidence of racial differences in survival was apparent for patients younger than 50 years old. This study suggests that factors other than access to care may be related to racial disparities in colon cancer survival among younger, but not older, patients. (C) 2013 AACR. C1 [Andaya, Abegail A.; Shriver, Craig D.; Stojadinovic, Alexander; Zhu, Kangmin] Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Rockville, MD 20852 USA. [Shriver, Craig D.; Stojadinovic, Alexander] Walter Reed Natl Mil Med Ctr, Gen Surg Serv, Rockville, MD 20852 USA. [Enewold, Lindsey; Zahm, Shelia H.; McGlynn, Katherine A.] NCI, NIH, Bethesda, MD 20892 USA. RP Zhu, KM (reprint author), Walter Reed Natl Mil Med Ctr, Div Mil Epidemiol & Populat Sci, John P Murtha Canc Ctr, 11300 Rockville Pike,Suite 1215, Rockville, MD 20852 USA. EM kangmin.zhu@usuhs.edu RI Zahm, Shelia/B-5025-2015 FU John P. Murtha Cancer Center; Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under Henry M. Jackson Foundation for the Advancement of Military Medicine; NCI; USMCI and Division of Cancer Epidemiology and Genetics, NCI FX This work was supported by John P. Murtha Cancer Center, Walter Reed National Military Medical Center via the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine, and by the intramural research program of the NCI. The original data linkage was supported by the USMCI and Division of Cancer Epidemiology and Genetics, NCI. NR 25 TC 14 Z9 14 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2013 VL 22 IS 6 BP 1030 EP 1036 DI 10.1158/1055-9965.EPI-13-0143 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 167PF UT WOS:000320643200004 PM 23576691 ER PT J AU Shiels, MS Engels, EA Linet, MS Clarke, CA Li, JM Hall, HI Hartge, P Morton, LM AF Shiels, Meredith S. Engels, Eric A. Linet, Martha S. Clarke, Christina A. Li, Jianmin Hall, H. Irene Hartge, Patricia Morton, Lindsay M. TI The Epidemic of Non-Hodgkin Lymphoma in the United States: Disentangling the Effect of HIV, 1992-2009 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FEATURING CANCERS; SURVEILLANCE DATA; TIME TRENDS; AIDS; RISK; MORTALITY; NATION; POPULATION; SARCOMA; PEOPLE AB Background: For decades, non-Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends inNHLincidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates. Methods: NHL incidence data during 1992-2009 were derived from 10 U. S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses. Results: Of 115,643 NHL cases diagnosed during 1992-2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (<= 1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992-2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992-2003, before becoming stable through 2009. Similar trends were observed for DLBCLs and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing. Conclusions: NHLincidence rates in the United States have plateaued over the last 5-10 years, independent of HIV infection. Impact: Although the causes of the long-term increase in NHL incidence rates in the United States remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV. (C) 2013 AACR. C1 [Shiels, Meredith S.; Engels, Eric A.; Linet, Martha S.; Hartge, Patricia; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Li, Jianmin; Hall, H. Irene] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA USA. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7059, Rockville, MD 20892 USA. EM shielsms@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute FX This study was funded by the Intramural Research Program of the National Cancer Institute. NR 35 TC 39 Z9 43 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2013 VL 22 IS 6 BP 1069 EP 1078 DI 10.1158/1055-9965.EPI-13-0040 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 167PF UT WOS:000320643200009 PM 23595542 ER PT J AU Gage, JC Schiffman, M Solomon, D Wheeler, CM Gravitt, PE Castle, PE Wentzensen, N AF Gage, Julia C. Schiffman, Mark Solomon, Diane Wheeler, Cosette M. Gravitt, Patti E. Castle, Philip E. Wentzensen, Nicolas TI Risk of Precancer Determined by HPV Genotype Combinations in Women with Minor Cytologic Abnormalities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASC-US CYTOLOGY; HUMAN-PAPILLOMAVIRUS; CERVICAL PRECANCER; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; ABSOLUTE RISK; CANCER; MANAGEMENT; TYPE-16 AB Background: Studies suggest that testing for individual human papillomavirus (HPV) genotypes can improve risk stratification in women with minor cytologic abnormalities. We evaluated genotyping for HPV16, HPV16/18, and HPV16/18/45 in carcinogenic HPV-positive women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. Methods: For women enrolled in the ASCUS-LSIL Triage Study (ALTS), we calculated the age-stratified (<30 and 30+ years) positivity and cumulative risk over two years of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) when testing positive or negative for three genotype combinations: HPV16, HPV16/18, and HPV16/18/45. Results: Among women with ASCUS cytology, HPV16 positivity was 17.1% and increased to 22.0% (P < 0.001) for HPV16/18 and 25.6% (P < 0.001) for HPV16/18/45. Among women with LSIL cytology, HPV16 positivity was 21.1% and increased to 30.0% (P < 0.001) for HPV16/18 and 34.0% (P = 0.017) for HPV16/18/45. Regardless of cytology and age group, the greatest risk difference between test positives and test negatives was observed for HPV16 with decreasing risk stratification for HPV16/18 and HPV16/18/45. However, testing negative for any of the three combinations while being positive for another carcinogenic type still implied a two-year risk of CIN3+ of 7.8% or more. Conclusions: Although genotyping for HPV16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytologic abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral. Impact: HPV genotyping in HPV-positive women with minor cytologic abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted. (c) 2013 AACR. C1 [Gage, Julia C.; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Solomon, Diane] NCI, Div Canc Prevent, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Wheeler, Cosette M.] Univ New Mexico, Dept Pathol, Ctr HPV Prevent, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Gage, JC (reprint author), NCI, DCEG, Clin Genet Branch, 6120 Execut Blvd,MSC 7231, Rockville, MD 20852 USA. EM gagej@mail.nih.gov FU Department of Health and Human Services, National Cancer Institute, NIH; [CN-55153]; [CN-55154]; [CN-55155]; [CN-55156]; [CN-55157]; [CN-55158]; [CN-55159]; [CN-55105] FX This work is supported by the intramural program of the Department of Health and Human Services, National Cancer Institute, NIH, and contracts CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. NR 17 TC 6 Z9 8 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2013 VL 22 IS 6 BP 1095 EP 1101 DI 10.1158/1055-9965.EPI-12-1455 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 167PF UT WOS:000320643200012 PM 23603204 ER PT J AU Mason, C Alfano, CM Smith, AW Wang, CY Neuhouser, ML Duggan, C Bernstein, L Baumgartner, KB Baumgartner, RN Ballard-Barbash, R McTiernan, A AF Mason, Caitlin Alfano, Catherine M. Smith, Ashley Wilder Wang, Ching-Yun Neuhouser, Marian L. Duggan, Catherine Bernstein, Leslie Baumgartner, Kathy B. Baumgartner, Richard N. Ballard-Barbash, Rachel McTiernan, Anne TI Long-Term Physical Activity Trends in Breast Cancer Survivors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID QUALITY-OF-LIFE; EXERCISE INTERVENTION; POSTMENOPAUSAL WOMEN; REHABILITATION NEEDS; UNITED-STATES; FOLLOW-UP; HEALTH; DIAGNOSIS; PATTERNS; STYLE AB Background: Physical activity is associated with reduced mortality and higher quality of life in breast cancer survivors; however, limited data on the prevalence of activity and long-term trends after diagnosis are available. Methods: A multiethnic cohort of 631 women (18-64 years) with stage 0 to IIIA breast cancer was followed for 10 years. Recreational aerobic activity (MET-h/wk) was ascertained for the year before diagnosis (baseline), 24 months, 5 years, and 10 years after enrollment. Women were classified according to U.S. physical activity guidelines (>= 150 min/wk moderate or >= 75 min/wk vigorous activity). The OR for meeting guidelines at 5 and 10 years according to baseline factors was estimated using logistic regression. The change in MET-h/wk was predicted using linear regression. Results: Prediagnosis, 34% of women met physical activity guidelines; 34.0%, 39.5%, and 21.4% met guidelines at 24 months, 5 years, and 10 years after enrollment, respectively. Less than 8% of survivors met guidelines at all follow-up periods. Over 10 years, recreational aerobic activity decreased by a mean +/- SD of 4.3 +/- 16.2 MET-h/wk. Meeting guidelines pre-diagnosis was strongly associated with meeting guidelines at 5 years [OR (95% confidence interval; CI): 2.76 (1.85-4.1)] and 10 years [OR (95% CI): 3.35 (2.13-5.28)]. No other demographic or prognostic factors were significantly associated with the 10-year change in MET-h/wk. Conclusion: The vast majority of early breast cancer survivors do not meet national exercise recommendations 10 years postdiagnosis. Impact: Physical activity levels are low in breast cancer survivors across the 10 years postdiagnosis; nonetheless, the predictors of activity in this population remain poorly understood. (c) 2013 AACR. C1 [Mason, Caitlin; Wang, Ching-Yun; Neuhouser, Marian L.; Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Neuhouser, Marian L.; McTiernan, Anne] Univ Washington, Seattle, WA 98195 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, NIH, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, NIH, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Canc Etiol, Duarte, CA 91010 USA. [Baumgartner, Kathy B.; Baumgartner, Richard N.] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M4-B874, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute [N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010]; National Institutes of Health [M01-RR-00037]; University of New Mexico [NCRR M01-RR-0997] FX The Health, Eating, Activity, and Lifestyle study was supported by National Cancer Institute Grants: N01-CN-75036-20, NO1-CN-05228, and NO1-PC-67010. Portions of this work were conducted through the Clinical Research Laboratory at the University of Washington, supported by the National Institutes of Health Grant M01-RR-00037, or through the University of New Mexico Grant NCRR M01-RR-0997. NR 40 TC 24 Z9 24 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2013 VL 22 IS 6 BP 1153 EP 1161 DI 10.1158/1055-9965.EPI-13-0141 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 167PF UT WOS:000320643200019 PM 23576689 ER PT J AU Wei, QO Jiang, H Baker, A Dodge, LK Gerard, M Young, MR Toledano, MB Colburn, NH AF Wei, Qiou Jiang, Hong Baker, Alyson Dodge, Lisa K. Gerard, Matthieu Young, Matthew R. Toledano, Michel B. Colburn, Nancy H. TI Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis SO CARCINOGENESIS LA English DT Article ID CYSTEINE-SULFINIC ACID; TUMOR PROGRESSION; TARGET GENE; PEROXIREDOXIN; CANCER; MOUSE; CELLS; NRF2; MACROPHAGES; PROTEIN AB Sulfiredoxin (Srx) is the enzyme that reduces the hyperoxidized inactive form of peroxiredoxins. To study the function of Srx in carcinogenesis in vivo, we tested whether loss of Srx protects mice from cancer development. Srx null mice were generated and colon carcinogenesis was induced by an azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Compared with either wild-type (Wt) or heterozygotes, Srx(/) mice had significantly reduced rates in both tumor multiplicity and volume. Mechanistic studies reveal that loss of Srx did not alter tumor cell proliferation; however, increased apoptosis and decreased inflammatory cell infiltration were obvious in tumors from Srx null mice compared with those from Wt control. In addition to the AOM/DSS model, examination of Srx expression in human reveals a tissue-specific expression pattern. Srx expression was also demonstrated in tumors from colorectal cancer patients and the levels of expression were associated with patients clinic stages. These data provide the first in vivo evidence that loss of Srx renders mice resistant to AOM/DSS-induced colon carcinogenesis, suggesting that Srx has a critical oncogenic role in cancer development, and Srx may be used as a marker for human colon cancer pathogenicity. C1 [Wei, Qiou; Baker, Alyson; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Wei, Qiou; Jiang, Hong] Univ Kentucky, Grad Ctr Toxicol, Coll Med, Lexington, KY 40536 USA. [Wei, Qiou; Jiang, Hong] Univ Kentucky, Markey Canc Ctr, Coll Med, Lexington, KY 40536 USA. [Dodge, Lisa K.] SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD 21702 USA. [Gerard, Matthieu] CEA Saclay, Epigenet Regulat & Canc Grp, Inst Biol & Technol Saclay iBiTecS, F-91191 Gif Sur Yvette, France. [Toledano, Michel B.] CEA Saclay, Oxidat Stress & Canc Grp LSOC, Inst Biol & Technol Saclay iBiTecS, F-91191 Gif Sur Yvette, France. RP Wei, QO (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. EM qiou.wei@uky.edu RI GERARD, Matthieu/D-2235-2014 OI GERARD, Matthieu/0000-0001-8956-0597 FU National Cancer Institute Intramural Research Program [Z01B-C010025] FX National Cancer Institute Intramural Research Program (Z01B-C010025 to N.H.C.). NR 34 TC 7 Z9 10 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUN PY 2013 VL 34 IS 6 BP 1403 EP 1410 DI 10.1093/carcin/bgt059 PG 8 WC Oncology SC Oncology GA 162NE UT WOS:000320271100026 PM 23393226 ER PT J AU de Jesus, AA Goldbach-Mansky, R AF de Jesus, Adriana Almeida Goldbach-Mansky, Raphaela TI Monogenic autoinflammatory diseases: Concept and clinical manifestations SO CLINICAL IMMUNOLOGY LA English DT Review DE Autoinflammatory diseases; CAPS; FMF; TRAPS; HIDS ID FAMILIAL MEDITERRANEAN FEVER; INTERLEUKIN-1 RECEPTOR ANTAGONIST; MULTISYSTEM INFLAMMATORY DISEASE; MEVALONATE KINASE-DEFICIENCY; PERIODIC SYNDROME TRAPS; HYPER-IGD SYNDROME; RECURRENT MULTIFOCAL OSTEOMYELITIS; HYPERIMMUNOGLOBULINEMIA-D SYNDROME; PEDIATRIC GRANULOMATOUS ARTHRITIS; MUCKLE-WELLS-SYNDROME AB The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD 14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency. Published by Elsevier Inc. C1 [de Jesus, Adriana Almeida; Goldbach-Mansky, Raphaela] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20814 USA. RP Goldbach-Mansky, R (reprint author), Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Translat Autoinflammatory Dis Sect, Ctr Clin, NIH, Bldg 10,Room 6D47-B,10 Ctr Dr, Bethesda, MD 20814 USA. EM goldbacr@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX Both authors's research is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 154 TC 49 Z9 50 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2013 VL 147 IS 3 SI SI BP 155 EP 174 DI 10.1016/j.clim.2013.03.016 PG 20 WC Immunology SC Immunology GA 168EO UT WOS:000320688700002 ER PT J AU Ganesan, A Masur, H AF Ganesan, Anuradha Masur, Henry TI Critical Care of Persons Infected with the Human Immunodeficiency Virus SO CLINICS IN CHEST MEDICINE LA English DT Article DE ICU; HIV; AIDS; Antiretroviral therapy ID ACTIVE ANTIRETROVIRAL THERAPY; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RECONSTITUTION INFLAMMATORY SYNDROME; SURVIVING SEPSIS CAMPAIGN; CORONARY-HEART-DISEASE; LIVER-RELATED DEATHS; ACUTE-RENAL-FAILURE; INTENSIVE-CARE; HIV-INFECTION; CEREBROSPINAL-FLUID AB Antiretroviral therapy (ART) has transformed the prognosis for patients infected with the human immunodeficiency virus (HIV). With effective ART, these individuals can expect to live almost as long as their HIV-negative counterparts. Given that more than a million people infected with HIV currently live in the United States, the likelihood that the practicing intensivist will manage a patient infected with HIV is high. This review discusses the challenges associated with management of critically ill patients infected with HIV, including the immune reconstitution inflammatory syndrome (a complication associated with ART initiation), ART-related toxicities, and the management of some common opportunistic infections. C1 [Ganesan, Anuradha] Uniformed Serv Univ Hlth Sci, Walter Reed Natl Mil Med Ctr, Div Infect Dis, Dept Med, Bethesda, MD 20889 USA. [Masur, Henry] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Ganesan, A (reprint author), Uniformed Serv Univ Hlth Sci, Walter Reed Natl Mil Med Ctr, Div Infect Dis, Dept Med, 8901,Wisconsin Ave,Bldg 7,Room 1416, Bethesda, MD 20889 USA. EM Anuradha.ganesan.civ@health.mil RI Andrade, Hugo/M-6631-2013 OI Andrade, Hugo/0000-0001-6781-6125 FU Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072] FX Supported by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. NR 80 TC 6 Z9 6 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 J9 CLIN CHEST MED JI Clin. Chest Med. PD JUN PY 2013 VL 34 IS 2 BP 307 EP + DI 10.1016/j.ccm.2013.01.011 PG 18 WC Respiratory System SC Respiratory System GA 167KX UT WOS:000320632000015 PM 23702179 ER PT J AU Kalyani, RR Egan, JM AF Kalyani, Rita Rastogi Egan, Josephine M. TI Diabetes and Altered Glucose Metabolism with Aging SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Diabetes; Aging; Insulin resistance; Beta-cell dysfunction ID DEPENDENT INSULINOTROPIC POLYPEPTIDE; LOWER-EXTREMITY DISABILITY; EXAMINATION SURVEY NHANES; OLDER-ADULTS; BODY-COMPOSITION; MUSCLE STRENGTH; FUNCTIONAL DISABILITY; SKELETAL-MUSCLE; WOMENS HEALTH; UNITED-STATES AB Diabetes and impaired glucose tolerance affect a substantial proportion of older adults. Abnormal glucose metabolism is not a necessary component of aging. Older adults with diabetes and altered glucose status likely represent a subset of the population at high risk for complications and adverse geriatric syndromes. Goals for treatment of diabetes in the elderly include control of hyperglycemia, prevention and treatment of diabetic complications, avoidance of hypoglycemia, and preservation of quality of life. Research exploring associations of dysglycemia and insulin resistance with the development of adverse outcomes in the elderly may ultimately inform use of future glucose-lowering therapies in this population. C1 [Kalyani, Rita Rastogi] Johns Hopkins Univ, Div Endocrinol & Metab, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. RP Kalyani, RR (reprint author), Johns Hopkins Univ, Div Endocrinol & Metab, Dept Med, Sch Med, 1830 East Monument St,Suite 333, Baltimore, MD 21287 USA. EM rrastogi@jhmi.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K23DK093583]; Intramural Research Program/National Institutes of Health; National Institute on Aging FX This work is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (R.R. Kalyani; K23DK093583) and the Intramural Research Program/National Institutes of Health, and the National Institute on Aging (J.M. Egan). NR 104 TC 23 Z9 24 U1 2 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 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD JUN PY 2013 VL 42 IS 2 BP 333 EP + DI 10.1016/j.ecl.2013.02.010 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 168XK UT WOS:000320741000011 PM 23702405 ER PT J AU Birbeck, GL Siddiqi, O Elafros, M Sikazwe, I Theodore, W Koralnik, IJ Bositis, C AF Birbeck, G. L. Siddiqi, O. Elafros, M. Sikazwe, I Theodore, W. Koralnik, I. J. Bositis, C. TI EARLY RECURRENT SEIZURES AND DEATH IN HIV plus ZAMBIAN ADULTS WITH NEW ONSET SEIZURE SO EPILEPSIA LA English DT Meeting Abstract CT 30th International Epilepsy Congress CY JUN 23-27, 2013 CL Montreal, CANADA SP Int Bur Epilepsy (IBE), Int League Against Epilepsy (ILAE) C1 [Birbeck, G. L.; Elafros, M.] Michigan State Univ, E Lansing, MI 48824 USA. [Birbeck, G. L.] Chikankata Hosp, Mazabuka, Zambia. [Siddiqi, O.; Koralnik, I. J.] Harvard Univ, Boston, MA 02115 USA. [Siddiqi, O.] Univ Zambia UNZA, Lusaka, Zambia. [Sikazwe, I] Minist Hlth, Lusaka, Zambia. [Theodore, W.] US NIH, Bethesda, MD USA. [Bositis, C.] Lawrence Gen Hosp, Lawrence, KS USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUN PY 2013 VL 54 SU 3 SI SI BP 272 EP 272 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 165GS UT WOS:000320472001162 ER PT J AU Morciano, P Zhang, Y Cenci, G Rong, YKS AF Morciano, Patrizia Zhang, Yi Cenci, Giovanni Rong, Yikang S. TI A Hypomorphic Mutation Reveals a Stringent Requirement for the ATM Checkpoint Protein in Telomere Protection During Early Cell Division in Drosophila SO G3-GENES GENOMES GENETICS LA English DT Article DE ATM kinase; Drosophila hypomorphic mutation; MRN complex; maternal lethal; telomere protection ID SACCHAROMYCES-CEREVISIAE; DNA-DAMAGE; CHROMOSOME ENDS; MAINTENANCE; STABILITY; PATHWAYS; YEAST; PHOSPHORYLATION; RADIATION; KINASE AB Using Drosophila as a model system, we identified a stringent requirement for the conserved function of Ataxia Telangiectasia Mutated (ATM) in telomere protection during early embryonic development. Animals homozygous for a hypomorphic mutation in atm develop normally with minimal telomere dysfunction. However, mutant females produce inviable embryos that succumb to mitotic failure caused by covalent fusions of telomeric DNA. Interestingly, although the atm mutation encodes a premature stop codon, it must not have eliminated the production of the mutant protein, and the mutant protein retains kinase activity upon DNA damage. Moreover, although the embryonic phenotype of this mutation resembles that of hypomorphic mutations in the MRN complex, the function of MRN appears normal in the atm embryos. In contrast, there is a prominent reduction of the level of HipHop, an essential member of the Drosophila capping complex. How ATM functions in telomere protection remains poorly understood. The amenability of Drosophila embryos to molecular and biochemical investigations ensures that this newly identified mutation will facilitate future studies of ATM in telomere maintenance. C1 [Morciano, Patrizia; Zhang, Yi; Rong, Yikang S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Morciano, Patrizia; Cenci, Giovanni] Univ Rome, I-00185 Rome, Italy. RP Rong, YKS (reprint author), NIH, Bldg 37,Room 6056,37 Convent Dr, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI Morciano, Patrizia/K-8871-2016; OI Morciano, Patrizia/0000-0002-8101-0096; Cenci, Giovanni/0000-0002-9628-1411 FU National Cancer Institute (USA); Italian Association for Cancer Research (AIRC) [IG12749] FX We thank Dr. Jemima Barrowman at the National Cancer Institute for editing the manuscript. We thank Ming Gong for her assistance in characterizing the genetic requirement for damage induced H2AvD phosphorylation. We thank Natalia Wesolowska for her assistance in immunostaining HipHop. We thank Dr. Bob Glaser at Wadsworth Center NY for anti-H2AvD antibody. Research in the Rong laboratory is supported by the intramural research program of the National Cancer Institute (USA). Research in the Cenci laboratory is supported by a grant from Italian Association for Cancer Research (AIRC; IG12749). NR 29 TC 1 Z9 1 U1 1 U2 5 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUN 1 PY 2013 VL 3 IS 6 BP 1043 EP 1048 DI 10.1534/g3.113.006312 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 169GT UT WOS:000320768700012 PM 23604076 ER PT J AU Moy, KA Jiao, L Freedman, ND Weinstein, SJ Sinha, R Virtamo, J Albanes, D Stolzenberg-Solomon, RZ AF Moy, Kristin A. Jiao, Li Freedman, Neal D. Weinstein, Stephanie J. Sinha, Rashmi Virtamo, Jarmo Albanes, Demetrius Stolzenberg-Solomon, Rachael Z. TI Soluble receptor for advanced glycation end products and risk of liver cancer SO HEPATOLOGY LA English DT Article ID PANCREATIC-CANCER; CARBOXYMETHYL-LYSINE; SERUM-LEVELS; HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; ELEVATED LEVELS; MALE SMOKERS; FORM SRAGE; RAGE; DISEASE AB Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by the AGE/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or NE-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample between 1985 and 1988. During follow-up beginning 5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentrations of sRAGE, CML-AGE, glucose, and insulin were measured in case subjects and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available in most cases and in a subset of the study population. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) adjusted for age, years of smoking, and body mass index. sRAGE and CML-AGE concentrations were inversely associated with liver cancer. Further adjustment for glucose and insulin or exclusion of case subjects with chronic HBV or HCV did not change the associations. Conclusion: Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and nonsmokers. (HEPATOLOGY 2013 ) C1 [Moy, Kristin A.; Freedman, Neal D.; Weinstein, Stephanie J.; Sinha, Rashmi; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Jiao, Li] Baylor Coll Med, Dept Med, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Moy, KA (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM moyka@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098 FU National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute; National Institutes of Health, Department of Health and Human Services, Bethesda, MD FX Supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. NR 45 TC 21 Z9 21 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2013 VL 57 IS 6 BP 2338 EP 2345 DI 10.1002/hep.26264 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 162PC UT WOS:000320276400027 PM 23325627 ER PT J AU Choi, SM Kim, Y Shim, JS Park, JT Wang, RH Leach, SD Liu, JO Deng, CX Ye, ZH Jang, YY AF Choi, Su Mi Kim, Yonghak Shim, Joong Sup Park, Joon Tae Wang, Rui-Hong Leach, Steven D. Liu, Jun O. Deng, Chuxia Ye, Zhaohui Jang, Yoon-Young TI Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells SO HEPATOLOGY LA English DT Article ID ZINC-FINGER NUCLEASES; ALPHA-1-ANTITRYPSIN DEFICIENCY; IN-VIVO; AUTOPHAGY; CANCER; TALENS; IPSCS; HEPATOCYTES; DISRUPTION; GENERATION AB Patient-specific induced pluripotent stem cells (iPSCs) represent a potential source for developing novel drug and cell therapies. Although increasing numbers of disease-specific iPSCs have been generated, there has been limited progress in iPSC-based drug screening/discovery for liver diseases, and the low gene-targeting efficiency in human iPSCs warrants further improvement. Using iPSC lines from patients with alpha-1 antitrypsin (AAT) deficiency, for which there is currently no drug or gene therapy available, we established a platform to discover new drug candidates and correct disease-causing mutation with a high efficiency. A high-throughput format screening assay, based on our hepatic differentiation protocol, was implemented to facilitate automated quantification of cellular AAT accumulation using a 96-well immunofluorescence reader. To expedite the eventual application of lead compounds to patients, we conducted drug screening utilizing our established library of clinical compounds (the Johns Hopkins Drug Library) with extensive safety profiles. Through a blind large-scale drug screening, five clinical drugs were identified to reduce AAT accumulation in diverse patient iPSC-derived hepatocyte-like cells. In addition, using the recently developed transcription activator-like effector nuclease technology, we achieved high gene-targeting efficiency in AAT-deficiency patient iPSCs with 25%-33% of the clones demonstrating simultaneous targeting at both diseased alleles. The hepatocyte-like cells derived from the gene-corrected iPSCs were functional without the mutant AAT accumulation. This highly efficient and cost-effective targeting technology will broadly benefit both basic and translational applications. Conclusions: Our results demonstrated the feasibility of effective large-scale drug screening using an iPSC-based disease model and highly robust gene targeting in human iPSCs, both of which are critical for translating the iPSC technology into novel therapies for untreatable diseases. (HEPATOLOGY 2013;57:2458-2468) C1 [Choi, Su Mi; Kim, Yonghak; Jang, Yoon-Young] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21231 USA. [Shim, Joong Sup; Liu, Jun O.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21231 USA. [Park, Joon Tae; Leach, Steven D.] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21231 USA. [Park, Joon Tae; Leach, Steven D.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21231 USA. [Wang, Rui-Hong; Deng, Chuxia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Ye, Zhaohui; Jang, Yoon-Young] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21231 USA. RP Jang, YY (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Stem Cell Biol Program, 1550 Orleans St,CRB2 Room 552, Baltimore, MD 21231 USA. EM zye1@jhmi.edu; yjan3@jhmi.edu RI deng, chuxia/N-6713-2016; Shim, Joong Sup/G-8383-2011; Shim, Joong Sup/O-2848-2016; OI Shim, Joong Sup/0000-0003-0167-7307; Shim, Joong Sup/0000-0003-0167-7307; Ye, Zhaohui/0000-0001-5272-9168 FU National Institutes of Health (NIH) [AA020020]; Maryland Stem Cell Research Fund (MSCRF) [2010-MSCRFII-0101-00, 2011-MSCRFE-0087, 2012-MSCRFF-0152-00]; NIH Center for Regenerative Medicine; NIH [DK61215]; Paul K. Neumann Professorship at Johns Hopkins University; National Cancer Institute [R01CA122814]; National Center for Research Resources, a component of the NIH [UL1 RR 025005] FX This work was supported by the National Institutes of Health (NIH; grant no.: AA020020) and the Maryland Stem Cell Research Fund (MSCRF; grant nos.: 2010-MSCRFII-0101-00, 2011-MSCRFE-0087, and 2012-MSCRFF-0152-00). This work was also supported by the NIH Center for Regenerative Medicine. S. D. L. is supported by the NIH (grant no.: DK61215) and the Paul K. Neumann Professorship at Johns Hopkins University. The maintenance of Johns Hopkins Drug Library was supported, in part, by the National Cancer Institute (R01CA122814), the Flight Attendant Medical Research Institute, and by grant number UL1 RR 025005 from the National Center for Research Resources, a component of the NIH and the NIH Roadmap for Medical Research (to Johns Hopkins School of Medicine). NR 49 TC 77 Z9 80 U1 4 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2013 VL 57 IS 6 BP 2458 EP 2468 DI 10.1002/hep.26237 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 162PC UT WOS:000320276400039 PM 23325555 ER PT J AU Hosgood, HD Au, WY Kim, HN Liu, J Hu, W Tse, J Song, B Wong, KF Lee, JJ Chanock, SJ Siu, LP Purdue, MP Shin, MH Yu, JM Liang, R Kim, HJ Rothman, N Lan, Q AF Hosgood, H. Dean, III Au, Wing-Yan Kim, Hee Nam Liu, Jie Hu, Wei Tse, Jovic Song, Bao Wong, Kit-fai Lee, Je-Jung Chanock, Stephen J. Siu, L. P. Purdue, Mark P. Shin, Min-ho Yu, Jinming Liang, Raymond Kim, Hyeoung-Joon Rothman, Nathaniel Lan, Qing TI IL10 and TNF variants and risk of non-Hodgkin lymphoma among three Asian populations SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE NHL; DLBCL; Subtype; Asia; IL10; TNF ID INTERLYMPH-CONSORTIUM; POLYMORPHISMS; SUSCEPTIBILITY; INTERLEUKIN-10; EPIDEMIOLOGY; FREQUENCY; GENOTYPE; CHINESE; NHL AB Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case-control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08-1.45; p (trend) = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08-1.53; p (trend) = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13-1.82; p (trend) = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64-0.91; p (trend) = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55-0.86; p (trend) = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations. C1 [Hosgood, H. Dean, III; Hu, Wei; Chanock, Stephen J.; Purdue, Mark P.; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Div Epidemiol, Bronx, NY 10461 USA. [Au, Wing-Yan; Tse, Jovic; Liang, Raymond] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Kim, Hee Nam; Kim, Hyeoung-Joon] Chonnam Natl Univ, Hwasun Hosp, Genome Res Ctr Hematopoiet Dis, Hwasun, Jeollanam Do, South Korea. [Liu, Jie; Song, Bao; Yu, Jinming] Shandong Canc Hosp & Inst, Key Lab Radiat Oncol Shandong Prov, Jinan, Shandong, Peoples R China. [Wong, Kit-fai; Siu, L. P.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Lee, Je-Jung; Kim, Hyeoung-Joon] Chonnam Natl Univ, Sch Med, Res Inst Med Sci, Dept Hematol Oncol, Kwangju, South Korea. [Shin, Min-ho] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Kwangju, South Korea. RP Hosgood, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Div Epidemiol, 1300 Morris Pk Ave,Belfer 1309, Bronx, NY 10461 USA. EM dean.hosgood@einstein.yu.edu RI Hu, Wei/M-3524-2013; Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Kim, Hee Nam/0000-0002-6153-2612; Shin, Min-Ho/0000-0002-2217-5624 FU National Institutes of Health (NIH) [National Cancer Institute (NCI)]; Science Technology of Shandong Province [ZR2009CM093, 2011GSF11820]; Ministry of Health and Welfare, Republic of Korea [A01-0385-A70604-07M7-00000A] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) [National Cancer Institute (NCI)], by Science Technology of Shandong Province grants ZR2009CM093 and 2011GSF11820, and by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A01-0385-A70604-07M7-00000A). NR 16 TC 16 Z9 16 U1 0 U2 7 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0925-5710 EI 1865-3774 J9 INT J HEMATOL JI Int. J. Hematol. PD JUN PY 2013 VL 97 IS 6 BP 793 EP 799 DI 10.1007/s12185-013-1345-5 PG 7 WC Hematology SC Hematology GA 165SX UT WOS:000320505200017 PM 23640160 ER PT J AU Nalls, MA Duran, R Lopez, G Kurzawa-Akanbi, M McKeith, IG Chinnery, PF Morris, CM Theuns, J Crosiers, D Cras, P Engelborghs, S De Deyn, PP Van Broeckhoven, C Mann, DMA Snowden, J Pickering-Brown, S Halliwell, N Davidson, Y Gibbons, L Harris, J Sheerin, UM Bras, J Hardy, J Clark, L Marder, K Honig, LS Berg, D Maetzler, W Brockmann, K Gasser, T Novellino, F Quattrone, A Annesi, G De Marco, EV Rogaeva, E Masellis, M Black, SE Bilbao, JM Foroud, T Ghetti, B Nichols, WC Pankratz, N Halliday, G Lesage, S Klebe, S Durr, A Duyckaerts, C Brice, A Giasson, BI Trojanowski, JQ Hurtig, HI Tayebi, N Landazabal, C Knight, MA Keller, M Singleton, AB Wolfsberg, TG Sidransky, E AF Nalls, Michael A. Duran, Raquel Lopez, Grisel Kurzawa-Akanbi, Marzena McKeith, Ian G. Chinnery, Patrick F. Morris, Christopher M. Theuns, Jessie Crosiers, David Cras, Patrick Engelborghs, Sebastiaan De Deyn, Peter Paul Van Broeckhoven, Christine Mann, David M. A. Snowden, Julie Pickering-Brown, Stuart Halliwell, Nicola Davidson, Yvonne Gibbons, Linda Harris, Jenny Sheerin, Una-Marie Bras, Jose Hardy, John Clark, Lorraine Marder, Karen Honig, Lawrence S. Berg, Daniela Maetzler, Walter Brockmann, Kathrin Gasser, Thomas Novellino, Fabiana Quattrone, Aldo Annesi, Grazia De Marco, Elvira Valeria Rogaeva, Ekaterina Masellis, Mario Black, Sandra E. Bilbao, Juan M. Foroud, Tatiana Ghetti, Bernardino Nichols, William C. Pankratz, Nathan Halliday, Glenda Lesage, Suzanne Klebe, Stephan Durr, Alexandra Duyckaerts, Charles Brice, Alexis Giasson, Benoit I. Trojanowski, John Q. Hurtig, Howard I. Tayebi, Nahid Landazabal, Claudia Knight, Melanie A. Keller, Margaux Singleton, Andrew B. Wolfsberg, Tyra G. Sidransky, Ellen TI A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies SO JAMA NEUROLOGY LA English DT Article ID PARKINSONS-DISEASE; GAUCHER-DISEASE; ALPHA-SYNUCLEIN; BODY DISORDERS; GBA MUTATIONS; RISK-FACTOR; GENE; SUSCEPTIBILITY; PATHOLOGY; CONFER AB Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). Design: We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. Setting: Eleven centers from sites around the world performing genotyping. Participants: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. Main Outcome Measures: Frequency of GBA1 mutations in cases and controls. Results: We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. Conclusions and Relevance: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease. C1 [Nalls, Michael A.; Keller, Margaux; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Lopez, Grisel; Tayebi, Nahid; Landazabal, Claudia; Knight, Melanie A.; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Wolfsberg, Tyra G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Duran, Raquel; Hardy, John] UCL, Inst Neurol, Reta Lila Weston Res Labs, London, England. [Sheerin, Una-Marie; Bras, Jose; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Kurzawa-Akanbi, Marzena; Morris, Christopher M.] Newcastle Univ, Med Toxicol Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kurzawa-Akanbi, Marzena; Chinnery, Patrick F.] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [McKeith, Ian G.] Newcastle Univ, Inst Ageing & Hlth, Biomed Res Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Theuns, Jessie; Crosiers, David; Van Broeckhoven, Christine] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium. [Theuns, Jessie; Crosiers, David; Cras, Patrick; Engelborghs, Sebastiaan; De Deyn, Peter Paul; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium. [Engelborghs, Sebastiaan; De Deyn, Peter Paul] Hosp Network Antwerp Middelheim & Hoge Beuken, Dept Neurol & Memory Clin, Antwerp, Belgium. [Crosiers, David; Cras, Patrick] Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium. [De Deyn, Peter Paul] Univ Groningen, Univ Med Ctr Groningen, Dept Neurol, NL-9713 AV Groningen, Netherlands. [De Deyn, Peter Paul] Univ Groningen, Univ Med Ctr Groningen, Alzheimer Res Ctr, NL-9713 AV Groningen, Netherlands. [Mann, David M. A.; Snowden, Julie; Pickering-Brown, Stuart; Halliwell, Nicola; Davidson, Yvonne; Gibbons, Linda; Harris, Jenny] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Clark, Lorraine] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA. [Clark, Lorraine; Marder, Karen; Honig, Lawrence S.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Marder, Karen; Honig, Lawrence S.] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. [Marder, Karen] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Marder, Karen; Honig, Lawrence S.] Columbia Univ, Coll Phys & Surg, Gertrude H Sergievsky Ctr, New York, NY USA. [Berg, Daniela; Maetzler, Walter; Brockmann, Kathrin; Gasser, Thomas] Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany. [Berg, Daniela; Maetzler, Walter; Brockmann, Kathrin; Gasser, Thomas] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Novellino, Fabiana; Quattrone, Aldo] Magna Graecia Univ Catanzaro, Natl Res Council, Neuroimaging Res Unit, Catanzaro, Italy. [Quattrone, Aldo] Magna Graecia Univ Catanzaro, Inst Neurol, Catanzaro, Italy. [Annesi, Grazia; De Marco, Elvira Valeria] CNR, Inst Neurol Sci, Cosenza, Italy. [Rogaeva, Ekaterina] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [Rogaeva, Ekaterina; Masellis, Mario; Black, Sandra E.] Univ Toronto, Dept Med, Div Neurol, Toronto, ON, Canada. [Masellis, Mario; Black, Sandra E.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, LC Campbell Cognit Neurol Res Unit, Toronto, ON, Canada. [Bilbao, Juan M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Pathol, Toronto, ON, Canada. [Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Ghetti, Bernardino] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA. [Nichols, William C.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA. [Nichols, William C.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Pankratz, Nathan] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Halliday, Glenda] Neurosci Res Australia, Randwick, NSW, Australia. [Halliday, Glenda] Univ New S Wales, Randwick, NSW, Australia. [Lesage, Suzanne; Klebe, Stephan; Durr, Alexandra; Duyckaerts, Charles; Brice, Alexis] INSERM, Inst Cerveau & Moelle Epiniere CRICM, Ctr Rech, Unite Mixte Rech S975, F-ORIGINAL Paris, France. [Lesage, Suzanne; Klebe, Stephan; Durr, Alexandra; Duyckaerts, Charles; Brice, Alexis] Univ Paris 06, Unite Mixte Rech S975, F-75013 Paris, France. [Lesage, Suzanne; Klebe, Stephan; Durr, Alexandra; Duyckaerts, Charles; Brice, Alexis] CNRS, Unite Mixte Rech 7225, F-75013 Paris, France. [Klebe, Stephan; Durr, Alexandra; Brice, Alexis] AP HP, Dept Genet & Cytogenet, F-75013 Paris, France. [Giasson, Benoit I.] Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA. [Trojanowski, John Q.] Univ Penn, Sch Med, Inst Aging, Alzheimers Dis Ctr, Philadelphia, PA 19104 USA. [Trojanowski, John Q.] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hurtig, Howard I.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Landazabal, Claudia] Washington Univ, St Louis, MO USA. [Keller, Margaux] Temple Univ, Philadelphia, PA 19122 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A-213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov RI Hardy, John/C-2451-2009; Halliday, Glenda/E-8555-2011; Singleton, Andrew/C-3010-2009; Bras, Jose/A-1428-2011; Pickering-Brown, Stuart/D-4008-2009; QUATTRONE, Aldo/A-6734-2016; DURAN , RAQUEL/D-7784-2016; Maetzler, Walter/A-6796-2011; OI Black, Sandra/0000-0001-7093-8289; Snowden, Julie/0000-0002-3976-4310; Halliday, Glenda/0000-0003-0422-8398; NOVELLINO, FABIANA/0000-0002-5898-938X; Pickering-Brown, Stuart/0000-0003-1561-6054; QUATTRONE, Aldo/0000-0003-2001-957X; DURAN , RAQUEL/0000-0002-5749-8968; Theuns, Jessie/0000-0001-5087-7650; DEMARCO, ELVIRAVALERIA/0000-0002-4947-8481; Bras, Jose/0000-0001-8186-0333 FU UK Medical Research Council (MRC) [G1100540]; UK National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases; UK National Institute for Health Research (NIHR) Biomedical Research Unit in Lewy Body Disease; Alzheimer's Society; Alzheimer's Research Trust as part of the Brains for Dementia Research Project; Parkinson's Disease UK [K-0901]; National Research Agency in the ERANET NEURON framework [ANR-08-NEUR-004-01]; program Investissements d'aveni [ANR-10-IAIHU-06]; UK Lewy Body Disease Society; UK Health Protection Agency; Methusalem excellence program of the Flemish government; Centre of Excellence grant from the University Research Fund of the University of Antwerp; Research Foundation Flanders; Agency for Innovation by Science and Technology Flanders; Interuniversity Attraction Poles program of the Belgian Science Policy Office; Foundation for Alzheimer Research Belgium; Belgian Parkinson Foundation; Alzheimers Research UK; Alzheimer's Society under the Brains for Dementia Research initiative; MRC; Wellcome Trust; Wellcome Trust/MRC Joint Call in Neurodegeneration [WT089698]; Alfonso Martin Escudero Foundation; Reta Lilla Trust; National Institute of Neurological Disorders and Stroke, NIH [5R01NS060113, R56NS036630]; National Institute on Aging, NIH [P50AG08702, 2R56NS037167, 2P30AG010133]; Panasci Fund for Lewy Body Research; Alzheimer Disease Drug Discovery Foundation; Parkinson's Disease Foundation; European Project on Mendelian Forms of Parkinson's Disease grant from the European Community's Seventh Framework Programme [241791, FP7/2007-2013]; Canadian Institutes of Health Research; New Investigator Award from the Parkinson Society Canada; National Health and Medical Research Council of Australia [630434, 1008307]; Agence Nationale pour la Recherche; High Q; National Institute of Neurological Disorders and Stroke [NS053488]; Intramural Research Program of the National Human Genome Research Institute, NIH; National Institute on Aging from the Intramural Research Program of the NIH [Z01 AG000949-02] FX Certain tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by grant G1100540 from the UK Medical Research Council (MRC) and awards from the UK National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases and Biomedical Research Unit in Lewy Body Disease to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust, and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project (Drs Kurzawa-Akanbi, McKeith, Chinnery, and Morris). The clinical sample collection was partly supported by Parkinson's Disease UK grant K-0901. Human brain tissue samples for DNA extraction were received from the Sydney Brain Bank, which has approval to collect and distribute human brain tissue for research studies by the Human Research Ethics Committee of the University of New South Wales under the Human Tissue Act 1983. The French project was supported by contract ANR-08-NEUR-004-01 from the National Research Agency in the ERANET NEURON framework, and the research leading to these results has received funding from the program Investissements d'avenir ANR-10-IAIHU-06. Some of the human brain tissue samples for DNA extraction were received from the Massachusetts Alzheimer Disease Research Center and the Harvard Brain Tissue Research Center.; In addition, this study was supported by the UK Lewy Body Disease Society (Dr Kurzawa-Akanbi); by the UK Health Protection Agency (Dr Morris); by the Methusalem excellence program of the Flemish government, a Centre of Excellence grant from the University Research Fund of the University of Antwerp, the Research Foundation Flanders, the Agency for Innovation by Science and Technology Flanders, the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research Belgium, and the Belgian Parkinson Foundation (Drs Theuns, Crosiers, Cras, Engelborghs, De Deyn, and Van Broeckhoven); by Alzheimers Research UK and Alzheimer's Society through their funding of the Manchester Brain Bank under the Brains for Dementia Research initiative (Drs Mann, Snowden, and Pickering-Brown and Mss Halliwell, Davidson, Gibbons, and Harris); by the MRC and Wellcome Trust (Drs Mann and Pickering-Brown); by award WT089698 from the Wellcome Trust/MRC Joint Call in Neurodegeneration to the UK Parkinson's Disease Consortium whose members are from the Institute of Neurology, University College London, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee (Drs Duran, Sheerin, Bras, and Hardy); by a postdoctoral fellowship from Alfonso Martin Escudero Foundation (Dr Duran); by the Reta Lilla Trust (Dr Hardy); by grants 5R01NS060113 (Dr Clark) and R56NS036630 (Dr Marder) from the National Institute of Neurological Disorders and Stroke, NIH; by grant P50AG08702 (Drs Honig and Clark) from the National Institute on Aging, NIH; by the Panasci Fund for Lewy Body Research (Dr Honig), Alzheimer Disease Drug Discovery Foundation (Dr Honig), and the Parkinson's Disease Foundation (Drs Clark and Dr Marder); by European Project on Mendelian Forms of Parkinson's Disease grant agreements 241791 and FP7/2007-2013 from the European Community's Seventh Framework Programme (Drs Brockmann and Gasser); by research fund grants from the Canadian Institutes of Health Research (Drs Rogaeva and Black); by a New Investigator Award from the Parkinson Society Canada (Dr Masellis); by grants 2R56NS037167 and 2P30AG010133 from the National Institute on Aging, NIH (Dr Ghetti); by fellowship 630434 and project support 1008307 from the National Health and Medical Research Council of Australia (Dr Halliday); by grants from the Agence Nationale pour la Recherche (Drs Lesage, Klebe, Durr, Duyckaerts, and Brice); by High Q (Dr Durr); by grant NS053488 from the National Institute of Neurological Disorders and Stroke (Dr Ghetti); by the Intramural Research Program of the National Human Genome Research Institute, NIH (Drs Lopez, Tayebi, Knight, Wolfsberg, and Sidransky and Ms Landazabal); and by National Institute on Aging project Z01 AG000949-02 from the Intramural Research Program of the NIH (Drs Nalls and Singleton and Ms Keller). Online-Only Material: The eTable is available at http://www.jamaneuro.com. NR 31 TC 72 Z9 72 U1 0 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 J9 JAMA NEUROL JI JAMA Neurol. PD JUN PY 2013 VL 70 IS 6 BP 727 EP 735 DI 10.1001/jamaneurol.2013.1925 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 160PV UT WOS:000320132600008 PM 23588557 ER PT J AU Gergen, PJ AF Gergen, Peter J. TI The challenge of treating preschool wheezing SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE Wheeze ID CHILDHOOD ASTHMA; CHILDREN; PREDNISOLONE; FLUTICASONE C1 NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. RP Gergen, PJ (reprint author), NIAID, Div Allergy Immunol & Transplantat, 6610 Rockledge Dr,Rm 6600, Bethesda, MD 20892 USA. EM PGergen@niaid.nih.gov NR 11 TC 5 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1526 EP 1527 DI 10.1016/j.jaci.2013.03.011 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800009 PM 23632298 ER PT J AU Hsu, AP Sowerwine, KJ Lawrence, MG Davis, J Henderson, CJ Zarember, KA Garofalo, M Gallin, JI Kuhns, DB Heller, T Milner, JD Puck, JM Freeman, AF Holland, SM AF Hsu, Amy P. Sowerwine, Kathryn J. Lawrence, Monica G. Davis, Joie Henderson, Carolyn J. Zarember, Kol A. Garofalo, Mary Gallin, John I. Kuhns, Douglas B. Heller, Theo Milner, Joshua D. Puck, Jennifer M. Freeman, Alexandra F. Holland, Steven M. TI Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Somatic mosaicism; autosomal dominant hyper-IgE syndrome; Job syndrome; signal transducer and activator of transcription 3 ID STAT3 MUTATIONS; JOBS SYNDROME; INFECTION; CANDIDIASIS; DEFICIENCY; IMMUNITY; TISSUES; HUMANS; CELLS AB Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. Objective: Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. Methods: Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. Results: The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved T(H)17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. Conclusion: STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved T(H)17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low T(H)17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo. C1 [Hsu, Amy P.; Sowerwine, Kathryn J.; Davis, Joie; Henderson, Carolyn J.; Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lawrence, Monica G.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Zarember, Kol A.; Garofalo, Mary; Gallin, John I.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] SAIC Frederick, Appl Dev Res Directorate, Neutrophil Monitoring Lab, Frederick, MD USA. [Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Sowerwine, KJ (reprint author), 10 Ctr Dr,Rm B3-4233, Bethesda, MD 20892 USA. EM kathryn.sowerwine@nih.gov; smh@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, SAIC-Frederick, Frederick, Maryland; National Center for Research Resources NCRR UCSF CTSI [UL1 RR024131]; UCSF Jeffrey Modell Foundation Diagnostic Center for Primary Immunodeficiencies; National Institutes of Health; Jeffrey Modell Foundation FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, SAIC-Frederick, Frederick, Maryland. J.M.P. acknowledges support from the National Center for Research Resources NCRR UCSF CTSI (UL1 RR024131) and the UCSF Jeffrey Modell Foundation Diagnostic Center for Primary Immunodeficiencies. The views expressed in this article are those of the authors and do not reflect the official policy of the US Government.; Disclosure of potential conflict of interest: J. M. Puck has been supported by one or more grants from the National Institutes of Health and the Jeffrey Modell Foundation. The rest of the authors declare that they have no relevant conflicts of interest. NR 30 TC 17 Z9 17 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1586 EP 1593 DI 10.1016/j.jaci.2013.02.038 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800019 PM 23623265 ER PT J AU Uzel, G Sampaio, EP Lawrence, MG Hsu, AP Hackett, M Dorsey, MJ Noel, RJ Verbsky, JW Freeman, AF Janssen, E Bonilla, FA Pechacek, J Chandrasekaran, P Browne, SK Agharahimi, A Gharib, AM Mannurita, SC Yim, JJ Gambineri, E Torgerson, T Tran, DQ Milner, JD Holland, SM AF Uzel, Gulbu Sampaio, Elizabeth P. Lawrence, Monica G. Hsu, Amy P. Hackett, Mary Dorsey, Morna J. Noel, Richard J. Verbsky, James W. Freeman, Alexandra F. Janssen, Erin Bonilla, Francisco A. Pechacek, Joseph Chandrasekaran, Prabha Browne, Sarah K. Agharahimi, Anahita Gharib, Ahmed M. Mannurita, Sara C. Yim, Jae Joon Gambineri, Eleonora Torgerson, Troy Tran, Dat Q. Milner, Joshua D. Holland, Steven M. TI Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Signal transducer and activator of transcription 1; immune dysregulation-polyendocrinopathy-enteropathy-X-linked; forkhead box protein 3; regulatory T cell; chronic mucocutaneous candidiasis; aneurysms ID REGULATORY T-CELLS; CHRONIC MUCOCUTANEOUS CANDIDIASIS; IPEX; DEFICIENCY; IMMUNODEFICIENCY; EXPRESSION; DISEASES AB Background: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. Objective: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. Methods: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wildtype forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations. Results: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c. 1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-gamma, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation. Conclusions: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells. C1 [Uzel, Gulbu; Sampaio, Elizabeth P.; Hsu, Amy P.; Freeman, Alexandra F.; Pechacek, Joseph; Chandrasekaran, Prabha; Browne, Sarah K.; Agharahimi, Anahita; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Lawrence, Monica G.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Hackett, Mary; Torgerson, Troy] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Dorsey, Morna J.] Univ S Florida, Coll Med, Div Allergy Immunol & Rheumatol, St Petersburg, FL USA. [Noel, Richard J.; Verbsky, James W.] Med Coll Wisconsin, Dept Pediat, Div Gastroenterol, Milwaukee, WI 53226 USA. [Noel, Richard J.; Verbsky, James W.] Med Coll Wisconsin, Dept Pediat, Div Microbiol, Milwaukee, WI 53226 USA. [Noel, Richard J.; Verbsky, James W.] Med Coll Wisconsin, Dept Pediat, Div Mol Genet, Milwaukee, WI 53226 USA. [Janssen, Erin; Bonilla, Francisco A.] Childrens Hosp Boston, Div Immunol, Boston, MA USA. [Janssen, Erin; Bonilla, Francisco A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Agharahimi, Anahita] Frederick Natl Lab Clin Res, SAIC Frederick, Clin Res Directorate CMRP, Lab Clin Infectious Dis, Frederick, MD USA. [Gharib, Ahmed M.] Natl Inst Diabet Digest & Kidney Dis, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Mannurita, Sara C.; Gambineri, Eleonora] Univ Florence, Anna Meyer Childrens Hosp, Dept Sci Woman & Childs Hlth, I-50121 Florence, Italy. [Yim, Jae Joon] Seoul Natl Univ, Coll Med, Div Pulm & Crit Care Med, Seoul, South Korea. [Tran, Dat Q.] Univ Texas Med Sch, Dept Pediat, Div Pediat Res Ctr, Houston, TX USA. RP Holland, SM (reprint author), NIAID, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov RI Gharib, Ahmed/O-2629-2016; Gambineri, Eleonora/J-8747-2016 OI Gharib, Ahmed/0000-0002-2476-481X; Gambineri, Eleonora/0000-0002-4676-6541 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health; National Cancer Institute, National Institutes of Health, Bethesda, Maryland [HHSN261200800001E]; National Institutes of Health; CSL Behring; Baxter; Immune Deficiency Foundation; American Research Group; Grifols; New England Regional Genetics Group; Baxter Biosciences FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health and in part by the National Cancer Institute, National Institutes of Health (contract no. HHSN261200800001E), Bethesda, Maryland. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.; Disclosure of potential conflict of interest: E. P. Sampaio has received grants from the National Institutes of Health and is employed by Medical Science and Computing. M. J. Dorsey has received grants from CSL Behring. J. W. Verbsky has received lecture fees from Baxter. F. A. Bonilla has received consultancy fees from CSL Behring, Immune Deficiency Foundation, American Research Group, and Grifols; is employed by the US Food and Drug Administration; has received lecture fees from New England Regional Genetics Group; and has received royalties from UpToDate. T. Torgerson has received grants from the National Institutes of Health, Baxter Biosciences, and CSL Behring; has consultant arrangements with and receives payment for lectures and development of educational presentations from Baxter Biosciences; and receives royalties from New England Biolabs. The rest of the authors declare that they have no relevant conflicts of interest. NR 19 TC 73 Z9 75 U1 2 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1611 EP + DI 10.1016/j.jaci.2012.11.054 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800022 PM 23534974 ER PT J AU Sampaio, EP Hsu, AP Pechacek, J Bax, HI Dias, DL Paulson, ML Chandrasekaran, P Rosen, LB Carvalho, DS Ding, L Vinh, DC Browne, SK Datta, S Milner, JD Kuhns, DB Priel, DAL Sadat, MA Shiloh, M De Marco, B Alvares, M Gillman, JW Ramarathnam, V de la Morena, M Bezrodnik, L Moreira, I Uzel, G Johnson, D Spalding, C Zerbe, CS Wiley, H Greenberg, DE Hoover, SE Rosenzweig, SD Galgiani, JN Holland, SM AF Sampaio, Elizabeth P. Hsu, Amy P. Pechacek, Joseph Bax, Hannelore I. Dias, Dalton L. Paulson, Michelle L. Chandrasekaran, Prabha Rosen, Lindsey B. Carvalho, Daniel S. Ding, Li Vinh, Donald C. Browne, Sarah K. Datta, Shrimati Milner, Joshua D. Kuhns, Douglas B. Priel, Debra A. Long Sadat, Mohammed A. Shiloh, Michael De Marco, Brendan Alvares, Michael Gillman, Jason W. Ramarathnam, Vivek de la Morena, Maite Bezrodnik, Liliana Moreira, Ileana Uzel, Gulbu Johnson, Daniel Spalding, Christine Zerbe, Christa S. Wiley, Henry Greenberg, David E. Hoover, Susan E. Rosenzweig, Sergio D. Galgiani, John N. Holland, Steven M. TI Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Signal transducer and activator of transcription 1; IFN-gamma; progressive multifocal leukoencephalopathy; Histoplasma capsulatum; Coccidioides immitis; thrush ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; PIAS PROTEINS; ARGININE METHYLATION; IN-VIVO; DEFICIENCY; IMMUNITY; GAMMA; MYCOBACTERIAL; PATHWAYS; DISEASE AB Background: Impaired signaling in the IFN-gamma/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-gamma/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-gamma-induced gene expression, but we found impaired responses to IFN-gamma restimulation. Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-gamma-mediated inflammation. C1 [Sampaio, Elizabeth P.; Hsu, Amy P.; Pechacek, Joseph; Bax, Hannelore I.; Dias, Dalton L.; Chandrasekaran, Prabha; Rosen, Lindsey B.; Carvalho, Daniel S.; Ding, Li; Browne, Sarah K.; Uzel, Gulbu; Spalding, Christine; Zerbe, Christa S.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Datta, Shrimati; Milner, Joshua D.] NIAID, Allerg Inflammat Unit, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Sadat, Mohammed A.; Rosenzweig, Sergio D.] NIAID, Infect Dis Susceptibil Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIAID, Primary Immunodeficiency Clin, NIH, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.; Carvalho, Daniel S.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. [Bax, Hannelore I.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Bax, Hannelore I.] Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands. [Paulson, Michelle L.] NCI, Clin Res Directorate CMRP, SAIC Frederick, Frederick, MD 21701 USA. [Paulson, Michelle L.] NCI, Clin Serv Program, SAIC Frederick, Frederick, MD 21701 USA. [Vinh, Donald C.] McGill Univ, Ctr Hlth, Div Infect Dis, Montreal, PQ, Canada. [Shiloh, Michael; De Marco, Brendan; Gillman, Jason W.; Ramarathnam, Vivek; Greenberg, David E.] Univ Texas SW Med Ctr Dallas, Div Infect Dis, Dallas, TX USA. [Alvares, Michael; de la Morena, Maite] Univ Texas SW Med Ctr Dallas, Div Allergy & Immunol, Dallas, TX USA. [Bezrodnik, Liliana; Moreira, Ileana] Pediat Hosp R Gutierrez, Immunol Unit, Buenos Aires, DF, Argentina. [Johnson, Daniel] Univ Chicago, Comer Childrens Hosp, Chicago, IL 60637 USA. [Wiley, Henry] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Hoover, Susan E.; Galgiani, John N.] Univ Arizona, Valley Fever Ctr Excellence, Coll Med, Tucson, AZ 85721 USA. RP Holland, SM (reprint author), CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov RI Hoover, Susan/F-8580-2015; OI VINH, DONALD/0000-0003-1347-7767; Shiloh, Michael/0000-0003-4329-2253 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Canadian Institutes of Health Research; CSL Behring Canada; Astellas Canada; Sunovion/Sepracor FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.; Disclosure of potential conflict of interest: D. C. Vinh has received research support from the Canadian Institutes of Health Research Post-doctoral Fellowship, CSL Behring Canada, and Astellas Canada; has consultant arrangements with CSL Behring Canada and Pfizer Canada; and has received payment for lectures from CSL Behring Canada and Sunovion/Sepracor. D. B. Kuhns and D. A. Long Priel have received grants from the National Cancer Institute/National Institutes of Health. V. Ramarathnam is employed by Private Practice ID. S. D. Rosenzweig receives royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest. NR 36 TC 61 Z9 61 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1624 EP + DI 10.1016/j.jaci.2013.01.052 PG 28 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800023 PM 23541320 ER PT J AU Kim, DK Kim, HS Kim, AR Kim, JH Kim, B Noh, G Kim, HS Beaven, MA Kim, YM Choi, WS AF Kim, Do Kyun Kim, Hyuk Soon Kim, A-Ram Kim, Ji Hyung Kim, Bokyung Noh, Geunwoong Kim, Hyung Sik Beaven, Michael A. Kim, Young Mi Choi, Wahn Soo TI DJ-1 regulates mast cell activation and IgE-mediated allergic responses SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE DJ-1; reactive oxygen species; mast cells; allergy; Fc epsilon RI-mediated signals ID FC-EPSILON-RI; OXYGEN SPECIES GENERATION; NITRIC-OXIDE; IN-VIVO; FYN KINASE; ANTIGEN; PHOSPHORYLATION; DERMATITIS; INHIBITION; OXIDANTS AB Background: DJ-1 is an antioxidant protein known to reduce levels of reactive oxygen species (ROS), but its presence or function in mast cells and allergic diseases is unknown. Objectives: We sought to determine the role and mechanism of DJ-1 in allergic responses in vitro and in vivo. Methods: ROS and DJ-1 levels in serum or culture medium were measured with ELISA kits. The role of DJ-1 was evaluated in mast cell cultures and passive cutaneous anaphylaxis in normal or DJ-1 knockout (KO) mice. The mechanism of DJ-1 action was examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biological approaches. Results: Patients with atopic dermatitis had increased levels of ROS and diminished levels of DJ-1. DJ-1 KO mice exhibited enhanced passive cutaneous anaphylaxis and augmented ROS levels in sera and bone marrow-derived mast cells (BMMCs). Furthermore, antigen-induced degranulation and production of TNF-alpha and IL-4 were significantly amplified in DJ-1 KO and anti-DJ-1 small interfering RNA-transfected BMMCs compared with that seen in wild-type (WT) BMMCs. Studies with these cells and BMMCs transfected with small interfering RNAs against the phosphatases Src homology domain 2-containing protein tyrosine phosphatase (SHP) 1 and SHP-2 revealed that the DJ-1 KO phenotype could be attributed to suppression of SHP-1 activity and enhancement of SHP-2 activity, leading to strengthened signaling through linker for activation of T cells, phospholipase C gamma, and mitogen-activated protein kinases. Conclusions: A deficiency or constitutive activation of DJ-1 can have implications in mast cell-driven allergic diseases, such as asthma and anaphylaxis. C1 [Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Kim, Ji Hyung; Kim, Bokyung; Choi, Wahn Soo] Konkuk Univ, Coll Med, Funct Genom Inst, Dept Immunol & Physiol, Chungju 380701, South Korea. [Noh, Geunwoong] Chungnam Natl Univ Hosp, Dept Pediat, Subdiv Allergy & Clin Immunol, Taejon, South Korea. [Kim, Hyung Sik] Pusan Natl Univ, Coll Pharm, Pusan, South Korea. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Coll Med, Dept Immunol, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU National Research Foundation of Korea (NRF); Korean government (MEST) [2011-0028873]; Regional Innovation Center Program of the Ministry of Knowledge Economy at Konkuk University, Korea; Intramural Program of the National Heart, Lung, and Blood Institute, National Institutes of Health; National Research Foundation of Korea; Regional Innovation Center Program of the Ministry of Knowledge Economy, Korea FX Supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST, no. 2011-0028873) and in part by the Regional Innovation Center Program of the Ministry of Knowledge Economy at Konkuk University, Korea. M. A. B. was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, National Institutes of Health.; D. K. Kim, H. S. Kim, A.-R. Kim, J. H. Kim, and W. S. Choi have received research support from the National Research Foundation of Korea and in part from the Regional Innovation Center Program of the Ministry of Knowledge Economy, Korea. The rest of the authors declare that they have no relevant conflicts of interest. NR 42 TC 12 Z9 12 U1 0 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1653 EP + DI 10.1016/j.jaci.2012.10.012 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800026 PM 23182168 ER PT J AU Romberg, N Morbach, H Lawrence, MG Kim, S Kang, I Holland, SM Milner, JD Meffre, E AF Romberg, Neil Morbach, Henner Lawrence, Monica G. Kim, Sanghyun Kang, Insoo Holland, Steven M. Milner, Joshua D. Meffre, Eric TI Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; APOPTOSIS; INDUCTION; TRANS C1 [Romberg, Neil] Yale Univ, Sch Med, Dept Pediat, Div Allergy & Clin Immunol, New Haven, CT 06510 USA. [Morbach, Henner; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Kim, Sanghyun; Kang, Insoo] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Lawrence, Monica G.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kim, Sanghyun] Kangwon Natl Univ, Coll Med, Chunchon, South Korea. RP Romberg, N (reprint author), Yale Univ, Sch Med, Dept Pediat, Div Allergy & Clin Immunol, New Haven, CT 06510 USA. EM neil.romberg@yale.edu FU Intramural NIH HHS; NIAID NIH HHS [U19 AI082713, AI061093, AI071087, AI082713, AI095848, P01 AI061093, R01 AI071087, R21 AI095848]; NICHD NIH HHS [K12HD0141401-10] NR 7 TC 30 Z9 30 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1691 EP 1693 DI 10.1016/j.jaci.2013.01.004 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800030 PM 23403048 ER PT J AU Jaramillo, R Cohn, RD Crockett, PW Gowdy, KM Zeldin, DC Fessler, MB AF Jaramillo, Renee Cohn, Richard D. Crockett, Patrick W. Gowdy, Kymberly M. Zeldin, Darryl C. Fessler, Michael B. TI An alternative explanation for the inverse relationship between atopy and myocardial infarction Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID PLATELET ACTIVATION C1 [Jaramillo, Renee; Cohn, Richard D.; Crockett, Patrick W.] SRA Int, Durham, NC USA. [Gowdy, Kymberly M.; Zeldin, Darryl C.; Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Jaramillo, R (reprint author), SRA Int, Durham, NC USA. EM fesslerm@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES102005, Z01 ES025041] NR 7 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2013 VL 131 IS 6 BP 1715 EP 1716 DI 10.1016/j.jaci.2013.04.004 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 166CT UT WOS:000320532800042 PM 23642774 ER PT J AU Baker, CM Best, RB AF Baker, Christopher M. Best, Robert B. TI Matching of Additive and Polarizable Force Fields for Multiscale Condensed Phase Simulations SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID CLASSICAL DRUDE OSCILLATOR; MOLECULAR-DYNAMICS SIMULATIONS; ELECTRONIC CIRCULAR-DICHROISM; ATOMIC CHARGES; FREE-ENERGIES; WATER MODELS; AQUEOUS-SOLUTION; NUCLEIC-ACIDS; LIQUID WATER; SOLVATION AB Inclusion of electronic polarization effects is one of the key aspects in which the accuracy of current biomolecular force fields may be improved. The principal drawback of such approaches is the computational cost, which typically ranges from 3 to 10 times that of the equivalent additive model, and may be greater for more sophisticated treatments of polarization or other many-body effects. Here, we present a multiscale approach that may be used to enhance the sampling in simulations with polarizable models, by using the additive model as a tool to explore configuration space. We use a method based on information theory to determine the charges for an additive model that has optimal overlap with the polarizable one, and we demonstrate the feasibility of enhancing sampling via a hybrid replica exchange scheme for several model systems. An additional advantage is that, in the process, we obtain a systematic method for deriving charges for an additive model that will be the natural complement to its polarizable parent The additive charges are found by an effective coarse graining of the polarizable force field, rather than by ad hoc procedures. C1 [Baker, Christopher M.; Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM robertbe@helix.nih.gov RI Baker, Christopher/G-4743-2012; Baker, Christopher/A-5264-2010; Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU FEBS Return to Europe Fellowship; Royal Society University Research Fellowship; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) FX C.M.B. is supported by a FEBS Return to Europe Fellowship. R.B.B. was supported by a Royal Society University Research Fellowship and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The authors benefitted from a HECToR Class 2a computing allocation. NR 100 TC 15 Z9 15 U1 0 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD JUN PY 2013 VL 9 IS 6 BP 2826 EP 2837 DI 10.1021/ct400116g PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 165LD UT WOS:000320484500027 PM 23997691 ER PT J AU Lawlor, M Dastgir, J Rutkowski, A Alvarez, R Cossette, S Yan, K Hoffmann, R Sewry, C Hayashi, Y Goebel, HH Bonnemann, C AF Lawlor, Michael Dastgir, Jahannaz Rutkowski, Anne Alvarez, Rachel Cossette, Stacy Yan, Ke Hoffmann, Ray Sewry, Caroline Hayashi, Yukiko Goebel, Hans-Hilmar Bonnemann, Carsten TI Integration of Common Data Elements into Muscle Biopsy Reports SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 89th Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 20-23, 2013 CL Charleston, SC SP Amer Assoc Neuropathologists Inc C1 [Lawlor, Michael; Yan, Ke; Hoffmann, Ray] Childrens Hosp Wisconsin, Med Coll Wisconsin, Bethesda, MD USA. [Dastgir, Jahannaz; Bonnemann, Carsten] NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. [Rutkowski, Anne; Alvarez, Rachel; Cossette, Stacy] Cure Congenital Muscular Dystrophy, Olathe, KS USA. [Sewry, Caroline] Dubowitz Neuromuscular Ctr, London, England. [Hayashi, Yukiko] Natl Inst Neurosci, Tokyo, Japan. [Goebel, Hans-Hilmar] Johannes Gutenberg Univ Mainz, D-55122 Mainz, Germany. 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2013 VL 72 IS 6 MA 17 BP 544 EP 544 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 151IR UT WOS:000319454400025 ER PT J AU Rahimpour, S Tinaz, A Edwards, N Ray-Chaudhury, A Hallet, M AF Rahimpour, Shervin Tinaz, Aysesule Edwards, Nancy Ray-Chaudhury, Abhik Hallet, Mark TI Neuropathology of DYT-1 Primary Torsion Dystonia SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 89th Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 20-23, 2013 CL Charleston, SC SP Amer Assoc Neuropathologists Inc C1 [Rahimpour, Shervin; Tinaz, Aysesule; Edwards, Nancy; Ray-Chaudhury, Abhik; Hallet, Mark] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2013 VL 72 IS 6 MA 68 BP 558 EP 558 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 151IR UT WOS:000319454400076 ER PT J AU Ahsan, S Ballester, L Nazarian, J Warren, K Quezado, M Eberhart, C Rodriguez, F AF Ahsan, Sama Ballester, Leomar Nazarian, Javad Warren, Katherine Quezado, Martha Eberhart, Charles Rodriguez, Fausto TI Altered Histone 3 Lysine 27 Trimethylation(H3K27me3) and Histone 3 Lysine 9 Trimethylation(H3K9me3) Patterns in Glial Neoplasms SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 89th Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 20-23, 2013 CL Charleston, SC SP Amer Assoc Neuropathologists Inc C1 [Ahsan, Sama; Rodriguez, Fausto] Johns Hopkins, Baltimore, MD USA. [Ballester, Leomar; Quezado, Martha; Eberhart, Charles] NIH, Bethesda, MD USA. [Warren, Katherine] NCI, NIH, 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2013 VL 72 IS 6 MA 92 BP 565 EP 565 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 151IR UT WOS:000319454400100 ER PT J AU Curtis, M Mardekian, S Miettinen, M AF Curtis, Mark Mardekian, Stacey Miettinen, Markku TI Report of Two Cases of Spinal, Intradural, Extraosseous Ewing's Sarcoma/Peripheral Neuroectodermal Tumor SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 89th Annual Meeting of the American-Association-of-Neuropathologists-Inc CY JUN 20-23, 2013 CL Charleston, SC SP Amer Assoc Neuropathologists Inc C1 [Curtis, Mark; Mardekian, Stacey] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Miettinen, Markku] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2013 VL 72 IS 6 MA 106 BP 568 EP 569 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 151IR UT WOS:000319454400114 ER PT J AU Campanac, E Hoffman, DA AF Campanac, Emilie Hoffman, Dax A. TI Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE cocaine addiction; intrinsic excitability; interneurons; medial prefrontal cortex ID ACTIVATED CATION CURRENT; CURRENT I-H; INDUCED BEHAVIORAL SENSITIZATION; NUCLEOTIDE-GATED CHANNELS; BRAIN-STIMULATION REWARD; QUINOLINIC ACID LESIONS; DRUG-SEEKING BEHAVIOR; PYRAMIDAL NEURONS; SELF-STIMULATION; DOPAMINE MODULATION AB The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D-2 activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D-2 -receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN. C1 [Campanac, Emilie; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, NIH, Bethesda, MD USA. RP Campanac, E (reprint author), Eunice Kennedy Shriver NICHD, Mol Neurophysiol & Biophys Sect, NIH, 35 Convent Dr,Bldg 35,Room 3C908, Bethesda, MD 20892 USA. EM campanacea@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Child Health and Human Development Intramural Research Program FX This work was supported by the National Institute of Child Health and Human Development Intramural Research Program. NR 89 TC 5 Z9 6 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2013 VL 109 IS 11 BP 2781 EP 2792 DI 10.1152/jn.00596.2012 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 156GJ UT WOS:000319809600013 PM 23486201 ER PT J AU Buck, C AF Buck, Chris TI Developing vaccines against BK and JC polyomaviruses SO JOURNAL OF NEUROVIROLOGY LA English DT Meeting Abstract CT 5th International Conference on Polyomaviruses and Human Diseases - Basic and Clinical Perspectives CY MAY 09-11, 2013 CL Stresa, ITALY C1 [Buck, Chris] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2013 VL 19 IS 3 MA 59 BP 307 EP 307 PG 1 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 174CF UT WOS:000321129800071 ER PT J AU Jung, HM Patel, RS Phillips, BL Wang, H Cohen, DM Reinhold, WC Chang, LJ Yang, LJ Chan, EKL AF Jung, Hyun Min Patel, Rushi S. Phillips, Brittany L. Wang, Hai Cohen, Donald M. Reinhold, William C. Chang, Lung-Ji Yang, Li-Jun Chan, Edward K. L. TI Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SQUAMOUS-CELL CARCINOMA; MICRORNA-BINDING-SITES; ORAL-CANCER; HUMAN MALIGNANCIES; GASTRIC-CANCER; LUNG-CANCER; C-MYC; TARGETS; PROTEIN; DIFFERENTIATION AB MicroRNAs (miRNAs) are small, noncoding RNAs involved in posttranscriptional regulation of protein-coding genes in various biological processes. In our preliminary miRNA microarray analysis, miR-375 was identified as the most underexpressed in human oral tumor versus controls. The purpose of the present study is to examine the function of miR-375 as a candidate tumor suppressor miRNA in oral cancer. Cancerous inhibitor of PP2A (CIP2A), a guardian of oncoprotein MYC, is identified as a candidate miR-375 target based on bioinformatics. Luciferase assay accompanied by target sequence mutagenesis elucidates five functional miR-375-binding sites clustered in the CIP2A coding sequence close to the C-terminal domain. Overexpression of CIP2A is clearly demonstrated in oral cancers, and inverse correlation between miR-375 and CIP2A is observed in the tumors, as well as in NCI-60 cell lines, indicating the potential generalized involvement of the miR-375-CIP2A relationship in many other cancers. Transient transfection of miR-375 in oral cancer cells reduces the expression of CIP2A, resulting in decrease of MYC protein levels and leading to reduced proliferation, colony formation, migration, and invasion. Therefore this study shows that underexpression of tumor suppressor miR-375 could lead to uncontrolled CIP2A expression and extended stability of MYC, which contributes to promoting cancerous phenotypes. C1 [Jung, Hyun Min; Patel, Rushi S.; Phillips, Brittany L.; Chan, Edward K. L.] Univ Florida, Dept Oral Biol, Gainesville, FL 32610 USA. [Wang, Hai; Yang, Li-Jun] Univ Florida, Dept Pathol, Gainesville, FL 32610 USA. [Cohen, Donald M.] Univ Florida, Dept Oral & Maxillofacial Diagnost Sci, Gainesville, FL 32610 USA. [Chang, Lung-Ji] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Reinhold, William C.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. RP Chan, EKL (reprint author), Univ Florida, Dept Oral Biol, Gainesville, FL 32610 USA. EM echan@ufl.edu FU Alumni Graduate Fellowship; Andrew J. Semesco Foundation; University of Florida/Moffitt Collaborative Initiative grant FX We thank members of the Chan laboratory for technical assistance, discussion, and encouragement. We are grateful to tissue procurement at H. Lee Moffitt Cancer Center for providing specimens. We also thank Jukka Westermarck for constructive discussions. This work was supported in part by an Alumni Graduate Fellowship (H.M.J.), the Andrew J. Semesco Foundation (H.M.J., E. K.L.C.), and a University of Florida/Moffitt Collaborative Initiative grant (E.K.L.C). NR 70 TC 34 Z9 34 U1 0 U2 11 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN 1 PY 2013 VL 24 IS 11 BP 1638 EP 1648 DI 10.1091/mbc.E12-12-0891 PG 11 WC Cell Biology SC Cell Biology GA 174ZX UT WOS:000321199300003 PM 23552692 ER PT J AU Kannan, P Pike, VW Halldin, C Langer, O Gottesman, MM Innis, RB Hall, MD AF Kannan, Pavitra Pike, Victor W. Halldin, Christer Langer, Oliver Gottesman, Michael M. Innis, Robert B. Hall, Matthew D. TI Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood-Brain Barrier SO MOLECULAR PHARMACEUTICS LA English DT Review DE positron emission tomography (PET); ABC transporters; imaging blood-brain barrier; inhibitors; density ID CANCER RESISTANCE PROTEIN; DRUG EFFLUX TRANSPORTERS; IN-VIVO EVALUATION; PRECLINICAL EVALUATION; RAT-BRAIN; PET; EXPRESSION; INHIBITOR; RADIOSYNTHESIS; RADIOLIGANDS AB Efflux transporters located at the blood-brain barrier, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), regulate the passage of many drugs in and out of the brain. Changes in the function and density of these proteins, in particular P-gp, may play a role in several neurological disorders. Several radioligands have been developed for measuring P-gp function at the blood-brain barrier of human subjects with positron emission tomography (PET). However, attempts to measure P-gp density with radiolabeled inhibitors that bind to these proteins in vivo have not thus far provided useful, quantifiable PET signals. Herein, we argue that not only the low density of transporters in the brain as a whole but also their very high density in brain capillaries act to lower the concentration of ligand in the plasma and thereby contribute to absent or low signals in PET studies of P-gp density. Our calculations, based on published data and theoretical approximations, estimate that whole brain densities of many efflux transporters at the blood-brain barrier range from 0.04 to 5.19 nM. We conclude that the moderate affinities (>5 nM) of currently labeled inhibitors may not allow measurement of efflux transporter density at the blood-brain barrier, and inhibitors with substantially higher affinity will be needed for density imaging of P-gp and other blood-brain barrier transporters. C1 [Kannan, Pavitra; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Kannan, Pavitra; Halldin, Christer] Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden. [Langer, Oliver] AIT Austrian Inst Technol GmbH, Hlth & Environm Dept, A-2444 Seibersdorf, Austria. [Langer, Oliver] Med Univ Vienna, Dept Clin Pharmacol, A-1090 Vienna, Austria. [Gottesman, Michael M.; Hall, Matthew D.] NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. RP Innis, RB (reprint author), NIMH, 10 Ctr Dr,Rm B1D43, Bethesda, MD 20892 USA. EM robert.innis@nih.gov OI Langer, Oliver/0000-0002-4048-5781; Kannan, Pavitra/0000-0002-9170-6062 FU National Institute of Mental Health [Z01-MH-002852-04, MH002793-09]; National Cancer Institute [Z01-BC-005598]; Austrian Science Fund (FWF); European Community [201380] FX This research was supported by the Intramural Research Programs of the National Institute of Mental Health (Project Nos. Z01-MH-002852-04 and MH002793-09) and the National Cancer Institute (Project no. Z01-BC-005598). Oliver Langer's studies are funded by the Austrian Science Fund (FWF) project "Transmembrane Transporters in Health and Disease" (SFB F35) and by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 201380 ("EURIPIDES"). We thank George Leiman for editorial assistance. NR 43 TC 11 Z9 11 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUN PY 2013 VL 10 IS 6 BP 2222 EP 2229 DI 10.1021/mp400011g PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 159AE UT WOS:000320015600013 PM 23597242 ER PT J AU Cai, Y Zhu, L Zhang, F Niu, G Lee, S Kimura, S Chen, XY AF Cai, Yan Zhu, Lei Zhang, Fan Niu, Gang Lee, Seulki Kimura, Shioko Chen, Xiaoyuan TI Noninvasive Monitoring of Pulmonary Fibrosis by Targeting Matrix Metalloproteinases (MMPs) SO MOLECULAR PHARMACEUTICS LA English DT Article DE pulmonary fibrosis; matrix metalloproteinase; optical imaging; activatable probe; secretoglobin 3A2 ID POSITRON-EMISSION-TOMOGRAPHY; ALLERGIC AIRWAY INFLAMMATION; IN-VIVO; SECRETOGLOBIN 3A2; DRUG DEVELOPMENT; CLINICAL-TRIALS; TIME-COURSE; LUNG; BLEOMYCIN; CANCER AB While idiopathic pulmonary fibrosis (PF) is a devastating lung disease, the management of PP including effective monitoring of disease progression remains a challenge. Herein, we introduce a novel, fast, and ultrasensitive metalloproteinase (MMP) activatable optical probe, named MMP-P12, to noninvasively monitor PF progression and response to PF treatment A bleomycin (BLM)-induced mouse PF model was subjected noninvasively to optical imaging at various time points after BLM treatment The mouse PF model developed fibrosis during 21 days of experimental period, and the progression of PF was well correlated with the stepwise increase of MMP-2 expression as examined by quantitative RT-PCR and Western blot analysis on the 7-, 14-, and 21 day post-BLM administration. On these days, MMP-activated fluorescence images were acquired in vivo and ex vivo. Signal quantification showed time dependent lung specific incremental increases in fluorescence signals. As a treatment for PF, secretoglobin 3A2 was daily administered intravenously for five days starting on day seven of BLM administration, which resulted in reduced MMP-2 activity and reduction of PF as previously demonstrated Importantly, the fluorescence signal that reflected MMP activity also decreased in intensity. In conclusion, MMPs may play an important role in PF development and the, MMP-P12 probe, could be a promising tool for PP detection, even at an early stage of the disease as well as an indicator of therapy response. C1 [Cai, Yan; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Zhu, Lei; Zhang, Fan; Niu, Gang; Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov; shawn.chen@nih.gov RI Cai, Yan/P-4383-2015; Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU Major State Basic Research Development Program of China (973 Program) [2013CB733802]; National Science Foundation of China (NSFC) [81201129, 81101101, 81201086, 81201190, 51273165]; Chinese Academy of Sciences Professorship for Senior International Scientists [2011T2J06]; Key Project of Chinese Ministry of Education [212149]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Cancer Institute (NCI), National Institutes of Health (NIH) FX This work was supported by the Major State Basic Research Development Program of China (973 Program) (no. 2013CB733802), National Science Foundation of China (NSFC) (81201129, 81101101, 81201086, 81201190, and 51273165), Chinese Academy of Sciences Professorship for Senior International Scientists (2011T2J06), Key Project of Chinese Ministry of Education (212149), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Cancer Institute (NCI), National Institutes of Health (NIH). We thank Frank Gonzalez for his critical review of the manuscript. We also thank Jerrold M. Ward (Global Vet Pathology, Montgomery Village, Maryland) for histological analysis in this manuscript. NR 44 TC 13 Z9 15 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUN PY 2013 VL 10 IS 6 BP 2237 EP 2247 DI 10.1021/mp300613x PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 159AE UT WOS:000320015600015 PM 23607644 ER PT J AU Eilat-Adar, S Mete, M Fretts, A Fabsitz, RR Handeland, V Lee, ET Loria, C Xu, J Yeh, J Howard, BV AF Eilat-Adar, S. Mete, M. Fretts, A. Fabsitz, R. R. Handeland, V. Lee, E. T. Loria, C. Xu, J. Yeh, J. Howard, B. V. TI Dietary patterns and their association with cardiovascular risk factors in a population undergoing lifestyle changes: The Strong Heart Study SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE Cardiovascular risk; Dietary patterns; Lifestyle; Strong Heart Study ID AMERICAN-INDIANS; NUTRITION TRANSITION; PHYSICAL-ACTIVITY; NATIVE-AMERICANS; BLOOD-PRESSURE; DISEASE; QUESTIONNAIRE; CHOLESTEROL; PREVENTION; VALIDITY AB Background and aims: Rates of cardiovascular disease (CVD) are disproportionately high in American Indians (AI), and changes in lifestyle may be responsible. It is not known whether diverse dietary patterns exist in this population and whether the patterns are associated with CVD risk factors. This article describes the relationships between dietary patterns and CVD risk factors in this high-risk population. Methods and results: Nutrition data were collected via food frequency questionnaire from 3438 Strong Heart Study (SHS) participants, >= age 15 y. All participants were members of 94 extended families. The final sample consisted of 3172 men and women. Diet patterns were ascertained using factor analysis with the principal component factoring method. We derived four predominant dietary patterns: Western, traditional AI/Mexican, healthy, and unhealthy. Participants following the Western pattern had higher LDL cholesterol (LDL-C) (p < 0.001), slightly higher systolic blood pressure (BP) (p < 0.001), lower HDL cholesterol (HDL-C) (p < 0.001), and slightly lower homeostasis model assessment estimates of insulin resistance (HOMA-IR) in the lowest vs. highest deciles of adherence to this pattern (p < 0.001). The traditional diet was associated with higher HDL-C (p < 0.001), but higher body mass index (BMI) (p < 0.001) and HOMA-IR (p < 0.001). Followers of the healthy pattern had lower systolic BP, LDL-C, BMI, and HOMA-IR in increasing deciles (p < 0.001). The unhealthy pattern was associated with higher LDL-C. Conclusions: Dietary patterns reflect the changing lifestyle of AI and several of the patterns are associated with CVD risk factors. Evolving methods of food preparation have made the traditional pattern less healthy. (C) 2012 Elsevier B.V. All rights reserved. C1 [Eilat-Adar, S.; Mete, M.; Howard, B. V.] MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Eilat-Adar, S.] Zinman Coll Phys Educ & Sports, Wingate Inst, IL-42902 Netanya, Israel. [Fretts, A.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98052 USA. [Fabsitz, R. R.; Loria, C.] NHLBI, Bethesda, MD 20892 USA. [Handeland, V.] Diabet Prevent Project, Wagner Indian Hlth Serv, Wagner, SD 57380 USA. [Lee, E. T.; Yeh, J.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Xu, J.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Mete, M.; Howard, B. V.] Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC 20057 USA. RP Eilat-Adar, S (reprint author), Zinman Coll Phys Educ & Sports, Wingate Inst, IL-42902 Netanya, Israel. EM eilatsi@017.net.il FU National Heart, Lung, and Blood Institute [UO1HL-41642, U01HL-41652, UO1HL-41654, U01-HL65520, U01-HL65521]; National Center for Research Resources (NCRR), National Institutes of Health (NIH) [UL1RR031975] FX The Strong Heart Study is supported by grants (UO1HL-41642, U01HL-41652, UO1HL-41654, U01-HL65520, and U01-HL65521) from the National Heart, Lung, and Blood Institute. The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service. We gratefully acknowledge Rachel Schaperow, MedStar Health Research Institute, for editing the manuscript. Biostatistical support for this project has been funded in whole or in part with Federal funds (Grant # UL1RR031975) from the National Center for Research Resources (NCRR), National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA), a trademark of DHHS, part of the Roadmap Initiative, "Re-Engineering the Clinical Research Enterprise". NR 31 TC 21 Z9 21 U1 2 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD JUN PY 2013 VL 23 IS 6 BP 528 EP 535 DI 10.1016/j.numecd.2011.12.005 PG 8 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 167QE UT WOS:000320646000008 PM 22534653 ER PT J AU Zeuner, KE Knutzen, A Pedack, L Hallett, M Deuschl, G Volkmann, J AF Zeuner, Kirsten E. Knutzen, Arne Pedack, Lucas Hallett, Mark Deuschl, Guenther Volkmann, Jens TI Botulinum neurotoxin treatment improves force regulation in writer's cramp SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Focal hand dystonia; Writer's cramp; Force control; Botulinum neurotoxin treatment; Spindle afferents ID TONIC VIBRATION REFLEX; IDIOPATHIC FOCAL DYSTONIA; TOXIN TYPE-A; PRECISION GRIP; MUSCLE-SPINDLES; HAND DYSTONIA; RESPONSES; DISORDER; FINGER; INPUT AB Writer's cramp patients show poor force regulation during handwriting, but also in other experimental tasks requiring fine motor control. Botulinum neurotoxin (BoNT) treatment is clinically effective in a substantial portion of writer's cramp patients, but the full mechanism of action remains enigmatic. BoNT possibly influences alpha- and gamma-motoneurons through chemodenervation not only of extra-, but also intrafusal muscle fibres and might thus influence muscle spindle afferents. Hence, BoNT weakens injected muscles, but may also modulate sensory aspects of force control. Ten patients and 18 controls pressed their index finger on a force sensor tracking two visual targets: The first target consisted of five plateaus with successively higher force levels and alternated with ascending ramps. In the second target condition the same successive plateaus were to be reached by abrupt jumps. The generated force displayed as a time dependant curve. Root mean square of the difference between target and produced force level was calculated for each plateau/ramp/jump. Patients were treated with BoNT at week 4 and measured at baseline, weeks 2, 4, 6 and 8. Disturbed force regulation in patients for the plateaus and the second jump at baseline resolved after BoNT treatment, and the root mean square of force deviation decreased for the ramps. Fine force control was within the 95% confidence interval of the control group after treatment. In conclusion, force regulation was disturbed in patients and improved after BoNT treatment. This is not compatible with a simple muscle weakening and might thus reflect improved sensorimotor integration. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Zeuner, Kirsten E.; Knutzen, Arne; Pedack, Lucas; Deuschl, Guenther; Volkmann, Jens] Univ Kiel, Dept Neurol, Neurozentrum, D-24105 Kiel, Germany. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Volkmann, Jens] Univ Wurzburg, Dept Neurol, Wurzburg, Germany. RP Zeuner, KE (reprint author), Univ Kiel, Dept Neurol, Neurozentrum, Arnold Heller Str 3,Haus 41, D-24105 Kiel, Germany. EM k.zeuner@neurologie.uni-kiel.de RI Deuschl, Gunther/A-7986-2010; OI Volkmann, Jens/0000-0002-9570-593X FU Ipsen FX This work has been supported by an unrestricted grant from Ipsen. The authors report no conflict of interest. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 26 TC 3 Z9 3 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUN PY 2013 VL 19 IS 6 BP 611 EP 616 DI 10.1016/j.parkreldis.2013.02.011 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 171AG UT WOS:000320896200007 PM 23507416 ER PT J AU Pollack, MM Dean, JM Butler, J Holubkov, R Doctor, A Meert, KL Newth, CJL Berg, RA Moler, F Dalton, H Wessel, DL Berger, J Harrison, RE Carcillo, JA Shanley, TP Nicholson, CE AF Pollack, Murray M. Dean, J. Michael Butler, Jerry Holubkov, Richard Doctor, Allan Meert, Kathleen L. Newth, Christopher J. L. Berg, Robert A. Moler, Frank Dalton, Heidi Wessel, David L. Berger, John Harrison, Rick E. Carcillo, Joseph A. Shanley, Thomas P. Nicholson, Carol E. TI The Ideal Time Interval for Critical Care Severity-of-Illness Assessment SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE critical care; intensive care; outcome prediction; pediatric critical care; Pediatric Risk of Mortality score; pediatrics; scoring systems; severity of illness ID INTENSIVE-CARE; MORTALITY PREDICTION; PEDIATRIC INDEX; BIAS; MODEL AB Objective: Determine if the shortest sampling interval for laboratory variables used to estimate baseline severity of illness in pediatric critical care is equivalently sensitive across multiple sites without site-specific bias, while accounting for the vast majority of dysfunction compared with the standard 0- to 12-hour Pediatric Risk of Mortality III score. Design: Prospective random patient selection. Setting: General/medical and cardiac/cardiovascular PICUs in eight hospitals. Patients: Patients younger than 18 years admitted to the PICU. Interventions: None. Measurements and Main Results: A total of 376 patients were included. Measurements for Pediatric Risk of Mortality III laboratory variables (pH, Pco(2), total CO2, Pao(2), glucose, potassium, blood urea nitrogen, creatinine, total WBC count, platelet count, and prothrombin time/partial thromboplastin time) were recorded from 2 hours prior to PICU admission through 12 hours of PICU care except for data in the operating room. Decreasing the observation period from 0 to 12 hours post-PICU admission resulted in progressive decreases in the Pediatric Risk of Mortality III laboratory variables measured. However, allowing the observation period to start 2 hours prior to PICU admission to 4 hours reduced this loss to only 3.4%. Similar trends existed for each of the individual laboratory Pediatric Risk of Mortality III variables. There was a nearly identical distribution of laboratory Pediatric Risk of Mortality III points within the -2- to 4-hour period compared with the standard period. We did not detect any institutional bias using the -2- to 4-hour time period compared with the baseline. Conclusions: Prognostically important laboratory physiologic data collected within the interval from 2 hours prior to PICU to admission through 4 hours after admission account for the vast majority of dysfunction that these variables would contribute to Pediatric Risk of Mortality III scores. There was no institutional bias associated with this sampling period. C1 [Pollack, Murray M.] Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ USA. [Pollack, Murray M.; Dalton, Heidi] Univ Arizona, Coll Med Phoenix, Phoenix, AZ USA. [Dean, J. Michael; Butler, Jerry; Holubkov, Richard] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Biochem, St Louis, MO 63110 USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Berg, Robert A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Moler, Frank; Shanley, Thomas P.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Dalton, Heidi] Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ USA. [Wessel, David L.; Berger, John] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Harrison, Rick E.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Carcillo, Joseph A.] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Nicholson, Carol E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Pollack, MM (reprint author), Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ USA. EM mpollack@phoenixchildrens.com OI Doctor, Allan/0000-0002-6096-6400 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD FX Supported, in part, by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD. NR 12 TC 9 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD JUN PY 2013 VL 14 IS 5 BP 448 EP 453 DI 10.1097/PCC.0b013e31828a7270 PG 6 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 157SV UT WOS:000319920300008 PM 23628831 ER PT J AU Miller, B O'Donnell, C AF Miller, Brett O'Donnell, Carol TI Opening a Window Into Reading Development: Eye Movements' Role Within a Broader Literacy Research Framework SO SCHOOL PSYCHOLOGY REVIEW LA English DT Article ID PERCEPTUAL SPAN; COMPREHENSION PROCESSES; VISUAL INFORMATION; CONTROL CHILDREN; SKILLED READERS; SPOKEN LANGUAGE; WORD-FREQUENCY; FIXATIONS; ATTENTION; ADULTS AB The cumulative body of eye movement research provides significant insight into how readers process text. The heart of this work spans roughly 40 years reflecting the maturity of both the topics under study and experimental approaches used to investigate reading. Recent technological advancements offer increased flexibility to the field, providing the potential to more concertedly study reading and literacy from an individual differences perspective. Historically, eye movement research focused far less on developmental issues related to individual differences in reading; however, this issue and the broader change it represents signal a meaningful transition inclusive of individual differences. The six articles in this special issue signify the recent increased attention to and recognition of eye movement research's transition to emphasize individual differences in reading while appreciating early contributions (e.g., Rayner, 1986) in this direction. We introduce these six articles and provide some historical context for the use of eye movement methodology to examine reading and context for the eye movement field's early transition to examining individual differences, culminating in future research recommendations. C1 [Miller, Brett] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reading Writing & Related Learning Disabil Res Pr, Child Dev & Behav Branch, Bethesda, MD 20892 USA. [O'Donnell, Carol] Inst Sci Educ, Teaching & Learning Div, Natl Ctr Educ Res, Washington, DC USA. RP Miller, B (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,Suite 4B05,MSC 7510, Bethesda, MD 20892 USA. EM brett.miller@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 88 TC 7 Z9 7 U1 1 U2 13 PU NATL ASSOC SCHOOL PSYCHOLOGISTS PI BETHESDA PA 4340 EAST WEST HWY, STE 402, BETHESDA, MD 20814 USA SN 0279-6015 J9 SCHOOL PSYCHOL REV JI Sch. Psychol. Rev. PD JUN PY 2013 VL 42 IS 2 BP 123 EP 139 PG 17 WC Psychology, Educational SC Psychology GA 165NS UT WOS:000320491200001 PM 24391304 ER PT J AU Antonioli, L Pacher, P Vizi, ES Hasko, G AF Antonioli, Luca Pacher, Pal Vizi, E. Sylvester Hasko, Gyoergy TI CD39 and CD73 in immunity and inflammation SO TRENDS IN MOLECULAR MEDICINE LA English DT Review DE cytokine; Treg; macrophage; neutrophil; sepsis; CD39; CD73; ectonucleotidase ID REGULATORY T-CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; ISCHEMIA-REPERFUSION INJURY; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; FOLLICULAR DENDRITIC CELLS; CENTRAL-NERVOUS-SYSTEM; HUMAN BREAST-CANCER; ECTO-5'-NUCLEOTIDASE CD73; EXTRACELLULAR ADENOSINE; TUMOR-GROWTH AB The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders. C1 [Antonioli, Luca] Univ Pisa, Dept Clin & Expt Med, I-56126 Pisa, Italy. [Antonioli, Luca; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Antonioli, Luca; Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ 07103 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Vizi, E. Sylvester] Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. [Vizi, E. Sylvester] Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, H-1445 Budapest, Hungary. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU National Institutes of Health [R01GM66189]; USAMRMC [09065004] FX This work was supported by National Institutes of Health grant R01GM66189 and USAMRMC grant 09065004. NR 172 TC 152 Z9 154 U1 4 U2 64 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD JUN PY 2013 VL 19 IS 6 BP 355 EP 367 DI 10.1016/j.molmed.2013.03.005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 174IY UT WOS:000321150100004 PM 23601906 ER PT J AU Ko, SBH Azuma, S Yokoyama, Y Yamamoto, A Kyokane, K Niida, S Ishiguro, H Ko, MSH AF Ko, Shigeru B. H. Azuma, Sakiko Yokoyama, Yukihiro Yamamoto, Akiko Kyokane, Kazuhiro Niida, Shumpei Ishiguro, Hiroshi Ko, Minoru S. H. TI Inflammation increases cells expressing ZSCAN4 and progenitor cell markers in the adult pancreas SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE autoimmune pancreatitis; facultative progenitor cells; regeneration ID STEM-CELLS; MOUSE PANCREAS; BETA-CELLS; DUCT CELLS; IDENTIFICATION; INSULIN; LINEAGE; DIFFERENTIATION; BIRTH AB We have recently identified the zinc finger and SCAN domain containing 4 (Zscan4), which is transiently expressed and regulates telomere elongation and genome stability in mouse embryonic stem (ES) cells. The aim of this study was to examine the expression of ZSCAN4 in the adult pancreas and elucidate the role of ZSCAN4 in tissue inflammation and subsequent regeneration. The expression of ZSCAN4 and other progenitor or differentiated cell markers in the human pancreas was immunohistochemically examined. Pancreas sections of alcoholic or autoimmune pancreatitis patients before and under maintenance corticosteroid treatment were used in this study. In the adult human pancreas a small number of ZSCAN4-positive (ZSCAN4(+)) cells are present among cells located in the islets of Langerhans, acini, ducts, and oval-shaped cells. These cells not only express differentiated cell markers for each compartment of the pancreas but also express other tissue stem/progenitor cell markers. Furthermore, the number of ZSCAN4(+) cells dramatically increased in patients with chronic pancreatitis, especially in the pancreatic tissues of autoimmune pancreatitis actively regenerating under corticosteroid treatment. Interestingly, a number of ZSCAN4(+) cells in the pancreas of autoimmune pancreatitis returned to the basal level after 1 yr of maintenance corticosteroid treatment. In conclusion, coexpression of progenitor cell markers and differentiated cell markers with ZSCAN4 in each compartment of the pancreas may indicate the presence of facultative progenitors for both exocrine and endocrine cells in the adult pancreas. C1 [Ko, Shigeru B. H.; Ko, Minoru S. H.] Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med, Tokyo 1608582, Japan. [Azuma, Sakiko; Kyokane, Kazuhiro] Natl Ctr Geriatr & Gerontol, Dept Gastroenterol, Aichi, Japan. [Azuma, Sakiko; Niida, Shumpei] Natl Ctr Geriatr & Gerontol, Lab Genom & Prote, Aichi, Japan. [Yokoyama, Yukihiro] Nagoya Univ, Grad Sch Med, Dept Surg, Aichi, Japan. [Yamamoto, Akiko; Ishiguro, Hiroshi] Nagoya Univ, Grad Sch Med, Human Nutr Lab, Aichi, Japan. [Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, SBH (reprint author), Keio Univ, Sch Med, Dept Syst Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM kos@a6.keio.jp RI Ko, Shigeru/H-3450-2012; Ko, Minoru/B-7969-2009; Yokoyama, Yukihiro/I-7379-2014; YAMAMOTO, Akiko/M-8932-2014; ISHIGURO, Hiroshi/M-8851-2014 OI Ko, Shigeru/0000-0003-1913-6357; Ko, Minoru/0000-0002-3530-3015; FU Japanese Ministry of Education, Culture, Sports, Science, and Technology; Ministry of Health, Labor and Welfare for intractable pancreatic diseases; Nagono Medical foundation; Japan Medical Association; Intramural Research Program of the National Institute on Aging FX This work was supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology; the Ministry of Health, Labor and Welfare for intractable pancreatic diseases; Nagono Medical foundation; and Japan Medical Association. This research was supported in part by the Intramural Research Program of the National Institute on Aging. NR 29 TC 8 Z9 8 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUN PY 2013 VL 304 IS 12 BP G1103 EP G1116 DI 10.1152/ajpgi.00299.2012 PG 14 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 164WN UT WOS:000320442300007 PM 23599043 ER PT J AU Compton, WM Dawson, DA Conway, KP Brodsky, M Grant, BF AF Compton, Wilson M. Dawson, Deborah A. Conway, Kevin P. Brodsky, Marc Grant, Bridget F. TI Transitions in Illicit Drug Use Status Over 3 Years: A Prospective Analysis of a General Population Sample SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE DISORDERS; UNITED-STATES; PERSONALITY-DISORDERS; PSYCHIATRIC-DISORDERS; ALCOHOL DEPENDENCE; EARLY-ONSET; ABUSE; COMORBIDITY; PREVALENCE AB Objective: The authors examined 3-year transitions among nonuse, asymptomatic use, and problem use of illicit drugs for U.S. adults in the general household population. Method: Data were from the nationally representative National Epidemiologic Survey on Alcohol and Related Conditions, a study of 34,653 adults interviewed twice, 3.years apart. Respondents were categorized on three mutually exclusive categories of baseline drug status: past-year nonusers (N=32,675), past-year asymptomatic drug users (N=861), and past-year symptomatic drug users (N=1,117). Symptomatic drug use, or problem use, was defined as presence of one or more symptoms that operationalize DSM-IV drug abuse and dependence criteria. The authors assessed sociodemographic, health, substance use, and psychiatric covariates for association with 3-year transitions to different status categories. Results: Among baseline nonusers, 95.4% continued to be nonusers at follow-up, 2.1% became asymptomatic users, and 2.5% developed problem use. Among baseline asymptomatic users, 66.6% had stopped using drugs at follow-up, 14.3% continued to be asymptomatic users, and 19.1% had developed problem use. Nearly half (49.0%) of those with problem use at baseline had stopped using drugs at follow-up, 10.9% had transitioned to asymptomatic use, and 40.1% continued to have problem use. Younger age, male sex, white race, and not being married were associated with progression from nonuse to use or problem use, as were alcohol and tobacco use and disorders, major depression, and schizotypal, borderline, and narcissistic personality disorders. Panic disorder and avoidant personality disorder were associated with, less progression. Conclusions: Transitions in drug use status are common. The finding that alcohol and tobacco variables and co-occurring psychopathology are important correlates of transitions suggests the value of addressing all co-occurring disorders and substance use in patient assessments and treatment planning, both to prevent adverse transitions and to promote positive transitions. C1 [Compton, Wilson M.] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. NIAAA, Lab Epidemiol & Biometry, Bethesda, MD USA. Kelly Govt Serv, Bethesda, MD USA. RP Compton, WM (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov OI Conway, Kevin/0000-0002-7638-339X FU NIAAA; NIAAA's Intramural Program FX The study on which this paper is based, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), is sponsored by NIAAA, with supplemental support from NIDA. This research was supported in part by NIAAA's Intramural Program. NR 42 TC 15 Z9 15 U1 2 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 JUN PY 2013 VL 170 IS 6 BP 660 EP 670 DI 10.1176/appi.ajp.2012.12060737 PG 11 WC Psychiatry SC Psychiatry GA 159VG UT WOS:000320074800016 PM 23511653 ER PT J AU Hashimoto, R Ikeda, M Ohi, K Yasuda, Y Yamamori, H Fukumoto, M Umeda-Yano, S Dickinson, D Aleksic, B Iwase, M Kazui, H Ozaki, N Weinberger, DR Iwata, N Takeda, M AF Hashimoto, Ryota Ikeda, Masashi Ohi, Kazutaka Yasuda, Yuka Yamamori, Hidenaga Fukumoto, Motoyuki Umeda-Yano, Satomi Dickinson, Dwight Aleksic, Branko Iwase, Masao Kazui, Hiroaki Ozaki, Norio Weinberger, Daniel R. Iwata, Nakao Takeda, Masatoshi TI Genome-Wide Association Study of Cognitive Decline in Schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter C1 [Hashimoto, Ryota] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka, Japan. Osaka Univ, Dept Psychiat, Grad Sch Med, Suita, Osaka, Japan. Japan Sci & Technol Agcy, Core Res Evolutionary Sci & Technol, Kawaguchi, Saitama, Japan. Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 47011, Japan. Osaka Univ, Dept Mol Neuropsychiat, Grad Sch Med, Suita, Osaka, Japan. NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA. RP Hashimoto, R (reprint author), Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka, Japan. RI Hashimoto, Ryota/P-8572-2014; Ozaki, Norio/M-8908-2014; Aleksic, Branko/G-1540-2011 OI Hashimoto, Ryota/0000-0002-5941-4238; Ozaki, Norio/0000-0002-7360-4898; Aleksic, Branko/0000-0001-8982-4580 NR 3 TC 11 Z9 12 U1 2 U2 12 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2013 VL 170 IS 6 BP 683 EP 684 DI 10.1176/appi.ajp.2013.12091228 PG 2 WC Psychiatry SC Psychiatry GA 159VG UT WOS:000320074800022 PM 23732972 ER PT J AU Timbie, JW Ringel, JS Fox, S Pillemer, F Waxman, DA Moore, M Hansen, CK Knebel, AR Ricciardi, R Kellermann, AL AF Timbie, Justin W. Ringel, Jeanne S. Fox, Steven Pillemer, Francesca Waxman, Daniel A. Moore, Melinda Hansen, Cynthia K. Knebel, Ann R. Ricciardi, Richard Kellermann, Arthur L. TI Systematic Review of Strategies to Manage and Allocate Scarce Resources During Mass Casualty Events SO ANNALS OF EMERGENCY MEDICINE LA English DT Review ID CONSTRAINED TRIAGE METHOD; HEALTH-CARE; DISASTER RESPONSE; ANTHRAX BIOTERRORISM; EMERGENCY RESPONSE; HURRICANE KATRINA; MEDICAL RESPONSE; TRAUMA WORKLOAD; SURGE-CAPACITY; COMPUTER-MODEL AB Study objective: Efficient management and allocation of scarce medical resources can improve outcomes for victims of mass casualty events. However, the effectiveness of specific strategies has never been systematically reviewed. We analyze published evidence on strategies to optimize the management and allocation of scarce resources across a wide range of mass casualty event contexts and study designs. Methods: Our literature search included MEDLINE, Scopus, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Global Health, Web of Science, and the Cochrane Database of Systematic Reviews, from 1990 through late 2011. We also searched the gray literature, using the New York Academy of Medicine's Grey Literature Report and key Web sites. We included both English- and foreign-language articles. We included studies that evaluated strategies used in actual mass casualty events or tested through drills, exercises, or computer simulations. We excluded studies that lacked a comparison group or did not report quantitative outcomes. Data extraction, quality assessment, and strength of evidence ratings were conducted by a single researcher and reviewed by a second; discrepancies were reconciled by the 2 reviewers. Because of heterogeneity in outcome measures, we qualitatively synthesized findings within categories of strategies. Results: From 5,716 potentially relevant citations, 74 studies met inclusion criteria. Strategies included reducing demand for health care services (18 studies), optimizing use of existing resources (50), augmenting existing resources (5), implementing crisis standards of care (5), and multiple categories (4). The evidence was sufficient to form conclusions on 2 strategies, although the strength of evidence was rated as low. First, as a strategy to reduce demand for health care services, points of dispensing can be used to efficiently distribute biological countermeasures after a bioterrorism attack or influenza pandemic, and their organization influences speed of distribution. Second, as a strategy to optimize use of existing resources, commonly used field triage systems do not perform consistently during actual mass casualty events. The number of high-quality studies addressing other strategies was insufficient to support conclusions about their effectiveness because of differences in study context, comparison groups, and outcome measures. Our literature search may have missed key resource management and allocation strategies because of their extreme heterogeneity. lnterrater reliability was not assessed for quality assessments or strength of evidence ratings. Publication bias is likely, given the large number of studies reporting positive findings. Conclusion: The current evidence base is inadequate to inform providers and policymakers about the most effective strategies for managing or allocating scarce resources during mass casualty events. Consensus on methodological standards that encompass a range of study designs is needed to guide future research and strengthen the evidence base. Evidentiary standards should be developed to promote consensus interpretations of the evidence supporting individual strategies. C1 [Timbie, Justin W.; Ringel, Jeanne S.; Fox, Steven; Pillemer, Francesca; Waxman, Daniel A.; Moore, Melinda; Kellermann, Arthur L.] RAND Corp, Santa Monica, CA USA. [Hansen, Cynthia K.] US Dept HHS, Off Assistant Secretary Preparedness & Response, Bethesda, MD USA. [Knebel, Ann R.] NINR, NIH, Bethesda, MD 20892 USA. [Ricciardi, Richard] Agcy Healthcare Res & Qual, Rockville, MD USA. RP Timbie, JW (reprint author), RAND Corp, Santa Monica, CA USA. EM jtimbie@rand.org FU Southern California Evidence-based Practice Center from the Agency for Healthcare Research and Quality [290-2007-10062-I]; US Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response (ASPR) FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. This study was conducted by the Southern California Evidence-based Practice Center under contract 290-2007-10062-I from the Agency for Healthcare Research and Quality, with funding support from the US Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response (ASPR). Representatives of ASPR developed the research questions and contributed to the final article. NR 95 TC 17 Z9 17 U1 4 U2 40 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD JUN PY 2013 VL 61 IS 6 BP 677 EP 689 DI 10.1016/j.annemergmed.2013.02.005 PG 13 WC Emergency Medicine SC Emergency Medicine GA 161OZ UT WOS:000320204500016 PM 23522610 ER PT J AU Xin, HW Yang, JH Nguyen, DM AF Xin, Hong-Wu Yang, Jian-Hui Nguyen, Dao M. TI Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Requires E-Cadherin in Esophageal Cancer and Malignant Pleural Mesothelioma SO ANTICANCER RESEARCH LA English DT Article DE E-Cadherin; epidermal growth factor receptor; tyrosine kinase inhibitor; esophageal cancer; malignant pleural mesothelioma; epithelial to mesenchymal transition (EMT) ID CELL LUNG-CANCER; MESENCHYMAL TRANSITION; IN-VITRO; ERLOTINIB; EXPRESSION; ADHESION; METASTASIS; ACTIVATION; MUTATIONS; GEFITINIB AB Background/Aim: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has limited anticancer efficacy in EGFR -positive esophageal cancer (EsC) and malignant mesothelioma (MPM). The underlying molecular mechanism of resistance to EGFR-TKI in these types of cancer remains unclear. Materials and Methods: We tested sensitivity to EGFR-TKI, expression/activity of common signal transduction pathways and epithelial to mesenchymal transition (EMT) gene signatures in 14 EsC and MPM cultured cell lines in vitro. Results: More than 50% EGFR-positive EsC and MPM cells were resistant to EGFR-TKI, and susceptibility to EGFR-TKI growth-inhibitory effect correlated positively with expression of E-cadherin (epithelial gene marker) and negatively with mesenchymal gene markers. Acquired resistance to EGFR-TKI in intrinsically sensitive cancer cells coincided with spontaneous loss of E-cadherin, while ectopic expression of E-cadherin sensitized resistant cells to EGFR-TKI. Conclusion: E-Cadherin expression appears to be not only a strong biomarker but also a functional requirement and potential therapeutic target for sensitivity to EGFR-TKI. C1 [Xin, Hong-Wu; Yang, Jian-Hui; Nguyen, Dao M.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yang, Jian-Hui] First Peoples Hosp Yichang, Dept Gen Surg, Yichang, Hubei, Peoples R China. [Yang, Jian-Hui] China Three Gorges Univ, Peoples Hosp, Yichang City, Hubei, Peoples R China. [Nguyen, Dao M.] Univ Miami, Dept Surg, Div Cardiothorac Surg, Sect Thorac Surg, Miami, FL USA. RP Nguyen, DM (reprint author), POB 016960 R-114, Miami, FL USA. EM dnguyen4@med.miami.edu FU Intramural Research Program of the National Cancer Institute, NIH, U.S.A. FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, U.S.A. We sincerely thank Dr. Douglas R. Lowy (NCI/NIH, MD, USA) for providing the E-cadherin plasmid, Dr. David Schrump (NCI/NIH, MD, USA) for providing the EsC and some of the MPM cell lines, Dr. Harvey I. Pass (NYU, NY, USA) for providing some of the MPM cells and Ms. Amy Loehfelm for her assistance. NR 25 TC 4 Z9 4 U1 0 U2 2 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUN PY 2013 VL 33 IS 6 BP 2401 EP 2408 PG 8 WC Oncology SC Oncology GA 165LC UT WOS:000320484400007 PM 23749888 ER PT J AU Cha, J Jo, HJ Kim, HJ Seo, SW Kim, HS Yoon, U Park, H Na, DL Lee, JM AF Cha, Jungho Jo, Hang Joon Kim, Hee Jin Seo, Sang Won Kim, Han-Soo Yoon, Uicheul Park, Hyunjin Na, Duk L. Lee, Jong-Min TI Functional alteration patterns of default mode networks: comparisons of normal aging, amnestic mild cognitive impairment and Alzheimer's disease SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE Alzheimer's disease; default mode network; functional magnetic resonance imaging; mild cognitive impairment; resting-state ID RESTING-STATE FMRI; INDEPENDENT COMPONENT ANALYSIS; POSTERIOR CINGULATE CORTEX; CORTICAL THICKNESS; BRAIN IMAGES; CONNECTIVITY; MRI; DEMENTIA; ROBUST; OPTIMIZATION AB Most default mode network (DMN) studies in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) are based on the comparison of only two groups, namely patients and controls. Information derived from comparing three groups, normal, aMCI and AD, simultaneously may lead us to better understand the progression of dementia. The purpose of this study was to evaluate functional connectivity of DMN in the continuum from normal through aMCI to AD. Differences in functional connectivity were compared between the three groups using independent component analysis. The relationship between functional connectivity and disease progression was investigated using multiple regression analysis with Mini-Mental State Examination (MMSE) scores. The results revealed differences throughout the left posterior cingulate cortex (PCC), left middle temporal gyrus (MTG), right middle frontal gyrus (MFG) and bilateral parahippocampal gyrus (PHG). Both patients with aMCI and those with AD showed decreased connectivity in the left PCC and left PHG compared with healthy subjects. Furthermore, patients with AD also showed decreased connectivity in the left MTG and right PHG. Increased functional connectivity was observed in the right MFG of patients with AD compared with other groups. MMSE scores exhibited significant positive and negative correlations with functional connectivity in PCC, MTG and MFG regions. Taken together, increased functional connectivity in the MFG for AD patients might compensate for the loss of function in the PCC and MTG via compensatory mechanisms in corticocortical connections. C1 [Cha, Jungho; Kim, Han-Soo; Lee, Jong-Min] Hanyang Univ, Dept Biomed Engn, Seoul 133791, South Korea. [Jo, Hang Joon] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kim, Hee Jin; Seo, Sang Won; Na, Duk L.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurol, Seoul, South Korea. [Yoon, Uicheul] Catholic Univ Daegu, Coll Hlth & Med Sci, Dept Biomed Engn, Gyongsan, South Korea. [Park, Hyunjin] Sungkyunkwan Univ, Sch Elect & Elect Engn, Suwon, South Korea. RP Lee, JM (reprint author), Hanyang Univ, Dept Biomed Engn, Seoul 133791, South Korea. EM ljm@hanyang.ac.kr RI JO, HANG JOON/D-1775-2011; Park, Hyunjin/A-1164-2007 OI JO, HANG JOON/0000-0002-9180-3831; Park, Hyunjin/0000-0001-5681-8918 FU National Research Foundation of Korea (NRF); Korea government (MEST) [2011-0028333]; Korean Healthcare Technology RD Project [A102065]; Basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0014862]; NIMH; NINDS Intramural Research Program of the NIH FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0028333) and also supported by Korean Healthcare Technology R&D Project (A102065). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014862). H.J.J is supported by NIMH and NINDS Intramural Research Program of the NIH. Thanks for helpful discussion of our paper to Professors Martin Sarter and Doug Munoz. NR 52 TC 15 Z9 17 U1 1 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2013 VL 37 IS 12 SI SI BP 1916 EP 1924 DI 10.1111/ejn.12177 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 165GA UT WOS:000320470200005 PM 23773060 ER PT J AU Gameiro, SR Jammeh, ML Hodge, JW AF Gameiro, Sofia R. Jammeh, Momodou L. Hodge, James W. TI Cancer vaccines targeting carcinoembryonic antigen: state-of-the-art and future promise SO EXPERT REVIEW OF VACCINES LA English DT Review DE carcinoembryonic antigen; clinical trials; immunotherapy; preclinical studies; vaccine ID REGULATORY T-CELLS; METASTATIC COLORECTAL-CANCER; ANTITUMOR IMMUNE-RESPONSES; MURINE DENDRITIC CELLS; POXVIRAL-BASED VACCINE; COLON-CANCER; LUNG-CANCER; ENHANCED COSTIMULATION; RECOMBINANT VACCINE; COMBINATION THERAPY AB Concurrent with the US FDA's approval of the first therapeutic cancer vaccine, and supported by mounting clinical evidence indicating that targeting carcinoembryonic antigen (CEA) can safely overcome pre-existing tolerance, a multitude of novel CEA cancer vaccines are now in various stages of development. Since cancer-driven immune suppression often limits the efficacy of vaccines, numerous strategies are being examined in both preclinical and clinical settings to overcome immunosuppressive elements, including the combined use of vaccines with certain chemotherapies, immune checkpoint inhibitors, small-molecule targeted therapies and radiation. This review discusses the current state and future direction of therapeutic cancer vaccines targeting CEA, based on advances achieved over the last 5 years. C1 [Gameiro, Sofia R.; Jammeh, Momodou L.; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU NIH; Center for Cancer Research, National Cancer Institute, NIH FX ML Jammeh is an awardee of the NIH Undergraduate Scholar Program. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. 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 88 TC 11 Z9 11 U1 0 U2 11 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUN PY 2013 VL 12 IS 6 BP 617 EP 629 DI 10.1586/ERV.13.40 PG 13 WC Immunology SC Immunology GA 161CO UT WOS:000320169300009 PM 23750792 ER PT J AU Hoofnagle, JH AF Hoofnagle, Jay H. TI Drug-Induced Liver Injury: Icelandic Lessons SO GASTROENTEROLOGY LA English DT Editorial Material ID CLINICAL-FEATURES C1 [Hoofnagle, Jay H.] NIH, NIDDK, Div Digest Dis & Nutr, Liver Dis Res Branch, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDK, DDN, Liver Dis Branch, 6707 Democracy Blvd,Room 644, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov NR 12 TC 3 Z9 3 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2013 VL 144 IS 7 BP 1335 EP 1336 DI 10.1053/j.gastro.2013.04.026 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 151ZI UT WOS:000319498500009 PM 23623967 ER PT J AU Fusco, DN Brisac, C John, SP Huang, YW Chin, CR Xie, T Zhao, H Jilg, N Zhang, LL Chevaliez, S Wambua, D Lin, WY Peng, L Chung, RT Brass, AL AF Fusco, Dahlene N. Brisac, Cynthia John, Sinu P. Huang, Yi-Wen Chin, Christopher R. Xie, Tiao Zhao, Hong Jilg, Nikolaus Zhang, Leiliang Chevaliez, Stephane Wambua, Daniel Lin, Wenyu Peng, Lee Chung, Raymond T. Brass, Abraham L. TI A Genetic Screen Identifies Interferon-alpha Effector Genes Required to Suppress Hepatitis C Virus Replication SO GASTROENTEROLOGY LA English DT Article DE Treatment; Gene Regulation; Virology; Mechanism ID RAT-LIVER; PATHWAYS; PROTEINS; CELLS; EXPRESSION; COFACTOR; GAMMA AB BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon-alpha (IFN alpha) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFN alpha (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFN alpha. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach. METHODS: We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFN alpha and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further. RESULTS: The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, alpha-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidylpeptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, beta 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, beta isoform; peroxisomal proliferator-activated receptor-gamma-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFN alpha-mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFN alpha to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFN alpha; these genes represent a heretofore unknown class of non-IFN-stimulated gene IEGs. CONCLUSIONS: We performed a whole-genome loss-of-function screen to identify genes that mediate the effects of IFN alpha against human pathogenic viruses. We found that IFN alpha restricts HCV via actions of general and specific IEGs. C1 [Fusco, Dahlene N.; Brisac, Cynthia; Jilg, Nikolaus; Chevaliez, Stephane; Wambua, Daniel; Lin, Wenyu; Peng, Lee; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [John, Sinu P.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Huang, Yi-Wen] Natl Taiwan Univ, Coll Med, Dept Internal Med, Taipei, Taiwan. [Huang, Yi-Wen] Cathay Gen Hosp, Med Ctr, Hosp Liver Ctr, Taipei, Taiwan. [Huang, Yi-Wen] Taipei Med Univ, Sch Med, Taipei, Taiwan. [Chin, Christopher R.; Brass, Abraham L.] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01605 USA. [Xie, Tiao] Harvard Univ, Sch Med, Image & Data Anal Core, Boston, MA USA. [Zhao, Hong] Peking Univ, Hosp Beijing 1, Dept Infect Dis, Beijing, Peoples R China. [Zhang, Leiliang] Chinese Acad Med Sci, Inst Pathogen Biol, MOH Key Lab Syst Biol Pathogens, Beijing 100730, Peoples R China. [Zhang, Leiliang] Peking Union Med Coll, Beijing 100021, Peoples R China. [Chevaliez, Stephane] Univ Paris Est, Dept Virol, Hosp Univ Henri Mondor, Creteil, France. [John, Sinu P.; Chin, Christopher R.; Brass, Abraham L.] Ragon Inst, Charlestown, MA USA. RP Brass, AL (reprint author), Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, 55 Lake Ave North, Worcester, MA 01605 USA. EM rtchung@partners.org; abraham.brass@umassmed.edu FU NIH [U19 AI082630, 1R01AI091786]; American Association for the Study of Liver Disease; ANRS (French National Agency for Research on AIDS and Viral Hepatitis); Gilead FX This work was supported by NIH U19 AI082630 (R. T. Chung, A. L. Brass, and D. N. Fusco). D. N. Fusco is grateful for support from a Clinical and Translational Research Award from the American Association for the Study of Liver Disease. S. Chevalier is grateful for support from ANRS (French National Agency for Research on AIDS and Viral Hepatitis) and Gilead. A. L. Brass is grateful to the Charles H. Hood Foundation, the Bill and Melinda Gates Foundation, the Phillip T. and Susan M. Ragon Foundation, the University of Massachusetts Medical School Center for AIDS Research, and the NIH (1R01AI091786) for their generous support. NR 30 TC 21 Z9 21 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2013 VL 144 IS 7 BP 1438 EP U210 DI 10.1053/j.gastro.2013.02.026 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 151ZI UT WOS:000319498500027 PM 23462180 ER PT J AU Ayele, FT Alemu, G Davey, G Ahrens, C AF Ayele, Fasil Tekola Alemu, Getahun Davey, Gail Ahrens, Christel TI Community-based survey of podoconiosis in Bedele Zuria woreda, west Ethiopia SO INTERNATIONAL HEALTH LA English DT Article DE Podoconiosis; Non-filarial elephantiasis; Lymphoedema; Prevalence; Survey; Ethiopia ID NON-FILARIAL ELEPHANTIASIS; SOUTHERN ETHIOPIA; BANCROFTIAN FILARIASIS; NORTHERN ETHIOPIA; HIGH PREVALENCE; WOLAITA ZONE; DISTRICT; STIGMA; EAST; EPISODES AB Podoconiosis is a neglected tropical disease resulting in progressive bilateral swelling of the lower legs in barefoot individuals exposed to red-clay soil derived from volcanic rocks. It is a considerable public health problem in countries across tropical Africa, Central America and northern India. The present study aimed to assess the prevalence and clinical features of podoconiosis, and patients experience of disease prevention and treatment, in Bedele Zuria woreda (district), west Ethiopia. The study was conducted during 2011 and involved a house-to-house survey in all 2285 households of five randomly selected rural kebeles (villages). The prevalence of podoconiosis was 5.6 (379/6710) (95 CI 5.16.2) and was significantly greater among women than men (6.6 vs 4.7; p 0.001). A total of 311 (16.9) households had at least one member with podoconiosis, and 128 (33.8) study participants reported having a blood relative with podoconiosis. Two hundred and forty-three (76.4) podoconiosis patients were in the economically productive age group of 1564 years. On average, a patient experienced at least six episodes of adenolymphangitis per year resulting in a loss of 25 working days per year. This study has revealed a high burden of podoconiosis in west Ethiopia, and suggests that disease prevention and treatment programmes are needed. C1 [Ayele, Fasil Tekola] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Alemu, Getahun] SOS Childrens Villages Int, Addis Ababa, Ethiopia. [Davey, Gail] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Ahrens, Christel] Int Inst Child Hlth, London, England. RP Ayele, FT (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4044,12 South Dr, Bethesda, MD 20892 USA. EM ayeleft@mail.nih.gov OI Tekola-Ayele, Fasil/0000-0003-4194-9370 FU International Orthodox Christian Charities (IOCC) Podoconiosis Research FX This work was supported by a donation through International Orthodox Christian Charities (IOCC) Podoconiosis Research for undertaking baseline surveys, capacity building, and training in North Ethiopia. NR 28 TC 10 Z9 10 U1 1 U2 2 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 JUN PY 2013 VL 5 IS 2 BP 119 EP 125 DI 10.1093/inthealth/iht003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 164KM UT WOS:000320408000005 ER PT J AU Wind, JJ Lonser, RR Nieman, LK DeVroom, HL Chang, R Oldfield, EH AF Wind, Joshua J. Lonser, Russell R. Nieman, Lynnette K. DeVroom, Hetty L. Chang, Richard Oldfield, Edward H. TI The Lateralization Accuracy of Inferior Petrosal Sinus Sampling in 501 Patients With Cushing's Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY VENOUS EFFLUENT; DIFFERENTIAL-DIAGNOSIS; PROLACTIN; ACTH; ADENOMAS; MARKER; TUMORS AB Context: It is often difficult to find an adenoma in patients with Cushing's disease (CD) whose preoperative magnetic resonance imaging (MRI) is normal. Better localizing modalities are needed. Objective: The aim of this study was to determine the accuracy of inferior petrosal sinus sampling (IPSS) in predicting adenoma lateralization. Design and Setting: We conducted a prospective observational study at a tertiary care clinical research center. Patients: A total of 501 consecutive patients (363 female) with confirmed ACTH adenomas and IPSS were included. Main Outcome Measure: We measured the accuracy of IPSS to predict the intrasellar location of an adenoma. Results: IPSS confirmed a pituitary source of ACTH secretion in 491 patients (98%). All 10 patients with false-negative results had peak IPSS ACTH concentrations (before or after CRH) of < 400 pg/ml. Interpetrosal (side-to-side) ratios were >= 1.4 in 491 patients (98%). This ratio correctly predicted lateralization in 273 of 396 patients (positive predictive value = 69%) with a lateral adenoma. Left-sided IPSS lateralization (P = .008) and consistent lateralization before and after CRH administration (P = .02) were associated with enhanced accuracy. When positive, preoperative MRI correlated with adenoma location in 171 of 201 patients (positive predictive value = 86%). Conclusions: Potential false-negative results, the most common type of diagnostic error with IPSS for the differential diagnosis of CS, can be identified by peak IPSS ACTH values < 400 pg/ml. When MRI is normal, IPSS can be used to guide surgical exploration in patients with negative preoperative imaging. However, because of the limited accuracy of lateralization, thorough exploration of the pituitary gland is required when an adenoma is not readily discovered based on predicted location. C1 [Wind, Joshua J.; Lonser, Russell R.; DeVroom, Hetty L.; Oldfield, Edward H.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20824 USA. [Wind, Joshua J.] George Washington Univ, Dept Neurol Surg, Med Ctr, Washington, DC 20037 USA. [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Chang, Richard] NINDS, Dept Radiol, NIH, Bethesda, MD 20824 USA. [Oldfield, Edward H.] Univ Virginia, Dept Neurol Surg, Hlth Sci Ctr, Charlottesville, VA 22908 USA. RP Oldfield, EH (reprint author), Univ Virginia, Dept Neurol Surg, POB 800212, Charlottesville, VA 22908 USA. EM eho4u@virginia.edu FU National Institute of Neurologic Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health; Development at the National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Neurologic Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Development at the National Institutes of Health. NR 23 TC 23 Z9 24 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2013 VL 98 IS 6 BP 2285 EP 2293 DI 10.1210/jc.2012-3943 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 155GS UT WOS:000319736500032 PM 23553862 ER PT J AU Schwartz, AV Sigurdsson, S Hue, TF Lang, TF Harris, TB Rosen, CJ Vittinghoff, E Siggeirsdottir, K Sigurdsson, G Oskarsdottir, D Shet, K Palermo, L Gudnason, V Li, XJ AF Schwartz, Ann V. Sigurdsson, Sigurdur Hue, Trisha F. Lang, Thomas F. Harris, Tamara B. Rosen, Clifford J. Vittinghoff, Eric Siggeirsdottir, Kristin Sigurdsson, Gunnar Oskarsdottir, Diana Shet, Keerthi Palermo, Lisa Gudnason, Vilmundur Li, Xiaojuan TI Vertebral Bone Marrow Fat Associated With Lower Trabecular BMD and Prevalent Vertebral Fracture in Older Adults SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; MINERAL DENSITY; AGES-REYKJAVIK; ADIPOSE-TISSUE; WOMEN; ADIPOCYTES; MEN; PROLIFERATION; OSTEOPOROSIS; PERFUSION AB Context: Bone marrow fat (BMF) and bone mineral density (BMD) by dual x-ray energy absorptiometry (DXA) are negatively correlated. However, little is known about the association of BMF with fracture or with separate trabecular and cortical bone compartments. Objective: Our objective was to assess the relationships between vertebral BMF, BMD by quantitative computed tomography, and fracture in older adults. Design, Setting, and Participants: We conducted a cross-sectional study in the Age Gene/Environment Susceptibility-Reykjavik cohort. Main Outcome Measures: Outcomes measures included vertebral BMF (L1-L4) measured with magnetic resonance spectroscopy, quantitative computed tomography and DXA scans of the hip and spine, and DXA vertebral fracture assessments. Previous clinical fracture was determined from medical records. Results: In 257 participants without recent bone-active medication use, mean age was 79 (SD 3.1) years. Mean BMF was 53.5% +/- 8.1% in men and 55.0% +/- 8.4% in women. Those with prevalent vertebral fracture (21 men, 32 women) had higher mean BMF in models adjusted for BMD. In separate models by sex, the difference was statistically significant only in men the spine (-10.5% difference for each 1 SD increase in BMF, P < 0.01), total hip, and femoral neck, but not with cortical vBMD, in women. In men, BMF was marginally associated with trabecular spine vBMD (-6.1%, P = 0.05). Total hip and spine areal BMD (aBMD) were negatively correlated with BMF in women only. Conclusion: Higher marrow fat correlated with lower trabecular, but not cortical, BMD in older women but not men. Higher marrow fat was associated with prevalent vertebral fracture in men, even after adjustment for BMD. C1 [Schwartz, Ann V.; Hue, Trisha F.; Lang, Thomas F.; Vittinghoff, Eric; Siggeirsdottir, Kristin; Palermo, Lisa; Li, Xiaojuan] Univ Calif San Francisco, San Francisco, CA 94107 USA. [Sigurdsson, Sigurdur; Oskarsdottir, Diana; Shet, Keerthi; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Rosen, Clifford J.] Maine Med Ctr Res Inst, Scarborough, ME 04074 USA. [Sigurdsson, Gunnar; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Sigurdsson, Gunnar] Landspitali Univ Hosp, Dept Endocrinol & Metab, IS-101 Reykjavik, Iceland. RP Schwartz, AV (reprint author), 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM aschwartz@psg.ucsf.edu RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Lang, Thomas/0000-0002-3720-8038 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR057819]; National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Althingi (The Icelandic Parliament); National Institute of Diabetes and Digestive and Kidney Diseases [R24DK092759]; Hjartavernd (The Icelandic Heart Association) FX This ancillary study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR057819). The AGES Reykjavik Study is supported by funding from the National Institutes of Health (Contract N01-AG-12100), the National Institute on Aging Intramural Research Program, Hjartavernd (The Icelandic Heart Association), and the Althingi (The Icelandic Parliament). C.R. received support from the National Institute of Diabetes and Digestive and Kidney Diseases (R24DK092759). NR 31 TC 40 Z9 41 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2013 VL 98 IS 6 BP 2294 EP 2300 DI 10.1210/jc.2012-3949 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 155GS UT WOS:000319736500033 PM 23553860 ER PT J AU Smallridge, RC Copland, JA Brose, MS Wadsworth, JT Houvras, Y Menefee, ME Bible, KC Shah, MH Gramza, AW Klopper, JP Marlow, LA Heckman, MG Von Roemeling, R AF Smallridge, R. C. Copland, J. A. Brose, M. S. Wadsworth, J. T. Houvras, Y. Menefee, M. E. Bible, K. C. Shah, M. H. Gramza, A. W. Klopper, J. P. Marlow, L. A. Heckman, M. G. Von Roemeling, R. TI Efatutazone, an Oral PPAR-gamma Agonist, in Combination With Paclitaxel in Anaplastic Thyroid Cancer: Results of a Multicenter Phase 1 Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARCINOMA; DOCETAXEL; GROWTH; RHOB AB Purpose: A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer. Experimental Design: Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics. Results: Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3mgof efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had >= 1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients. Conclusions: Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity. C1 [Smallridge, R. C.; Copland, J. A.; Menefee, M. E.; Marlow, L. A.; Heckman, M. G.] Mayo Clin, Jacksonville, FL 32224 USA. [Brose, M. S.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Wadsworth, J. T.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Houvras, Y.] Weill Cornell Med Coll, New York, NY 10021 USA. [Bible, K. C.] Mayo Clin, Rochester, MN 55905 USA. [Shah, M. H.] Ohio State Univ, Columbus, OH 43210 USA. [Gramza, A. W.] NCI, Bethesda, MD 20892 USA. [Klopper, J. P.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Von Roemeling, R.] Daiichi Sankyo Pharma Dev, Edison, NJ 08837 USA. RP Smallridge, RC (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM smallridge.robert@mayo.edu FU National Institutes of Health/National Cancer Institute [R01 CA136665]; Daiichi Sankyo; Bayer Healthcare; Onyx; Exelixis; Novartis; Genentech/Roche; AstraZeneca; Bristol-Myers Squibb; OXi-GENE FX The immunohistochemistry analyses were funded in part by National Institutes of Health/National Cancer Institute Grant R01 CA136665 (to J.A.C. and R.C.S.).; J.A.C. has received research funding from Daiichi Sankyo. M.S.B. has received research funding and honoraria from Bayer Healthcare, Onyx, and Exelixis, research funding from Novartis and Genentech/Roche, and consulting fees from AstraZeneca, Bristol-Myers Squibb, and OXi-GENE. Y.H. has received consulting fees from Exelixis. M.H.S. has received research funding from Daiichi Sankyo. R.V.R. is an employee of Daiichi Sankyo. The other authors have nothing to disclose. NR 23 TC 31 Z9 31 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2013 VL 98 IS 6 BP 2392 EP 2400 DI 10.1210/jc.2013-1106 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 155GS UT WOS:000319736500045 PM 23589525 ER PT J AU van Ballegooijen, AJ Visser, M Cotch, MF Arai, AE Garcia, M Harris, TB Launer, LJ Eiriksdottir, G Gudnason, V Brouwer, IA AF van Ballegooijen, A. J. Visser, M. Cotch, M. F. Arai, A. E. Garcia, M. Harris, T. B. Launer, L. J. Eiriksdottir, G. Gudnason, V. Brouwer, I. A. TI Serum Vitamin D and Parathyroid Hormone in Relation to Cardiac Structure and Function: The ICELAND-MI Substudy of AGES-Reykjavik SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LEFT-VENTRICULAR GEOMETRY; CONGESTIVE-HEART-FAILURE; D DEFICIENCY; CARDIOVASCULAR-DISEASE; MAGNETIC-RESONANCE; PRIMARY HYPERPARATHYROIDISM; CONTRACTILE PERFORMANCE; CORONARY-ANGIOGRAPHY; MYOCARDIAL STRUCTURE; 25-HYDROXYVITAMIN D AB Context: Emerging evidence suggests that vitamin D and PTH may play a role in the development of cardiac diseases. Objective: We investigated whether 25-hydroxyvitamin D (25OHD) and PTH concentrations are cross-sectionally associated with cardiac structure and function using magnetic resonance imaging (MRI). Design, Setting, and Participants: ICELAND-MI is a substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study, an older-aged community-dwelling cohort with oversampling of participants with diabetes (29%) and measurements between 2004 and 2007. Serum 25OHD concentrations were measured using an immunoassay (n = 992). Intact PTH concentrations were measured using a 2-site immunoassay (n = 203). We included 969 participants for this cross-sectional analysis (mean age 76 +/- 5.3 years, 51% female). Mean 25OHD was 54.2 +/- 25.5 nmol/L and the median PTH was 4.5 pmol/L (range 1.5-18). Main Outcomes: MRI to measure cardiac structure and function was the main outcome. Results: The lowest 25OHD category (< 25 nmol/L) compared with the highest category (< 75 nmol/L) was associated with a smaller left and right atrial area in unadjusted analyses; however, the associations became nonsignificant after adjustment for covariates. The highest PTH quartile compared with the lowest quartile was significantly associated with a 7.3 g (95% confidence interval 0.8, 13.8) greater left ventricular (LV) mass and a 5.1% (-9.1, -1.1) lower LV ejection fraction compared with the lowest PTH quartile in the fully adjusted model. Conclusions: Serum 25OHD concentrations were not associated with MRI measures in an older white population. Higher PTH concentrations were associated with greater LV mass and lower systolic function and may point to a potential role for PTH as a determinant of cardiac remodeling. C1 [van Ballegooijen, A. J.; Visser, M.; Brouwer, I. A.] Vrije Univ Amsterdam, Dept Hlth Sci, NL-1081 HV Amsterdam, Netherlands. [van Ballegooijen, A. J.; Visser, M.; Brouwer, I. A.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands. [Visser, M.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1081 HV Amsterdam, Netherlands. [Cotch, M. F.] NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. [Arai, A. E.] NHLBI, NIH, Bethesda, MD 20824 USA. NIA, Lab Epidemiol, Bethesda, MD 20892 USA. [Garcia, M.; Harris, T. B.; Launer, L. J.] NIA, Biometry Intramural Res Program, Bethesda, MD 20892 USA. [Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc, IS-201 Kapovogur, Iceland. [Gudnason, V.] Univ Iceland, IS-101 Reykjavik, Iceland. RP van Ballegooijen, AJ (reprint author), Vrije Univ Amsterdam, Dept Hlth Sci, Fac Earth & Life Sci, Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands. EM hanne.van.ballegooijen@vu.nl RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350 FU Royal Netherlands Academy of Arts and Sciences; National Institutes on Aging Intramural Research Program [N01-AG-12100]; National of Heart, Lung, and Blood Institute Intramural Research Program [ZIAHL004607-08 CE]; National Eye Institute Intramural Research Program [ZIAEY000401]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Icelandic National Bioethics Committee [VSN: 00-063]; Medstar Research Institute [2003-145] FX This work was supported by the Royal Netherlands Academy of Arts and Sciences and was supported by Contract N01-AG-12100 from the National Institutes on Aging Intramural Research Program; Grant ZIAHL004607-08 CE from the National of Heart, Lung, and Blood Institute Intramural Research Program; Grant ZIAEY000401 from the National Eye Institute Intramural Research Program; the Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Medstar Research Institute (Project 2003-145). NR 42 TC 25 Z9 25 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2013 VL 98 IS 6 BP 2544 EP 2552 DI 10.1210/jc.2012-4252 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 155GS UT WOS:000319736500063 PM 23585664 ER PT J AU Nash, TE AF Nash, Theodore E. TI Unraveling how Giardia infections cause disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID LAMBLIA AB A 40-year-old NIH male scientist camped and fished in a remote lake in Alaska. On his return, he developed diarrhea, cramps, and loose stools without blood or mucus in the absence of fever and was diagnosed with giardiasis. A 3-year-old female living in the Florida Keys complained of intermittent stomachaches over a 2-month period. Her stools were variably loose. The patient was diagnosed with giardiasis, which led to examination of her mother, father, and brother, who were mildly symptomatic; all 3 were subsequently diagnosed with giardiasis. The child's only exposure was from swimming in a local community pool. A 40-year-old male from Mexico, who resided in Virginia and worked as a cook in a fast food restaurant, was diagnosed with giardiasis. He denied any symptoms and was not allowed to prepare food. Treatment with metronidazole, nitazoxanide, and albendazole failed to eradicate the infection. He was successfully treated with the combination of paromomycin and metronidazole. C1 NIAID, Gastrointestinal Parasites Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAID, Gastrointestinal Parasites Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 424, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov FU NIAID, NIH FX This commentary was supported by the Intramural Research Program of NIAID, NIH. NR 11 TC 4 Z9 5 U1 1 U2 16 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2013 VL 123 IS 6 BP 2346 EP 2347 DI 10.1172/JCI69956 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 160CD UT WOS:000320093100003 PM 23728165 ER PT J AU Vannucci, A Tanofsky-Kraff, M Crosby, RD Ranzenhofer, LM Shomaker, LB Field, SE Mooreville, M Reina, SA Kozlosky, M Yanovski, SZ Yanovski, JA AF Vannucci, Anna Tanofsky-Kraff, Marian Crosby, Ross D. Ranzenhofer, Lisa M. Shomaker, Lauren B. Field, Sara E. Mooreville, Mira Reina, Samantha A. Kozlosky, Merel Yanovski, Susan Z. Yanovski, Jack A. TI Latent Profile Analysis to Determine the Typology of Disinhibited Eating Behaviors in Children and Adolescents SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE loss of control eating; emotional eating; eating in the absence of hunger; obesity; eating disorders ID DISORDER EXAMINATION; OVERWEIGHT CHILDREN; MODEL-SELECTION; PSYCHOMETRIC PROPERTIES; DEPRESSION INVENTORY; HISPANIC CHILDREN; PARENTAL CONTROL; NEGATIVE AFFECT; ADULT OBESITY; DUAL-PATHWAY AB Objective: We used latent profile analysis (LPA) to classify children and adolescents into subtypes based on the overlap of disinhibited eating behaviors-eating in the absence of hunger, emotional eating, and subjective and objective binge eating. Method: Participants were 411 youths (8-18 years) from the community who reported on their disinhibited eating patterns. A subset (n = 223) ate ad libitum from two test meals. Results: LPA produced five subtypes that were most prominently distinguished by objective binge eating (OBE; n = 53), subjective binge eating (SBE; n = 59), emotional eating (EE; n = 62), a mix of emotional eating and eating in the absence of hunger (EE-EAH; n = 172), and no disinhibited eating (No-DE; n = 64). Accounting for age, sex, race, and body mass index z score (BMI-z), the four disinhibited eating groups had more problem behaviors than the no disinhibited eating group (p = .001). OBE and SBE subtypes had greater BMI-z, percent fat mass, disordered eating attitudes, and trait anxiety than EE, EE-EAH, and No-DE subtypes (ps < .01). However, the OBE subtype reported the highest eating concern (p < .001), and the OBE, SBE, and EE subtypes reported higher depressive symptoms than the EE-EAH and No-DE subtypes. Across both test meals, OBE and SBE subtypes consumed a lesser percentage of protein and a higher percentage of carbohydrate than the other subtypes (ps < .02), adjusting for age, sex, race, height, lean mass, percent fat mass, and total intake. EE subtypes also consumed a greater percentage of carbohydrate and a lower percentage of fat than the EE-EAH and No-DE subtypes (ps < .03). The SBE subtype consumed the least total calories (p < .01). Discussion: We conclude that behavioral subtypes of disinhibited eating may be distinguished by psychological characteristics and objective eating behavior. Prospective data are required to determine whether subtypes predict the onset of eating disorders and obesity. C1 [Vannucci, Anna; Tanofsky-Kraff, Marian; Ranzenhofer, Lisa M.; Shomaker, Lauren B.; Field, Sara E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Vannucci, Anna; Tanofsky-Kraff, Marian; Ranzenhofer, Lisa M.; Shomaker, Lauren B.; Field, Sara E.; Mooreville, Mira; Reina, Samantha A.; Yanovski, Susan Z.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Crosby, Ross D.] Neuropsychiat Res Inst, Fargo, ND USA. [Crosby, Ross D.] Univ N Dakota, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. [Kozlosky, Merel] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Yanovski, Susan Z.] NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637; Crosby, Ross/0000-0001-9131-1629 FU Intramural NIH HHS [Z01 HD000641-12]; NICHD NIH HHS [F32 HD056762, ZIA HD000641]; NIDDK NIH HHS [R01 DK080906] NR 90 TC 12 Z9 12 U1 3 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 2013 VL 81 IS 3 BP 494 EP 507 DI 10.1037/a0031209 PG 14 WC Psychology, Clinical SC Psychology GA 150RA UT WOS:000319407300012 PM 23276121 ER PT J AU Fangusaro, J Warren, KE AF Fangusaro, Jason Warren, Katherine E. TI Unclear standard of care for pediatric high grade glioma patients SO JOURNAL OF NEURO-ONCOLOGY LA English DT Letter ID TEMOZOLOMIDE; ASTROCYTOMA; CHILDREN; TRIAL C1 [Fangusaro, Jason] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Warren, Katherine E.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Fangusaro, J (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. EM jfangusaro@luriechildrens.org NR 4 TC 6 Z9 7 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JUN PY 2013 VL 113 IS 2 BP 341 EP 342 DI 10.1007/s11060-013-1104-8 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 162CD UT WOS:000320241100020 PM 23471572 ER PT J AU Rashid, MA Katakura, M Kharebava, G Kevala, K Kim, HY AF Rashid, Mohammad A. Katakura, Masanori Kharebava, Giorgi Kevala, Karl Kim, Hee-Yong TI N-docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE CREB; docosahexaenoic acid; neurogenesis; omega-3 fatty acids; PKA; synaptamide ID POLYUNSATURATED FATTY-ACIDS; RETINOID-X-RECEPTOR; DOCOSAHEXAENOIC ACID; NEURONAL DIFFERENTIATION; TRANSCRIPTION FACTORS; NEURITE OUTGROWTH; ADULT HIPPOCAMPUS; ARACHIDONIC-ACID; NERVOUS-SYSTEM; MOUSE-BRAIN AB Docosahexaenoic acid (DHA) has been shown to promote neuronal differentiation of neural stem cells (NSCs) in vivo and in vitro. Previously, we found that N-docosahexaenoylethanolamine (synaptamide), an endogenous DHA metabolite with an endocannabinoid-like structure, promotes neurite growth, synaptogenesis, and synaptic function. In this study, we demonstrate that synaptamide potently induces neuronal differentiation of NSCs. Differentiating NSCs were capable of synthesizing synaptamide from DHA. Treatment of NSCs with synaptamide at low nanomolar concentrations significantly increased the number of MAP2 and Tuj-1-positive neurons with concomitant induction of protein kinase A (PKA)/cAMP response element binding protein (CREB) phosphorylation. Conversely, PKA inhibitors or PKA knockdown abolished the synaptamide-induced neuronal differentiation of NSCs. URB597, a fatty acid amide hydrolase (FAAH) inhibitor, elevated the level of DHA-derived synaptamide and further potentiated the DHA- or synaptamide-induced neuronal differentiation of NSCs. Similarly, NSCs obtained from FAAH KO mice exhibited greater capacity to induce neuronal differentiation in response to DHA or synaptamide compared to the wild type NSCs. Neither synaptamide nor DHA affected NSC differentiation into GFAP-positive glia cells. These results suggest that endogenously produced synaptamide is a potent mediator for neurogenic differentiation of NSCs acting through PKA/CREB activation. C1 [Rashid, Mohammad A.; Katakura, Masanori; Kharebava, Giorgi; Kevala, Karl; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, DICBR, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, NIH, 5625 Fishers Lane,Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov OI Katakura, Masanori/0000-0002-2237-9651 FU Shimane University, Japan; National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health FX We thank Dr. Arthur Spector for helpful comments on the manuscript. MK was supported by Shimane University, Japan. This study was supported by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. The authors have no conflict of interest to declare. NR 51 TC 25 Z9 25 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2013 VL 125 IS 6 BP 869 EP 884 DI 10.1111/jnc.12255 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 159JM UT WOS:000320041700008 PM 23570577 ER PT J AU Alves, G Yu, YK AF Alves, Gelio Yu, Yi-Kuo TI Improving Peptide Identification Sensitivity in Shotgun Proteomics by Stratification of Search Space SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE shotgun proteomics; nontryptic peptides; semitryptic peptides; Peptide Identification Sensitivity ID MASS-SPECTROMETRY; PROTEIN IDENTIFICATION; TRYPTIC PEPTIDES; SPECTRA; ANNOTATION AB Because of its high specificity, trypsin is the enzyme of choice in shotgun proteomics.. Nonetheless, several publications do report the identification of semitryptic and nontryptic peptides. Many of these peptides are thought to be signaling peptides or to have formed during sample preparation. It is known that only a small fraction of tandem mass spectra from a trypsin-digested protein mixture can be confidently matched to tryptic peptides. If other possibilities such as post-translational modifications and single-amino acid polymorphisms are ignored, this suggests that many unidentified spectra originate from semitryptic and nontryptic peptides. To include them in database searches, however, may not improve overall peptide identification because of the possible sensitivity reduction from search space expansion. To circumvent this issue for E-value-based search methods, we have designed a scheme that categorizes qualified peptides (i.e., peptides whose differences in molecular weight from the parent ion are within a specified error tolerance) into three tiers: tryptic, semitryptic, and nontryptic. This classification allows peptides that belong to different tiers to have different Bonferroni correction factors. Our results show that this scheme can significantly improve retrieval performance compared to those of search strategies that assign equal Bonferroni correction factors to all qualified peptides. C1 [Alves, Gelio; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health; National Institutes of Health FX We thank the administrative group of the National Institutes of Health Biowulf Clusters, where all the computational tasks were conducted. This work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. Funding for Open Access publication charges for this article was provided by the National Institutes of Health. NR 30 TC 4 Z9 4 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2013 VL 12 IS 6 BP 2571 EP 2581 DI 10.1021/pr301139y PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 162XF UT WOS:000320298600021 PM 23668635 ER PT J AU Kuzu, G Gursoy, A Nussinov, R Keskin, O AF Kuzu, Guray Gursoy, Attila Nussinov, Ruth Keskin, Ozlem TI Exploiting Conformational Ensembles in Modeling Protein-Protein Interactions on the Proteome Scale SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE protein-protein interaction prediction; PRISM; structural network; knowledge-based method; conformations; docking ID ENERGY LANDSCAPES; SYSTEMS BIOLOGY; BINDING-SITES; WEB SERVER; INTERFACES; DOCKING; COMPLEXES; SEQUENCE; PREDICTION; ALGORITHM AB Cellular functions are performed through protein-protein interactions; therefore, identification of these interactions is crucial for understanding biological processes. Recent studies suggest that knowledge-based approaches are more useful than "blind" docking for modeling at large scales. However, a caveat of knowledge-based approaches is that they treat molecules as rigid structures. The Protein Data Bank (PDB) offers a wealth of conformations. Here, we exploited an ensemble of the conformations in predictions by a knowledge-based method, PRISM. We tested "difficult" cases in a docking-benchmark data set, where the unbound and bound protein forms are structurally different. Considering alternative conformations for each protein, the percentage of successfully predicted interactions increased from similar to 26 to 66%, and 57% of the interactions were successfully predicted in an "unbiased" scenario, in which data related to the bound forms were not utilized. If the appropriate conformation, or relevant template interface, is unavailable in the PDB, PRISM could not predict the interaction successfully. The pace of the growth of the PDB promises a rapid increase of ensemble conformations emphasizing the merit of such knowledge-based ensemble strategies for higher success rates in protein-protein interaction predictions on an interactome scale. We constructed the structural network of ERK interacting proteins as a case study. C1 [Kuzu, Guray; Gursoy, Attila; Keskin, Ozlem] Koc Univ Rumelifeneri Yolu, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. [Kuzu, Guray; Gursoy, Attila; Keskin, Ozlem] Koc Univ Rumelifeneri Yolu, Coll Engn, TR-34450 Istanbul, Turkey. [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Gursoy, A (reprint author), Koc Univ Rumelifeneri Yolu, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. EM agursoy@ku.edu.tr; okeskin@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU TUBITAK (The Scientific and Technological Research Council of Turkey) fellowship; TUBITAK [109T343]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX Guray Kuzu is supported by a TUBITAK (The Scientific and Technological Research Council of Turkey) fellowship. This work has been supported by TUBITAK, Research Grant Number: 109T343. Ozlem Keskin acknowledges Science Academy (of Turkey). It has also been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 82 TC 23 Z9 23 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD JUN PY 2013 VL 12 IS 6 BP 2641 EP 2653 DI 10.1021/pr400006k PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 162XF UT WOS:000320298600027 PM 23590674 ER PT J AU Rahu, K Auvinen, A Hakulinen, T Tekkel, M Inskip, PD Bromet, EJ Boice, JD Rahu, M AF Rahu, Kaja Auvinen, Anssi Hakulinen, Timo Tekkel, Mare Inskip, Peter D. Bromet, Evelyn J. Boice, John D., Jr. Rahu, Mati TI Chernobyl cleanup workers from Estonia: follow-up for cancer incidence and mortality SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article ID TRADE-CENTER RESCUE; THYROID-CANCER; EMERGENCY WORKERS; RADIATION RISKS; ACCIDENT; EXPOSURE; RUSSIA; COHORT; LIQUIDATORS; DISORDERS AB This study examined cancer incidence (1986-2008) and mortality (1986-2011) among the Estonian Chernobyl cleanup workers in comparison with the Estonian male population. The cohort of 4810 men was followed through nationwide population, mortality and cancer registries. Cancer and death risks were measured by standardised incidence ratio (SIR) and standardised mortality ratio (SMR), respectively. Poisson regression was used to analyse the effects of year of arrival, duration of stay and time since return on cancer and death risks. The SIR for all cancers was 1.06 with 95% confidence interval 0.93-1.20 (232 cases). Elevated risks were found for cancers of the pharynx, the oesophagus and the joint category of alcohol-related sites. No clear evidence of an increased risk of thyroid cancer, leukaemia or radiation-related cancer sites combined was apparent. The SMR for all causes of death was 1.02 with 95% confidence interval 0.96-1.08 (1018 deaths). Excess mortality was observed for mouth and pharynx cancer, alcohol-related cancer sites together and suicide. Duration of stay rather than year of arrival was associated with increased mortality. Twenty-six years of follow-up of this cohort indicates no definite health effects attributable to radiation, but the elevated suicide risk has persisted. C1 [Rahu, Kaja; Tekkel, Mare; Rahu, Mati] Natl Inst Hlth Dev, Dept Epidemiol & Biostat, Tallinn, Estonia. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Radiat & Nucl Safety Author, Helsinki, Finland. [Hakulinen, Timo] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bromet, Evelyn J.] SUNY Stony Brook, Sch Med, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. [Boice, John D., Jr.] Natl Council Radiat Protect & Measurements, Bethesda, MD USA. [Boice, John D., Jr.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. RP Rahu, K (reprint author), Natl Inst Hlth Dev, Dept Epidemiol & Biostat, Tallinn, Estonia. EM kaja.rahu@tai.ee RI Rahu, Mati/A-9981-2008; OI Auvinen, Anssi/0000-0003-1125-4818 FU Estonian Ministry of Education and Science [SF0940026s07]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; US National Cancer Institute [N01-CP-85638-03] FX This study was supported financially by the Estonian Ministry of Education and Science (target funding SF0940026s07) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The initial work was financed by US National Cancer Institute Contract N01-CP-85638-03. The authors thank Dr Margit Magi and Pille Harmaorg from the Estonian Cancer Registry, and Gleb Denissov from the Estonian Cause of Death Registry for their invaluable contribution to data collection. NR 49 TC 8 Z9 9 U1 1 U2 17 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD JUN PY 2013 VL 33 IS 2 BP 395 EP 411 DI 10.1088/0952-4746/33/2/395 PG 17 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 157FV UT WOS:000319882300014 PM 23532116 ER PT J AU Rink, SM Mendola, P Mumford, SL Poudrier, JK Browne, RW Wactawski-Wende, J Perkins, NJ Schisterman, EF AF Rink, Stephanie M. Mendola, Pauline Mumford, Sunni L. Poudrier, Jill K. Browne, Richard W. Wactawski-Wende, Jean Perkins, Neil J. Schisterman, Enrique F. TI Self-Report of Fruit and Vegetable Intake that Meets the 5 A Day Recommendation Is Associated with Reduced Levels of Oxidative Stress Biomarkers and Increased Levels of Antioxidant Defense in Premenopausal Women SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Fruit and vegetable intake; Oxidative stress; Premenopausal women; Antioxidant ID LIPID-PEROXIDATION; MENSTRUAL-CYCLE; LUNG-CANCER; BIOLOGICAL VARIATION; BETA-CAROTENE; VITAMIN-C; MARKERS; SUPPLEMENTATION; CONSUMPTION; DIETARY AB Background Oxidative stress has been associated with a variety of chronic diseases and reproductive disorders. Fruits and vegetables (F/V) may contribute to antioxidant vitamin and micronutrient levels and reduce oxidative stress. Objective To investigate the effect of meeting the 5 A Day For Better Health Program recommendation for F/V consumption on biomarkers of oxidative damage and antioxidant defense. Design In this longitudinal study, healthy premenopausal women (n=258) were followed for <= 2 menstrual cycles with <= 16 oxidative stress measures timed to cycle phase. Main outcome measures Plasma concentrations of F-2-isoprostane, 9-hydroxyoctadecadieneoic acid, 13-hydroxyoctadecadieneoic acid, erythrocyte activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase, as well as blood micronutrient concentrations were measured. Dietary intake was assessed by food frequency questionnaires (FFQs) (1 per cycle), and 24-hour recalls (<= 4 per cycle). Statistical analyses performed Fruit and vegetable servings were dichotomized based on the recommendation to consume five servings of F/V each day. Linear mixed models with repeated measures were used to analyze lipid peroxidation markers, antioxidant vitamins, and antioxidant enzymes by cycle phase and in association with usual F/V intake. Results For both 24-hour recall (timed to cycle phase) and cycle-specific FFQ meeting the recommendation to consume five servings of F/V each day was associated with decreased F-2-isoprostanes (24-hour recall beta=-.10 [95% CI, -0.12 to -0.07]; FFQ beta=-.14 [95% CI, -0.18 to -0.11]). Glutathione reductase was lower in association with typical consumption of five or more servings of F/V by FFQ but not in the phase-specific analysis. Higher levels of ascorbic acid, lutein, beta carotene, and beta cryptoxanthin were observed with both intake measures. Conclusions Meeting the 5 A Day For Better Health Program recommendation was associated with lower oxidative stress and improved antioxidant status in analyses of typical diet (via FFQ) and in menstrual cycle phase-specific analyses using 24-hour recalls. Green salads were commonly eaten and increasing intake of salads may be a useful strategy to influence oxidation in reproductive aged women. C1 [Rink, Stephanie M.] Loyola Univ, Dept Nutr, Sch Nursing, Chicago, IL 60611 USA. [Rink, Stephanie M.; Mendola, Pauline; Mumford, Sunni L.; Poudrier, Jill K.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Poudrier, Jill K.] Henry M Jackson Fdn, Walter Reed Natl Mil Med Ctr, John P Murtha Canc Ctr, Rockville, MD USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Perkins, Neil/0000-0002-6802-4733; Mendola, Pauline/0000-0001-5330-2844; Schisterman, Enrique/0000-0003-3757-641X FU National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 49 TC 16 Z9 16 U1 2 U2 18 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 JUN PY 2013 VL 113 IS 6 BP 776 EP 785 DI 10.1016/j.jand.2013.01.019 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 161US UT WOS:000320219400009 PM 23522825 ER PT J AU Xie, H Lee, MH Zhu, F Reddy, K Huang, ZN Kim, DJ Li, Y Peng, C Lim, DY Kang, S Jung, SK Li, X Li, HT Ma, WY Lubet, RA Ding, J Bode, AM Dong, ZG AF Xie, Hua Lee, Mee-Hyun Zhu, Feng Reddy, Kanamata Huang, Zunnan Kim, Dong Joon Li, Yan Peng, Cong Lim, Do Young Kang, Soouk Jung, Sung Keun Li, Xiang Li, Haitao Ma, Weiya Lubet, Ronald A. Ding, Jian Bode, Ann M. Dong, Zigang TI Discovery of the Novel mTOR Inhibitor and Its Antitumor Activities In Vitro and In Vivo SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MAMMALIAN TARGET; CELL-GROWTH; PATHWAY; COMPLEX; CANCER; SENSITIVITY; MECHANISMS; KINASES; AKT/PKB; PI(3)K AB The phosphoinositide 3-kinase (PI3-K)/Akt andmTORsignaling pathway plays a critical role in cell survival and proliferation and is often aberrantly activated inmanytypes of cancer. ThemTORkinase protein, one of the key molecules in this pathway, has been shown to be an important target for cancer therapy. In the present study, a ligand docking method was used to screen for novel scaffold mTOR inhibitors. Sixty thousand compounds in the Natural Product Database were screened against the mTOR homologous structure, and 13 commercially available compounds listed in the top-ranked 100 compounds were selected for further examination. Compound [(E)-3-(4-(benzo[d][1,3] dioxol-5-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one; designated herein as 3HOI-BA-01] was then selected for further study of its antitumor activity. An in vitro study has shown that 3HOI-BA-01 inhibited mTOR kinase activity in a dose-dependent manner by directly binding with mTOR. In a panel of non-small cell lung cancer cells, the compound also attenuated mTOR downstream signaling, including the phosphorylation of p70S6K, S6, and Akt, resulting in G(1) cell-cycle arrest and growth inhibition. Results of an in vivo study have shown that intraperitoneal injection of 3HOI-BA-01 in A549 lung tumor-bearing mice effectively suppressed cancer growth without affecting the body weight of the mice. The expression of downstream signaling molecules in the mTOR pathway in tumor tissues was also reduced after 3HOI-BA-01 treatment. Taken together, we identified 3HOI-BA-01 as a novel and effective mTOR inhibitor. (C) 2013 AACR. C1 [Xie, Hua; Lee, Mee-Hyun; Zhu, Feng; Reddy, Kanamata; Huang, Zunnan; Kim, Dong Joon; Li, Yan; Peng, Cong; Lim, Do Young; Kang, Soouk; Jung, Sung Keun; Li, Xiang; Li, Haitao; Ma, Weiya; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lubet, Ronald A.] NCI, NIH, Bethesda, MD 20892 USA. [Xie, Hua; Ding, Jian] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu RI Li, Yan/L-2129-2013; OI Kanamata Reddy, Srinivasa Reddy/0000-0003-3733-7531; Huang, Zunnan/0000-0002-5821-703X FU Hormel Foundation; NIH [CA120388, R37 CA081064, ES016548]; NCI [HHSN261200533001 (N01-CN53301)] FX This work was supported by The Hormel Foundation and NIH grants CA120388, R37 CA081064, ES016548, and NCI Contract No. HHSN261200533001 (N01-CN53301). NR 29 TC 8 Z9 9 U1 2 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2013 VL 12 IS 6 BP 950 EP 958 DI 10.1158/1535-7163.MCT-12-1241 PG 9 WC Oncology SC Oncology GA 160HT UT WOS:000320110500011 PM 23536724 ER PT J AU Fischbeck, KH AF Fischbeck, Kenneth H. TI A role for androgen reduction treatment in kennedy disease? SO MUSCLE & NERVE LA English DT Editorial Material ID BULBAR MUSCULAR-ATROPHY; TRANSGENIC MOUSE MODEL C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS003037-07] NR 7 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2013 VL 47 IS 6 BP 789 EP 789 DI 10.1002/mus.23814 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 150SM UT WOS:000319411300001 PM 23408598 ER PT J AU Driscoll, CT AF Driscoll, Claire T. TI Staying happy and productive as a mid-career professional SO NATURE BIOTECHNOLOGY LA English DT Editorial Material C1 NHGRI, Technol Transfer Off, NIH, Rockville, MD USA. RP Driscoll, CT (reprint author), NHGRI, Technol Transfer Off, NIH, Rockville, MD USA. EM cdriscol@mail.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2013 VL 31 IS 6 BP 567 EP 568 DI 10.1038/nbt.2606 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 160IO UT WOS:000320113200038 PM 23752447 ER PT J AU Richards, JM Plate, RC Ernst, M AF Richards, Jessica M. Plate, Rista C. Ernst, Monique TI A systematic review of fMRI reward paradigms used in studies of adolescents vs. adults: The impact of task design and implications for understanding neurodevelopment SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Reward; Triadic Model; Adolescence; Development; Neuroimaging; Task design; Approach; Avoidance; Motivation; Emotion; Social; Pediatric; Incentive ID ANTERIOR CINGULATE CORTEX; INFERIOR FRONTAL GYRUS; PRIMATE BASAL GANGLIA; RISK-TAKING BEHAVIOR; EVENT-RELATED FMRI; DECISION-MAKING; COGNITIVE CONTROL; BRAIN-FUNCTION; DEVELOPMENTAL-CHANGES; RESPONSE-INHIBITION AB The neural systems underlying reward-related behaviors across development have recently generated a great amount of interest. Yet, the neurodevelopmental literature on reward processing is marked by inconsistencies due to the heterogeneity of the reward paradigms used, the complexity of the behaviors being studied, and the developing brain itself as a moving target. The present review will examine task design as one source of variability across findings by compiling this literature along three dimensions: (1) task structures, (2) cognitive processes, and (3) neural systems. We start with the presentation of a heuristic neural systems model, the Triadic Model, as a way to provide a theoretical framework for the neuroscience research on motivated behaviors. We then discuss the principles guiding reward task development. Finally, we review the extant developmental neuroimaging literature on reward-related processing, organized by reward task type. We hope that this approach will help to clarify the literature on the functional neurodevelopment of reward-related neural systems, and to identify the role of the experimental parameters that significantly influence these findings. Published by Elsevier Ltd. C1 [Richards, Jessica M.] Univ Maryland, Dept Psychol, College Pk, MD 20741 USA. [Plate, Rista C.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [Ernst, Monique] NIMH, Bethesda, MD 20817 USA. RP Ernst, M (reprint author), NIMH, NIMH Bldg 15-K,Room 110,MSC 2670, Bethesda, MD 20817 USA. EM jessic1@umd.edu; rplate@wisc.edu; ernstm@mail.nih.gov FU Intramural NIH HHS [ZIA MH002781-11]; NIAAA NIH HHS [R21 AA017685]; NIDA NIH HHS [R01 DA018647, R01 DA019405, R01 DA023384, T32 DA028855] NR 133 TC 56 Z9 56 U1 3 U2 42 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUN PY 2013 VL 37 IS 5 BP 976 EP 991 DI 10.1016/j.neubiorev.2013.03.004 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 160AE UT WOS:000320087600015 PM 23518270 ER PT J AU Csermely, P Korcsmaros, T Kiss, HJM London, G Nussinov, R AF Csermely, Peter Korcsmaros, Tamas Kiss, Huba J. M. London, Gabor Nussinov, Ruth TI Structure and dynamics of molecular networks: A novel paradigm of drug discovery A comprehensive review SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Cancer; Diabetes; Drug target; Network; Side-effects; Toxicity ID PROTEIN-PROTEIN INTERACTION; GENE-EXPRESSION DATA; SYSTEMS BIOLOGY APPROACH; TARGET INTERACTION PREDICTION; SIGNAL-TRANSDUCTION NETWORKS; METABOLIC-CONTROL ANALYSIS; CANDIDATE DISEASE GENES; SMALL-WORLD NETWORKS; COMPUTATIONAL CHEMISTRY APPROACH; BIOCHEMICAL REACTION NETWORKS AB Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only give a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The "central hit strategy" selectively targets central nodes/edges of the flexible networks of infectious agents or cancer cells to kill them. The "network influence strategy" works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved by targeting the neighbors of central nodes/edges. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach. (C) 2013 Elsevier Inc. All rights reserved. C1 [Csermely, Peter; Korcsmaros, Tamas; Kiss, Huba J. M.] Semmelweis Univ, Dept Med Chem, H-1444 Budapest 8, Hungary. [Korcsmaros, Tamas] Eotvos Lorand Univ, Dept Genet, H-1117 Budapest, Hungary. [Kiss, Huba J. M.] Semmelweis Univ, Dept Ophthalmol, H-1083 Budapest, Hungary. [London, Gabor] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Zurich, Switzerland. [Nussinov, Ruth] SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, NCI, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Csermely, P (reprint author), Semmelweis Univ, Dept Med Chem, POB 260, H-1444 Budapest 8, Hungary. EM csermely.peter@med.semmelweis-univ.hu RI Korcsmaros, Tamas/C-3526-2015 OI Korcsmaros, Tamas/0000-0003-1717-996X FU Hungarian National Science Foundation [OTKA K83314]; EU [TAMOP-4.2.2/B-10/1-2010-0013]; Hungarian Academy of Sciences; residence at the Rockefeller Foundation Bellagio Center; NCI, NIH [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX Authors thank Aditya Barve and Andreas Wagner (University of Zurich, Switzerland) for sharing the human homology of enzymes encoding superessential metabolic reactions, Haiyuan Yu, Xiujuan Wang (Department of Biological Statistics and Computational Biology, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca NY, USA) and Balks Papp (Szeged Biological Centre, Hungarian Academy of Sciences, Szeged, Hungary) for the critical reading of Sections 13.3 and 3.6, respectively. Authors thank Zoltan P. Spiro (Ecole Polytechnique Federale de Lausanne, Switzerland) for help in drawing Fig. 11, and the anonymous referee, members of the LINK-Group (www.linkgroup.hu), as well as more than twenty additional colleagues for reading the original version of the paper and for valuable suggestions. Work in the authors' laboratory was supported by research grants from the Hungarian National Science Foundation (OTKA K83314), by the EU (TAMOP-4.2.2/B-10/1-2010-0013), by a Bolyai Fellowship of the Hungarian Academy of Sciences (TK) and by a residence at the Rockefeller Foundation Bellagio Center (PC). This project has been funded, in part, with federal funds from the NCI, NIH, under contract HHSN261200800001E. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 1269 TC 234 Z9 242 U1 38 U2 488 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 JUN PY 2013 VL 138 IS 3 BP 333 EP 408 DI 10.1016/j.pharmthera.2013.01.016 PG 76 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 154XX UT WOS:000319711100003 PM 23384594 ER PT J AU Wang, J Barker, K Steel, J Park, J Saul, J Festa, F Wallstrom, G Yu, XB Bian, XF Anderson, KS Figueroa, JD LaBaer, J Qiu, J AF Wang, Jie Barker, Kristi Steel, Jason Park, Jin Saul, Justin Festa, Fernanda Wallstrom, Garrick Yu, Xiaobo Bian, Xiaofang Anderson, Karen S. Figueroa, Jonine D. LaBaer, Joshua Qiu, Ji TI A versatile protein microarray platform enabling antibody profiling against denatured proteins SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Antibody; Autoantibody; Biomarker; Denaturation; Protein microarray ID DISCOVERY; CANCER; ARRAYS AB Purpose We aim to develop a protein microarray platform capable of presenting both natural and denatured forms of proteins for antibody biomarker discovery. We will further optimize plasma screening protocols to improve detection. Experimental design We developed a new covalent capture protein microarray chemistry using HaloTag fusion proteins and ligand. To enhance protein yield, we used HeLa cell lysate as an in vitro transcription translation (IVTT) system. Escherichia coli lysates were added to the plasma blocking buffer to reduce nonspecific background. These protein microarrays were probed with plasma samples and autoantibody responses were quantified and compared with or without denaturing buffer treatment. Results We demonstrated that protein microarrays using the covalent attachment chemistry endured denaturing conditions. Blocking with E. coli lysates greatly reduced the background signals and expression with IVTT based on HeLa cell lysates significantly improved the antibody signals on protein microarrays probed with plasma samples. Plasma samples probed on denatured protein arrays produced autoantibody profiles distinct from those probed on natively displayed proteins. Conclusions and clinical relevance This versatile protein microarray platform allows the display of both natural and denatured proteins, offers a new dimension to search for disease-specific antibodies, broadens the repertoire of potential biomarkers, and will potentially yield clinical diagnostics with greater performance. C1 [Wang, Jie; Barker, Kristi; Steel, Jason; Park, Jin; Saul, Justin; Festa, Fernanda; Wallstrom, Garrick; Yu, Xiaobo; Bian, Xiaofang; Anderson, Karen S.; LaBaer, Joshua; Qiu, Ji] Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ 85287 USA. [Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Qiu, J (reprint author), Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, 1001 S McAllister Ave,POB 876401, Tempe, AZ 85287 USA. EM Joshua.LaBaer@asu.edu; Ji.Qiu@asu.edu RI Yu, Xiaobo/F-5997-2015 FU Early Detection Research Network [5U01CA117374-02]; National Cancer Institute, Department of Health and Human Services, USA FX We would like to thank Carlos Morales Betanzos for advice on preparing the figures. We would also like to thank Eliseo Mendoza Garcia for helping with manufacturing NAPPA. The research relevant to this paper was supported by a grant from the Early Detection Research Network (5U01CA117374-02) (J. L. and J. Q.). Samples from the Polish breast cancer study (PBCS) were collected under IRB protocol# OH99CN040, and supported by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Written consent was obtained from all human subjects under institutional review board approval. The PBCS would like to thank Montserrat Garcia-Closas, Louise Brinton, Mark Sherman, Jolanta Lissowska, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski for their efforts in launching and conduct of the study. NR 20 TC 20 Z9 21 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2013 VL 7 IS 5-6 SI SI BP 378 EP 383 DI 10.1002/prca.201200062 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KZ UT WOS:000320554800008 PM 23027520 ER PT J AU Zisook, S Shear, MK AF Zisook, Sidney Shear, M. Katherine TI This issue: Bereavement, Depression, and the DSM-5 SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Zisook, Sidney] Univ Calif San Diego, La Jolla, CA 92093 USA. [Zisook, Sidney] Vet Med Res Fdn, Schaumburg, IL USA. [Zisook, Sidney] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Zisook, Sidney] NIMH, Bethesda, MD USA. [Zisook, Sidney] Amer Psychiat Assoc, Washington, DC 20005 USA. [Shear, M. Katherine] Columbia Univ, Sch Social Work, New York, NY 10027 USA. [Shear, M. Katherine] Amer Psychiat Assoc Treatment Guidelines Pan Diso, Arlington, VA USA. [Shear, M. Katherine] Anxiety Disorders Assoc Amer, Arlington, VA USA. [Shear, M. Katherine] Assoc Clin Psychosocial Res, Stanford, CA USA. RP Zisook, S (reprint author), Univ Calif San Diego, La Jolla, CA 92093 USA. NR 14 TC 2 Z9 2 U1 1 U2 6 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUN PY 2013 VL 43 IS 6 BP 252 EP 254 DI 10.3928/00485713-20130605-03 PG 3 WC Psychiatry SC Psychiatry GA 165UK UT WOS:000320510600003 ER PT J AU Bat, T Leitman, SF Calvo, KR Chauvet, D Dunbar, CE AF Bat, Taha Leitman, Susan F. Calvo, Katherine R. Chauvet, Donna Dunbar, Cynthia E. TI Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion SO TRANSFUSION LA English DT Article ID STEM-CELL TRANSPLANTATION; FRACTION AB Background The ability to distinguish increased platelet (PLT) destruction from PLT hypoproduction is important in the care of patients with marrow failure syndromes and patients receiving high-dose chemotherapy. The measurement of immature circulating PLTs based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent PLT transfusion on measurement of immature PLT variables. Study Design and Methods The immature PLT fraction (IPF) and absolute immature PLT number (AIPN) were measured using a hematology analyzer before and after PLT transfusion in nine transfusion-dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia, or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in three plateletpheresis components collected from normal donors. Results PLT transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 +/- 4.6% on Day -1 to 2.3 +/- 1.4% on Day 0 before returning to 4.3 +/- 2.3% on Day +1. In the PLT component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored PLTs, no longer detected in vivo once the PLTs were transfused. Conclusion PLT transfusion decreases the IPF due to the resultant increase in circulating PLT count. However, PLT transfusion does not change the circulating AIPN, validating this assay as a reflection of ongoing PLT production by the marrow in various clinical settings, regardless of proximity to PLT transfusion. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 10CRC,Room 4E-5132, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov OI Calvo, Katherine/0000-0002-0771-4191 FU Intramural NIH HHS [Z99 HL999999] NR 6 TC 13 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2013 VL 53 IS 6 BP 1201 EP 1204 DI 10.1111/j.1537-2995.2012.03918.x PG 4 WC Hematology SC Hematology GA 161HI UT WOS:000320183000009 PM 23043309 ER PT J AU Kim, YJ Hernandez, MLG Balla, T AF Kim, Yeun Ju Hernandez, Maria-Luisa Guzman Balla, Tamas TI Inositol lipid regulation of lipid transfer in specialized membrane domains SO TRENDS IN CELL BIOLOGY LA English DT Review ID PHOSPHATIDYLINOSITOL TRANSFER PROTEIN; OXYSTEROL-BINDING-PROTEIN; 4-KINASE II-ALPHA; GOLGI-APPARATUS REQUIRES; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; SACCHAROMYCES-CEREVISIAE; STEROL MOVEMENT; CONTACT SITES; CALCIUM-ENTRY AB The highly dynamic membranous network of eukaryotic cells allows spatial organization of biochemical reactions to suit the complex metabolic needs of the cell. The unique lipid composition of organelle membranes in the face of dynamic membrane activities assumes that lipid gradients are constantly generated and maintained. Important advances have been made in identifying specialized membrane compartments and lipid transfer mechanisms that are critical for generating and maintaining lipid gradients. Remarkably, one class of minor phospholipids the phosphoinositides is emerging as important regulators of these processes. Here, we summarize several lines of research that have led to our current understanding of the connection between phosphoinositides and the transport of structural lipids and offer some thoughts on general principles possibly governing these processes. C1 [Kim, Yeun Ju; Hernandez, Maria-Luisa Guzman; Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in the National Institutes of Health FX The authors thank Dr Pietro De Camilli (Yale University) for sharing prepublication results. and Drs Gerald Hammond and Marko Jovic for reading the manuscript and for their valuable suggestions. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in the National Institutes of Health. NR 90 TC 17 Z9 17 U1 1 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JUN PY 2013 VL 23 IS 6 BP 270 EP 278 DI 10.1016/j.tcb.2013.01.009 PG 9 WC Cell Biology SC Cell Biology GA 165IV UT WOS:000320478000003 PM 23489878 ER PT J AU McEwen, JE Boyer, JT Sun, KY AF McEwen, Jean E. Boyer, Joy T. Sun, Kathie Y. TI Evolving approaches to the ethical management of genomic data SO TRENDS IN GENETICS LA English DT Review DE ethics; informed consent; privacy; identifiability; data sharing; return of results ID INFORMED-CONSENT; GENETIC RESEARCH; INCIDENTAL FINDINGS; PRIVACY; RETURN; BIOBANKS; PERSPECTIVES; CHALLENGES; LEGAL; ERA AB The ethical landscape in the field of genomics is rapidly shifting. Plummeting sequencing costs, along with ongoing advances in bioinformatics, now make it possible to generate an enormous volume of genomic data about vast numbers of people. The informational richness, complexity, and frequently uncertain meaning of these data, coupled with evolving norms surrounding the sharing of data and samples and persistent privacy concerns, have generated a range of approaches to the ethical management of genomic information. As calls increase for the expanded use of broad or even open consent, and as controversy grows about how best to handle incidental genomic findings, these approaches, informed by normative analysis and empirical data, will continue to evolve alongside the science. C1 [McEwen, Jean E.; Boyer, Joy T.; Sun, Kathie Y.] NHGRI, Eth Legal & Social Implicat Program, Div Genom & Soc, NIH, Bethesda, MD 20892 USA. RP McEwen, JE (reprint author), NHGRI, Eth Legal & Social Implicat Program, Div Genom & Soc, NIH, 5535 Fishers Lane,Suite 4076, Bethesda, MD 20892 USA. EM jm522n@nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 96 TC 17 Z9 18 U1 1 U2 30 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUN PY 2013 VL 29 IS 6 BP 375 EP 382 DI 10.1016/j.tig.2013.02.001 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 163PT UT WOS:000320350100007 PM 23453621 ER PT J AU Schwandt, ML Heilig, M Hommer, DW George, DT Ramchandani, VA AF Schwandt, Melanie L. Heilig, Markus Hommer, Daniel W. George, David T. Ramchandani, Vijay A. TI Childhood Trauma Exposure and Alcohol Dependence Severity in Adulthood: Mediation by Emotional Abuse Severity and Neuroticism SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcoholism; Adverse Experience; Personality; Early Life Stress ID ANXIETY DISORDERS; SEXUAL-ABUSE; FAMILY HISTORY; DRINKING; QUESTIONNAIRE; NEUROBIOLOGY; ASSOCIATION; COMORBIDITY; STRESS; SAMPLE AB Background Childhood trauma has been linked with a number of negative outcomes later in life, including alcohol dependence (AD). Previous studies have suggested a mediating role for neuroticism in the relationship between childhood trauma and psychopathology. In this study, we investigate the prevalence of multiple types of childhood trauma in treatment-seeking alcohol-dependent patients, and the associations between childhood trauma and AD severity using multiple mediation analysis. Methods The prevalence of 5 types of childhood traumaemotional abuse, sexual abuse, physical abuse, emotional neglect, and physical neglectwas assessed in treatment-seeking alcohol-dependent patients (n=280) and healthy controls (n=137) using the Childhood Trauma Questionnaire. Multiple mediation analyses were used to model associations between childhood trauma measures and alcohol-related outcomes, primarily the severity of AD in the alcohol-dependent sample. Results Childhood trauma was significantly more prevalent and more severe in the alcohol-dependent subjects. In addition, childhood trauma was found to influence AD severity, an effect that was mediated by neuroticism. When individual trauma types were examined, emotional abuse was found to be the primary predictor of AD severity, both directly and through the mediating effects of the impulsivity subfacet of neuroticism. Physical abuse also had a moderate direct effect on AD severity. Mediation analysis did not reveal any association between childhood trauma and Alcohol Use Disorders Identification Test score in the nondependent control sample. Conclusions Childhood trauma is highly prevalent in treatment-seeking alcoholics and may play a significant role in the development and severity of AD through an internalizing pathway involving negative affect. Our findings suggest that alcoholics with a history of childhood emotional abuse may be particularly vulnerable to severe dependence. C1 [Schwandt, Melanie L.; Heilig, Markus; Hommer, Daniel W.; George, David T.; Ramchandani, Vijay A.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. RP Schwandt, ML (reprint author), 10 Ctr Dr,10 CRC 1-5330, Bethesda, MD 20892 USA. EM melanies@mail.nih.gov RI Schwandt, Melanie/L-9866-2016; OI Heilig, Markus/0000-0003-2706-2482 FU National Institute on Alcohol Abuse and Alcoholism FX This study was supported by intramural research funding from the National Institute on Alcohol Abuse and Alcoholism. All study procedures were reviewed and approved by the National Institutes of Health Combined Neuroscience (CNS) Institutional Review Board. Voluntary, written informed consent was obtained from all participants. NR 50 TC 21 Z9 22 U1 5 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2013 VL 37 IS 6 BP 984 EP 992 DI 10.1111/acer.12053 PG 9 WC Substance Abuse SC Substance Abuse GA 152EN UT WOS:000319513700012 PM 23278300 ER PT J AU Desai, CS Ning, H Kang, J Folsom, AR Polak, JF Sibley, CT Tracy, R Lloyd-Jones, DM AF Desai, Chintan S. Ning, Hongyan Kang, Joseph Folsom, Aaron R. Polak, Joseph F. Sibley, Christopher T. Tracy, Russell Lloyd-Jones, Donald M. TI Competing Cardiovascular Outcomes Associated With Subclinical Atherosclerosis (from the Multi-Ethnic Study of Atherosclerosis) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ISOLATED SYSTOLIC HYPERTENSION; AMERICAN-HEART-ASSOCIATION; RANDOMIZED-TRIALS; STROKE PREVENTION; RISKS ANALYSIS; CORONARY; CALCIUM; DISEASE; UPDATE; METAANALYSIS AB Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously. The aim of this study was to determine the competing risks of specific CVD events and non-CVD death associated with varying burdens of subclinical atherosclerosis. A total of 3,095 men and 3,486 women from the Multi-Ethnic Study of Atherosclerosis (MESA), aged 45 to 84 years, from 4 ethnic. groups were included. Participants were stratified by CAC score (0, 1 to 99, and >= 100). Competing Cox models were used to determine competing cumulative incidences and hazard ratios within a group (e.g., those with CAC scores >= 100) and hazard ratios for specific events between groups (e.g., CAC score 100 vs 0). Risks were compared for specific CVD events and also against non-CVD death. In women, during a mean follow-up period of 7.1 years, the hazard ratios for any CVD event compared with a non-CVD death occurring first for CAC score 0 and CAC score >= 100 were 1.40 (95% confidence interval 0.97 to 2.04) and 3.07 (95% confidence interval 2.02 to 4.67), respectively. Coronary heart disease was the most common first CVD event type at all levels of CAC, and coronary heart disease rates were 9.5% versus 1.6% (hazard ratio 6.24, 95% confidence interval 3.99 to 9.75) for women with CAC scores >= 100 compared with CAC scores of 0. Similar results were observed in men. In conclusion, at all levels of CAC, coronary heart disease was the most common first CVD event, and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Desai, Chintan S.; Ning, Hongyan; Kang, Joseph; Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Polak, Joseph F.] Tufts Med Ctr, Boston, MA USA. [Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. [Tracy, Russell] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. RP Lloyd-Jones, DM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. EM dlj@northwestern.edu FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-95159, N01-HC-95169]; National Center for Research Resources, Bethesda, Maryland [UL1-RR-024156, UL1-RR-025005]; National Institutes of Health, Bethesda, Maryland [T32 HL-69771-8] FX This research was supported by Contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and by Grants UL1-RR-024156 and UL1-RR-025005 from the National Center for Research Resources, Bethesda, Maryland. Dr. Desai was supported by Grant T32 HL-69771-8 from the National Institutes of Health, Bethesda, Maryland. NR 23 TC 7 Z9 7 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2013 VL 111 IS 11 BP 1541 EP 1546 DI 10.1016/j.amjcard.2013.02.003 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 157JJ UT WOS:000319892100001 PM 23499272 ER PT J AU Tooze, JA Troiano, RP Carroll, RJ Moshfegh, AJ Freedman, LS AF Tooze, Janet A. Troiano, Richard P. Carroll, Raymond J. Moshfegh, Alanna J. Freedman, Laurence S. TI A Measurement Error Model for Physical Activity Level as Measured by a Questionnaire With Application to the 19992006 NHANES Questionnaire SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Berkson model; bias; energy metabolism; measurement error model; models; statistical; motor activity; self-assessment ID DOUBLY LABELED WATER; DIETARY MEASUREMENT ERROR; ENERGY-EXPENDITURE; PROTEIN-INTAKE; RELATIVE RISK; VALIDATION; HUMANS; LIMITATIONS; BIOMARKERS AB Systematic investigations into the structure of measurement error of physical activity questionnaires are lacking. We propose a measurement error model for a physical activity questionnaire that uses physical activity level (the ratio of total energy expenditure to basal energy expenditure) to relate questionnaire-based reports of physical activity level to true physical activity levels. The 19992006 National Health and Nutrition Examination Survey physical activity questionnaire was administered to 433 participants aged 4069 years in the Observing Protein and Energy Nutrition (OPEN) Study (Maryland, 19992000). Valid estimates of participants total energy expenditure were also available from doubly labeled water, and basal energy expenditure was estimated from an equation; the ratio of those measures estimated true physical activity level (truth). We present a measurement error model that accommodates the mixture of errors that arise from assuming a classical measurement error model for doubly labeled water and a Berkson error model for the equation used to estimate basal energy expenditure. The method was then applied to the OPEN Study. Correlations between the questionnaire-based physical activity level and truth were modest (r 0.320.41); attenuation factors (0.430.73) indicate that the use of questionnaire-based physical activity level would lead to attenuated estimates of effect size. Results suggest that sample sizes for estimating relationships between physical activity level and disease should be inflated, and that regression calibration can be used to provide measurement erroradjusted estimates of relationships between physical activity and disease. C1 [Tooze, Janet A.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Troiano, Richard P.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, Intercollegiate Fac Nutr, College Stn, TX 77843 USA. [Carroll, Raymond J.] Texas A&M Univ, Interdisciplinary Fac Toxicol, College Stn, TX USA. [Moshfegh, Alanna J.] USDA, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. [Freedman, Laurence S.] Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. RP Tooze, JA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jtooze@wakehealth.edu OI Troiano, Richard/0000-0002-6807-989X FU National Cancer Institute at the National Institutes of Health [R21CA139291, R27CA057030] FX This work was supported by the National Cancer Institute at the National Institutes of Health (grant R21CA139291 for J.A.T., R.J.C., and L. S. F.; and grant R27CA057030 for R.J.C.). NR 32 TC 18 Z9 18 U1 3 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2013 VL 177 IS 11 BP 1199 EP 1208 DI 10.1093/aje/kws379 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 155MM UT WOS:000319752400005 PM 23595007 ER PT J AU Mukherjee, S Edwards, DRV Baird, DD Savitz, DA Hartmann, KE AF Mukherjee, Sudeshna Edwards, Digna R. Velez Baird, Donna D. Savitz, David A. Hartmann, Katherine E. TI Risk of Miscarriage Among Black Women and White Women in a US Prospective Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE disparity; miscarriage; pregnancy; prospective cohort; race; reproductive epidemiology ID SPONTANEOUS-ABORTION; AFRICAN-AMERICAN; PRETERM BIRTH; GESTATIONAL-AGE; EARLY-PREGNANCY; POPULATION; OUTCOMES; 1ST-TRIMESTER; DISPARITIES; TIME AB Many adverse pregnancy outcomes differ by race. We examined the association between self-reported race and miscarriage (pregnancy loss at 20 weeks) in a community-based pregnancy cohort. Women from the southeastern United States (North Carolina, Texas, and Tennessee) were enrolled in Right from the Start from 2000 to 2009. They were recruited while trying to conceive or during early pregnancy. Participants completed study ultrasound examinations, interviews, and consent forms for review of medical records. We used proportional hazard models to examine miscarriage risk among black women compared with white women, adjusted for confounders. There were 537 observed miscarriages among 4,070 women, 23 of whom self-identified as black (n 932). The life tableadjusted cumulative risk of loss after gestational week 5 was 21.3. With adjustment for age and alcohol use, blacks had increased risk of miscarriage compared with whites (adjusted hazard ratio 1.57, 95 confidence interval: 1.27, 1.93). When risk of loss before gestational week 10 was dichotomized at the median gestational age, there was little difference, but black women had a greater risk thereafter compared with white women (adjusted hazard ratio 1.93, 95 confidence interval: 1.48, 2.51). Early pregnancy ultrasound examinations did not differ by race. In summary, self-reported race is independently associated with risk of miscarriage, and the higher risk for black women is concentrated in gestational weeks 1020. C1 [Mukherjee, Sudeshna; Edwards, Digna R. Velez; Hartmann, Katherine E.] Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Edwards, Digna R. Velez; Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Baird, Donna D.] NIEHS, Res Triangle Pk, NC 27709 USA. [Savitz, David A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Savitz, David A.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. RP Hartmann, KE (reprint author), Vanderbilt Univ, Inst Med & Publ Hlth, 2525 West End Ave,Suite 600, Nashville, TN 37203 USA. EM katherine.hartmann@vanderbilt.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD043883, R01HD049675]; American Water Works Association Research Foundation [2579]; Building Interdisciplinary Research Careers in Women's Health career development program [K12HD4383]; Vanderbilt Clinical and Translational Science Award [UL1 RR024975-01]; Intramural Research Program of the National Institutes of Health (National Institute of Environmental Health Sciences) FX The field research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grants R01HD043883 and R01HD049675) and the American Water Works Association Research Foundation (grant 2579). Additional funds were provided by the Building Interdisciplinary Research Careers in Women's Health career development program (grant K12HD4383), the Vanderbilt Clinical and Translational Science Award UL1 RR024975-01, and the Intramural Research Program of the National Institutes of Health (National Institute of Environmental Health Sciences). NR 34 TC 10 Z9 10 U1 1 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2013 VL 177 IS 11 BP 1271 EP 1278 DI 10.1093/aje/kws393 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 155MM UT WOS:000319752400013 PM 23558353 ER PT J AU Thompson, IA Liu, BY Sen, HN Jiao, XD Katamay, R Li, ZY Hu, MJ Hejtmancik, F Nussenblatt, RB AF Thompson, Ian A. Liu, Baoying Sen, H. Nida Jiao, Xiadong Katamay, Robert Li, Zhiyu Hu, Mengjun Hejtmancik, Fielding Nussenblatt, Robert B. TI Association of Complement Factor H Tyrosine 402 Histidine Genotype with Posterior Involvement in Sarcoid-Related Uveitis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID 1ST INTERNATIONAL WORKSHOP; MACULAR DEGENERATION; MULTIFOCAL CHOROIDITIS; OCULAR SARCOIDOSIS; S-ANTIGEN; AGE; CFH; POLYMORPHISM; GENE; DEFICIENCY AB PURPOSE: To determine whether the complement factor H (CFH) tyrosine 402 histidine (Y402H) variant, recently shown to be associated with age-related macular degeneration (AMD) and multifocal choroiditis, is associated with specific ocular sarcoidosis clinical phenotypes in black and white persons. DESIGN: Case-control study. METHODS: The CFH Y402H polymorphism (rs1061170) was genotyped in 41 subjects with ocular sarcoidosis and 393 control subjects. Allele frequencies in the ocular sarcoidosis cases were compared with controls using chi-square score tests. Genotypic model-based (dominant, recessive, and additive) associations of the rs1061170 allele were tested using multivariate logistic regression. Bayesian information criteria were used to formalize model selection. Genotypes were correlated with disease characteristics and severity of ocular inflammation. RESULTS: The C allele (rs1061170) was found in 35% of controls, but occurred with a significantly higher frequency (48.7%) in ocular sarcoidosis cases (odds ratio, 1.72; 95% confidence interval, 1.09 to 2.78; P = .018). Logistic regression demonstrated an association between rs1061170 and ocular sarcoidosis in 2 of 3 genetic models (additive, P = .0078; recessive, P = .0018). Posterior uveitis and panuveitis were overrepresented significantly in cases with the homozygous variant genotype (CC, 91%; P = .047). The population-attributable risk related to this CFH risk variant was 20%. CONCLUSIONS: The Y402H polymorphism of CFH seems to be associated with ocular sarcoidosis in black and white persons. Carriage of the CFH Y402H polymorphism in both alleles is associated with an increased risk for posterior uveitis and panuveitis presentation. The prognostic importance of this genotype will require prolonged follow-up studies. Published by Elsevier Inc. C1 [Thompson, Ian A.; Liu, Baoying; Sen, H. Nida; Katamay, Robert; Li, Zhiyu; Hu, Mengjun; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Jiao, Xiadong; Hejtmancik, Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU National Eye Institute, National Institutes of Health, Bethesda, Maryland FX Publication of this article was supported by intramural funding from the National Eye Institute, National Institutes of Health, Bethesda, Maryland (R.B.N.). Involved in Design of study (I.A.T., B.L., H.N.S., R.B.N.); Collection (I.A.T., B.L., H.N.S., X.J., R.K., Z.L., M.H., F.H., R.B.N.) and analysis and interpretation (I.A.T., B.L., H.N.S., F.H., R.B.N.) of data; and Preparation (I.A.T., B.L., H.N.S., R.B.N.), review (I.A.T., B.L., H.N.S., F.H., R.B.N.), and approval (I.A.T., B.L., H.N.S., X.J., R.K., Z.L., M.H., F.H., R.B.N.) of manuscript. This study of patient data was approved by the Neuroscience Institutional Review Board of the National Institute of Health. The authors thank Ms Karen Weikel from the American Red Cross for her valuable service in the recruitment of subjects. NR 39 TC 11 Z9 11 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2013 VL 155 IS 6 BP 1068 EP 1074 DI 10.1016/j.ajo.2013.01.019 PG 7 WC Ophthalmology SC Ophthalmology GA 157JU UT WOS:000319893200013 PM 23497844 ER PT J AU Avery, RA Dombi, E Hutcheson, KA Acosta, MT Baldwin, AM Madigan, WP Gillespie, A Fitzgibbon, EJ Packer, RJ Widemann, BC AF Avery, Robert A. Dombi, Eva Hutcheson, Kelly A. Acosta, Maria T. Baldwin, Andrea M. Madigan, William P. Gillespie, Andrea Fitzgibbon, Edmond J. Packer, Roger J. Widemann, Brigitte C. TI Visual Outcomes in Children With Neurofibromatosis Type 1 and Orbitotemporal Plexiform Neurofibromas SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OPTIC PATHWAY GLIOMAS; SURGICAL-MANAGEMENT; NF1; THERAPY AB PURPOSE: To describe the visual outcomes and volumetric magnetic resonance imaging (3D MRI) in children with neurofibromatosis type 1 (NF1) and orbitotemporal plexiform neurofibromas. DESIGN: Multicenter retrospective case series. METHODS: Two institutions with dedicated NF1 clinical research programs queried their established clinical databases for children with orbitotemporal plexiform neurofibromas. Visual acuity, refractive error, ambylopia, and treatment history were abstracted. Extent of orbitotemporal plexiform neurofibroma involvement was assessed clinically and with 3D MRI analysis. Children with optic pathway gliomas or ocular causes of decreased visual acuity (ie, cataracts, glaucoma) other than strabismus or anisometropia were excluded. RESULTS: Twenty-one children met inclusion criteria (median age 8 years, range 0.33-23 years). Orbitotemporal plexiform neurofibroma location was classified as isolated eyelid (n = 6), eyelid and orbit (n = 7), orbit and temporal region (n = 7), or diffuse orbit (n = 1). Three subjects had bilateral orbital involvement. Amblyopia secondary to the orbitotemporal plexiform neurofibroma was present in 13 subjects (62%) and was caused by strabismus (n = 2, 10%), occlusion from ptosis (n = 9, 43%), or anisometropia (n = 9, 43%), or a combination of factors (n = 6, 29%). MRI-derived volumes were measured in, 19 subjects (median 41.8 mL, range 2.7-754 mL). All subjects with amblyopia had orbitotemporal plexiform neurofibroma volumes greater than 10 mL. CONCLUSION: In our series, amblyopia occurs in more than half of NF1 children with orbitotemporal plexiform neurofibromas, most commonly because of ptosis and anisometropia. The 3D MRI analysis allowed for sensitive measurement of orbitotemporal plexiform neurofibroma size, and larger volumes were associated with development of amblyopia. (c) 2013 by Elsevier Inc. All rights reserved. C1 [Avery, Robert A.; Acosta, Maria T.; Packer, Roger J.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Avery, Robert A.; Acosta, Maria T.; Packer, Roger J.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Hutcheson, Kelly A.; Madigan, William P.] Childrens Natl Med Ctr, Dept Ophthalmol, Washington, DC 20010 USA. [Avery, Robert A.; Acosta, Maria T.; Packer, Roger J.] Childrens Natl Med Ctr, Gilbert Family Neurofibromatosis Inst, Washington, DC 20010 USA. [Avery, Robert A.; Acosta, Maria T.; Packer, Roger J.] Childrens Natl Med Ctr, Ctr Neurosci & Behav, Washington, DC 20010 USA. [Dombi, Eva; Baldwin, Andrea M.; Gillespie, Andrea; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fitzgibbon, Edmond J.] NEI, Bethesda, MD 20892 USA. RP Avery, RA (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave,NW, Washington, DC 20010 USA. EM ravery@childrensnational.org OI Avery, Robert/0000-0003-1453-7282 FU Gilbert Family Neurofibromatosis Institute; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland FX Publication of this article was supported by funding from the Gilbert Family Neurofibromatosis Institute and the intramural research program of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Contributions of authors: design of the study (R.A.A., E.D., A.M.B., A.G., R.J.P., B.C.W.), conduct of the study (R.A.A., E.D., A.G., R.J.P., B.C.W.); collection, management, analysis, and interpretation of the data (R.A.A., E.D., K.H., M.T.A., A.M.B., W.P.M., A.G., E.J.F., R.J.P., B.C.W.); and preparation, approval, and review of the manuscript (R.A.A., E.D., K.H., M.T.A., A.M.B., W.P.M., A.G., E.J.F., R.J.P., BOW.). NR 17 TC 9 Z9 9 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2013 VL 155 IS 6 BP 1089 EP 1094 DI 10.1016/j.ajo.2013.01.011 PG 6 WC Ophthalmology SC Ophthalmology GA 157JU UT WOS:000319893200015 PM 23453281 ER PT J AU Pan, CW Klein, BEK Cotch, MF Shrager, S Klein, R Folsom, A Kronmal, R Shea, SJ Burke, GL Saw, SM Wong, TY AF Pan, Chen-Wei Klein, Barbara E. K. Cotch, Mary Frances Shrager, Sandi Klein, Ronald Folsom, Aaron Kronmal, Richard Shea, Steven J. Burke, Gregory L. Saw, Seang-Mei Wong, Tien Y. TI Racial Variations in the Prevalence of Refractive Errors in the United States: The Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID AGE-RELATED MACULOPATHY; BEAVER DAM EYE; SINGAPORE MALAY EYE; BLUE MOUNTAINS EYE; RISK-FACTORS; DEPRIVATION MYOPIA; VISUAL IMPAIRMENT; PARENTAL HISTORY; OLDER POPULATION; CHILDREN AB PURPOSE: To describe racial variations in the prevalence of refractive errors among adult white, Chinese, Hispanic, and black subjects in the United States. DESIGN: Cross-sectional data from a prospective cohort study-the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: A total of 6000 adults aged 45 to 84 years living in the United States participated in the study. Refractive error was assessed, without cycloplegia, in both eyes of all participants using an autorefractor. After excluding eyes with cataract, cataract surgery, or previous refractive surgery, the eye with the larger absolute spherical equivalent (SE) value for each participant was used to classify refractive error. Any myopia was defined as SE of -1.0 diopters (D) or less; high myopia was defined as SE of -5.0 D or less; any hyperopia was defined as SE of +1.0 D or more; clinically significant hyperopia was defined as SE of +3.0 D or more. Astigmatism was defined as a cylinder value of +1.0 D or more. RESULTS: After excluding 508 participants with cataracts in both eyes, 838 participants with cataract surgery, 90 participants with laser refractive surgery, and 134 participants who refused to remove their contact lenses for the refraction measurement, 4430 adults with refractive error assessment in at least 1 eye contributed to the analysis. The prevalence of myopia among MESA participants was 25.1%, with lowest rates in Hispanic participants (14.2%), followed by black (21.5%) and white participants (31.0%), and highest rates in Chinese participants (37.2%). The overall rates of high myopia and astigmatism were 4.6% and 45.0%, respectively, with Chinese subjects also having the highest rates of high myopia (11.8%) and astigmatism (53.4%). The overall prevalence of any hyperopia was 38.2% and clinically significant hyperopia was 6.1%, with Hispanic participants having the highest rates of hyperopia (50.2%) and clinically significant hyperopia (8.8%). In multivariate analyses adjusting for age, sex, race, and study site, higher education level, being employed, and being taller were associated with a higher prevalence of myopia. In contrast, lower educational level and being shorter were associated with a higher prevalence of hyperopia. CONCLUSIONS: Myopia and astigmatism were most prevalent in the Chinese population, with Chinese subjects having 3 times the prevalence of myopia as Hispanic subjects. Hyperopia was most common in Hispanic subjects. These findings provide further insights into variations in refractive errors among different racial groups and have important implications for the eye care services in the United States. ((c) 2013 by Elsevier Inc. All rights reserved.) C1 [Pan, Chen-Wei; Saw, Seang-Mei; Wong, Tien Y.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Saw, Seang-Mei; Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 117548, Singapore. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Cotch, Mary Frances] NEI, US NIH, Bethesda, MD 20892 USA. [Shrager, Sandi; Kronmal, Richard] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Folsom, Aaron] Univ Minnesota, Dept Epidemiol, Minneapolis, MN USA. [Shea, Steven J.] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven J.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Burke, Gregory L.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Saw, Seang-Mei; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. RP Wong, TY (reprint author), Singapore Eye Res Inst, 11 3rd Hosp Ave,05-00, Singapore 168751, Singapore. EM ophwty@nus.edu.sg RI Pan, Chen-Wei/E-6205-2015; OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 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-95169]; National Institute of Health Intramural Research award from the National Eye Institute (M.F.C.), Bethesda, Maryland [ZAIEY000403] FX Publication of this article was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and National Institute of Health Intramural Research award ZAIEY000403 from the National Eye Institute (M.F.C.), Bethesda, Maryland. Contributions of authors: involved in design of study (B.E.K., Ro.K., A.F., T.Y.W); conduct of study (B.E.K., M.F.C., S.S., Ro.K., A.F., Ri.K., S.J.S, G.L.B., T.Y.W.); collection of data (B.E.K., M.F.C., S.S., Ro.K., A.F., Ri.K., S.J.S, G.L.B., T.Y.W.); management (T.Y.W.), analysis (C.W.P., S.S., S.M.S.), and interpretation (C.W.P., B.E.K., M.F.C., S.S., Ro.K., A.F., Ri.K., S.J.S, G.L.B., S.M.S., T.Y.W.) of data; preparation of manuscript (C.W.P., B.E.K., M.F.C., S.S., Ro.K., A.F., Ri.K., S.J.S., G.L.B., S.M.S., T.Y.W.); and review and approval of manuscript (C.W.P., B.E.K., M.F.C., S.S., Ro.K., A.F., Ri.K., S.J.S, G.L.B., S.M.S., T.Y.W.). NR 44 TC 21 Z9 21 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2013 VL 155 IS 6 BP 1129 EP 1138 DI 10.1016/j.ajo.2013.01.009 PG 10 WC Ophthalmology SC Ophthalmology GA 157JU UT WOS:000319893200022 PM 23453694 ER PT J AU Gril, B Palmieri, D Qian, YZ Anwar, T Liewehr, DJ Steinberg, SM Andreu, Z Masana, D Fernandez, P Steeg, PS Vidal-Vanaclocha, F AF Gril, Brunilde Palmieri, Diane Qian, Yongzhen Anwar, Talha Liewehr, David J. Steinberg, Seth M. Andreu, Zoraida Masana, Daniel Fernandez, Paloma Steeg, Patricia S. Vidal-Vanaclocha, Fernando TI Pazopanib Inhibits the Activation of PDGFR beta-Expressing Astrocytes in the Brain Metastatic Microenvironment of Breast Cancer Cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MULTIPLE-SCLEROSIS LESIONS; GROWTH-FACTOR RECEPTOR; IN-VIVO; REACTIVE ASTROCYTES; ALPHA-RECEPTOR; TUMORS; OVEREXPRESSION; COLONIZATION; BARRIER; INJURY AB Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected M DA-M B-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor beta (at tyrosine 751; p751-PDGFR beta was identified around perivascular brain micrometastases. p751-PDGFR beta(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFR beta(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients. C1 [Gril, Brunilde; Palmieri, Diane; Qian, Yongzhen; Anwar, Talha; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Ctr Canc Res, Natl Canc Res, Rockville, MD USA. [Andreu, Zoraida; Masana, Daniel; Fernandez, Paloma; Vidal-Vanaclocha, Fernando] CEU San Pablo Univ Sch Med, Madrid 28668, Spain. [Andreu, Zoraida; Masana, Daniel; Fernandez, Paloma; Vidal-Vanaclocha, Fernando] Hosp Madrid Sci Fdn, Inst Appl Mol Med IMMA, Madrid 28668, Spain. RP Vidal-Vanaclocha, F (reprint author), CEU San Pablo Univ Sch Med, Inst Appl Mol Med IMMA, Madrid 28668, Spain. EM grilbrun@mail.nih.gov; fernando.vidalvanaclocha@ceu.es RI Palmieri, Diane/B-4258-2015 FU National Cancer Institute; Department of Defense Breast Cancer Research Program [W81XWH-062-0033]; GlaxoSmithKline; Carlos III Health Institute (FIS, Madrid) [ADE09/90041]; Burdinola Professorship on Molecular Medicine FX Supported by the intramural program of the National Cancer Institute (P.S.S.), the Department of Defense Breast Cancer Research Program grant W81XWH-062-0033 (P.S.S.), GlaxoSmithKline (P.S.S.), the Carlos III Health Institute (FIS, Madrid) grant ADE09/90041 (F.V.-V.), and the Burdinola Professorship on Molecular Medicine (F.V.-V.). NR 66 TC 18 Z9 18 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2013 VL 182 IS 6 BP 2368 EP 2379 DI 10.1016/j.ajpath.2013.02.043 PG 12 WC Pathology SC Pathology GA 155WT UT WOS:000319781800039 PM 23583652 ER PT J AU Yaniv, Y Spurgeon, HA Ziman, BD Lyashkov, AE Lakatta, EG AF Yaniv, Yael Spurgeon, Harold A. Ziman, Bruce D. Lyashkov, Alexey E. Lakatta, Edward G. TI Mechanisms that match ATP supply to demand in cardiac pacemaker cells during high ATP demand SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE calcium-activated adenylyl cyclase; bioenergetics; pacemaker automaticity ID SINOATRIAL NODE CELLS; MITOCHONDRIAL CA2+ UPTAKE; HEART IN-VIVO; ADENYLYL-CYCLASE; MAMMALIAN HEART; MYOCYTES; CONTRACTION; PROTEIN; SYSTEM; KINASE AB The spontaneous action potential (AP) firing rate of sinoatrial node cells (SANCs) involves high-throughput signaling via Ca2+-calmodulin activated adenylyl cyclases (AC), cAMP-mediated protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of SR Ca2+ cycling and surface membrane ion channel proteins. When the throughput of this signaling increases, e.g., in response to beta-adrenergic receptor activation, the resultant increase in spontaneous AP firing rate increases the demand for ATP. We hypothesized that an increase of ATP production to match the increased ATP demand is achieved via a direct effect of increased mitochondrial Ca2+ (Ca2+ m) and an indirect effect via enhanced Ca2+-cAMP/PKA-CaMKII signaling to mitochondria. To increase ATP demand, single isolated rabbit SANCs were superfused by physiological saline at 35 +/- 0.5 degrees C with isoproterenol, or by phosphodiesterase or protein phosphatase inhibition. We measured cytosolic and mitochondrial Ca2+ and flavoprotein fluorescence in single SANC, and we measured cAMP, ATP, and O-2 consumption in SANC suspensions. Although the increase in spontaneous AP firing rate was accompanied by an increase in O-2 consumption, the ATP level and flavoprotein fluorescence remained constant, indicating that ATP production had increased. Both Ca2+ m and cAMP increased concurrently with the increase in AP firing rate. When Ca2+ m was reduced by Ru360, the increase in spontaneous AP firing rate in response to isoproterenol was reduced by 25%. Thus, both an increase in Ca2+ m and an increase in Ca2+ activated cAMP-PKA-CaMKII signaling regulate the increase in ATP supply to meet ATP demand above the basal level. C1 [Yaniv, Yael; Spurgeon, Harold A.; Ziman, Bruce D.; Lyashkov, Alexey E.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 44 TC 14 Z9 14 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2013 VL 304 IS 11 BP H1428 EP H1438 DI 10.1152/ajpheart.00969.2012 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 156FW UT WOS:000319808200003 PM 23604710 ER PT J AU Engels, EA Clarke, CA Pfeiffer, RM Lynch, CF Weisenburger, DD Gibson, TM Landgren, O Morton, LM AF Engels, Eric A. Clarke, Christina A. Pfeiffer, Ruth M. Lynch, Charles F. Weisenburger, Dennis D. Gibson, Todd M. Landgren, Ola Morton, Lindsay M. TI Plasma Cell Neoplasms in US Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Epstein-Barr virus; immunosuppression; multiple myeloma; plasmacytoma; primary biliary cirrhosis; posttransplant lymphoproliferative disorder ID PRIMARY BILIARY-CIRRHOSIS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; EPSTEIN-BARR-VIRUS; STAGE RENAL-DISEASE; MULTIPLE-MYELOMA; CANCER INCIDENCE; EXTRAMEDULLARY PLASMACYTOMA; UNDETERMINED SIGNIFICANCE; KIDNEY-TRANSPLANTATION; LIVER-TRANSPLANTATION AB Transplant recipients have elevated risk for plasma cell neoplasms (PCNs, comprising multiple myeloma and plasmacytoma), but little is known about risk factors in the transplant setting. Through linkage of the US solid organ transplant registry with 15 state/regional cancer registries, we identified 140 PCNs in 202600 recipients (1987-2009). PCN risk was 1.8-fold increased relative to the general population (standardized incidence ratio [SIR] 1.80, 95%CI 1.51-2.12). Among cases, 102 were multiple myeloma (SIR 1.41) and 38 were plasmacytoma (SIR 7.06). PCN incidence increased with age, but due to the rarity of PCNs in younger people in the general population, SIRs were highest in younger transplant recipients (p=0.03). PCN risk was especially high in recipients who were Epstein-Barr virus (EBV) seronegative at transplantation (SIR 3.93). EBV status was known for 18 tumors, of which 7 (39%) were EBV positive. Following liver transplantation, PCN risk was higher in recipients with cholestatic liver disease (SIR 2.78); five of these cases had primary biliary cirrhosis (PBC). A role for primary EBV infection after transplantation is supported by the increased PCN risk in young EBV seronegative recipients and the presence of EBV in tumors. PBC may be another risk factor, perhaps by causing chronic immune activation. C1 [Engels, Eric A.; Pfeiffer, Ruth M.; Gibson, Todd M.; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Lynch, Charles F.] Univ Iowa, Iowa City, IA USA. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Duarte, CA USA. [Landgren, Ola] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM engelse@exchange.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural Research Program of the National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Cancer Institute. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (15-0351), North Carolina (U58DP000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (N01-PC-35143), New Jersey (HHSN261201000027C N01-PC-54405), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, NewJersey, NewYork (Cancer Surveillance Improvement Initiative 14-2491), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA. NR 49 TC 11 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JUN PY 2013 VL 13 IS 6 BP 1523 EP 1532 DI 10.1111/ajt.12234 PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA 154WM UT WOS:000319706900019 PM 23635036 ER PT J AU Mejia, R Vicuna, Y Broncano, N Sandoval, C Vaca, M Chico, M Cooper, PJ Nutman, TB AF Mejia, Rojelio Vicuna, Yosselin Broncano, Nely Sandoval, Carlos Vaca, Maritza Chico, Martha Cooper, Philip J. Nutman, Thomas B. TI A Novel, Multi-Parallel, Real-Time Polymerase Chain Reaction Approach for Eight Gastrointestinal Parasites' Provides Improved Diagnostic Capabilities to Resource-Limited At-Risk Populations SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ENZYME-IMMUNOASSAY; GIARDIA-LAMBLIA; PCR METHOD; DNA; INFECTIONS; SPECIMENS; BANGLADESH; EXTRACTION; ENTAMOEBA; HELMINTHS AB Diagnosis of gastrointestinal parasites has traditionally relied on stool microscopy, which has low diagnostic sensitivity and specificity. We have developed a novel, rapid, high-throughput quantitative multi-parallel real-time polymerase chain reaction (qPCR) platform. Species-specific primers/probes were used for eight common gastrointestinal parasite pathogens: Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Giardia lamblia, Cryptosporidium spp., Entamoeba histolytica, Trichuris trichiura, and Strongyloides stercoralis. Stool samples from 400 13-month-old children in rural Ecuador were analyzed and the qPCR was compared with a standard direct wet mount slide for stool microscopy, as were 125 8-14-year-old children before and after anthelmintic treatment. The qPCR showed higher detection rates for all parasites compared with direct microscopy, Ascaris (7.0% versus 5.5%) and for Giardia (31.5% versus 5.8%). Using an enhanced DNA extraction method, we were able to detect T. trichiura DNA. These assays will be useful to refine treatment options for affected populations, ultimately leading to better health outcomes. C1 [Nutman, Thomas B.] NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Fdn Ecuatoriana Invest Salud, Quito, Ecuador. Univ San Francisco Quito, Colegio Ciencias Salud, Quito, Ecuador. Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Mejia, Rojelio] Baylor Coll Med, Natl Sch Trop Med, Houston, TX 77030 USA. [Vicuna, Yosselin; Broncano, Nely; Sandoval, Carlos; Vaca, Maritza; Chico, Martha; Cooper, Philip J.] Univ San Francisco Quito, Fdn Ecuatoriana Invest Salud, Colegio Ciencias Salud, Quito, Ecuador. RP Nutman, TB (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bldg 4,Room B1-03,4 Ctr Dr, Bethesda, MD 20892 USA. EM rojelio.mejia@bcm.edu; yossvi@gmail.com; nelyes@hotmail.es; sandoval_acarlos@hotmail.com; marimar_ecq@yahoo.com; marthachico6@yahoo.es; p.j.cooper@liverpool.ac.uk; tnutman@niaid.nih.gov FU Wellcome Trust [088862] NR 26 TC 31 Z9 32 U1 3 U2 17 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2013 VL 88 IS 6 BP 1041 EP 1047 DI 10.4269/ajtmh.12-0726 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 158GO UT WOS:000319957700006 PM 23509117 ER PT J AU Papadi, B Boudreaux, C Tucker, JA Mathison, B Bishop, H Eberhard, ME AF Papadi, Bhavesh Boudreaux, Carole Tucker, J. Allan Mathison, Blaine Bishop, Henry Eberhard, Mark E. TI Case Report: Halicephalobus gingivalis: A Rare Cause of Fatal Meningoencephalomyelitis in Humans SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID OF-THE-LITERATURE; INFECTION; HORSE; MICRONEMA; DELETRIX AB The genus Halicephalobus consists of eight species of free-living nematodes. Only one species (H. gingivalis) has been reported to infect vertebrates. Human infection is extremely rare, and only four cases have been reported in the literature. These nematodes seem to exhibit neurotropism, but their life cycle, mode of infection, and risk factors are poorly understood. Neurohelminthiases are not commonly recognized in the United States and when they do occur, pose great diagnostic challenges because of lack of appropriate non-invasive screening and/or confirmatory tests. We report a challenging case of meningoencephalomyelitis caused by a Halicephalobus sp., in which the patient had a rapidly deteriorating clinical course. The case did not raise any clinical suspicion of neurohelminthiases, although increased eosinophils were present in the cerebrospinal fluid. This case presents an opportunity to highlight the importance of considering parasitic infection in meningoencephalitis or meningoencephalomyelitis presenting atypically. C1 Univ S Alabama, Med Ctr, Mobile, AL USA. [Mathison, Blaine; Bishop, Henry; Eberhard, Mark E.] Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Atlanta, GA USA. [Papadi, Bhavesh] NCI, NIH, Bethesda, MD 20892 USA. [Boudreaux, Carole; Tucker, J. Allan] Univ S Alabama, Med Ctr, Dept Pathol, Mobile, AL USA. RP Papadi, B (reprint author), NCI, NIH, 10 Ctr Dr,Room 2A19, Bethesda, MD 20892 USA. EM bhavesh2papadi@yahoo.com; cboudrea@usouthal.edu; atucker@usouthal.edu; gqa4@cdc.gov; hsb2@cdc.gov; mle1@cdc.gov FU University of South Alabama Medical Center FX We thank the laboratory of University of South Alabama Medical Center for support. The American Committee on Clinical Tropical Medicine and Travelers' Health (ACCTMTH) assisted with publication expenses. NR 13 TC 4 Z9 4 U1 1 U2 8 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2013 VL 88 IS 6 BP 1062 EP 1064 DI 10.4269/ajtmh.12-0730 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 158GO UT WOS:000319957700009 PM 23509120 ER PT J AU Tsetsarkin, KA Sampson-Johannes, A Sawyer, L Kinsey, J Higgs, S Vanlandingham, DL AF Tsetsarkin, Konstantin A. Sampson-Johannes, Adam Sawyer, Lynette Kinsey, John Higgs, Stephen Vanlandingham, Dana L. TI Photochemical Inactivation of Chikungunya Virus in Human Apheresis Platelet Components by Amotosalen and UVA Light SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID WAVELENGTH ULTRAVIOLET-LIGHT; PATHOGEN INACTIVATION; INDIAN-OCEAN; REUNION-ISLAND; PLASMA COMPONENTS; LA-REUNION; INFECTION; PSORALEN; EPIDEMIC; OUTBREAK AB Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that recently re-emerged in Africa and rapidly spread into countries of the Indian Ocean basin and South-East Asia. The mean viremic blood donation risk for CHIKV on La Reunion reached 1.5% at the height of the 2005-2006 outbreaks, highlighting the need for development of safety measures to prevent transfusion-transmitted infections. We describe successful inactivation of CHIKV in human platelets and plasma using photochemical treatment with amotosalen and long wavelength UVA illumination. Platelet components in additive solution and plasma units were inoculated with two different strains of high titer CHIKV stock (6.0-8.0 logs/mL), and then treated with amotosalen and exposure to 1.0-3.0 J/cm(2) UVA. Based on in vitro assays of infectious virus pre- and post-treatment to identify endpoint dilutions where virus was not detectable, mean viral titers could effectively be reduced by > 6.4 +/- 0.6 log(10) TCID50/mL in platelets and >= 7.6 +/- 1.4 logs in plasma, indicating this treatment has the capacity to prevent CHIKV transmission in human blood components collected from infected donors in or traveling from areas of CHIKV transmission. C1 Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Sampson-Johannes, Adam; Sawyer, Lynette; Kinsey, John] Cerus Corp, Concord, CA USA. [Higgs, Stephen] Kansas State Univ, Biosecur Res Inst, Manhattan, KS 66506 USA. [Tsetsarkin, Konstantin A.] NIAID, Neurotrop Flaviviruses Sect, Bethesda, MD 20892 USA. [Vanlandingham, Dana L.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. RP Vanlandingham, DL (reprint author), Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, 1800 Denison Ave, Manhattan, KS 66506 USA. EM tsetsarkinka@niaid.nih.gov; Dna.3@sbcglobal.net; LSawyer@cerus.com; shotokando@aol.com; shiggs@k-state.edu; dlvanlan@vet.k-state.edu FU Cerus Corporation FX Funding for this study was provided by Cerus Corporation. NR 70 TC 6 Z9 6 U1 0 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2013 VL 88 IS 6 BP 1163 EP 1169 DI 10.4269/ajtmh.12-0603 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 158GO UT WOS:000319957700024 PM 23530077 ER PT J AU Kuhn, JH Bao, YM Bavari, S Becker, S Bradfute, S Brister, JR Bukreyev, AA Cai, YY Chandran, K Davey, RA Dolnik, O Dye, JM Enterlein, S Gonzalez, JP Formenty, P Freiberg, AN Hensley, LE Honko, AN Ignatyev, GM Jahrling, PB Johnson, KM Klenk, HD Kobinger, G Lackemeyer, MG Leroy, EM Lever, MS Lofts, LL Muhlberger, E Netesov, SV Olinger, GG Palacios, G Patterson, JL Paweska, JT Pitt, L Radoshitzky, SR Ryabchikova, EI Saphire, EO Shestopalov, AM Smither, SJ Sullivan, NJ Swanepoel, R Takada, A Towner, JS van der Groen, G Volchkov, VE Wahl-Jensen, V Warren, TK Warfield, KL Weidmann, M Nichol, ST AF Kuhn, Jens H. Bao, Yiming Bavari, Sina Becker, Stephan Bradfute, Steven Brister, J. Rodney Bukreyev, Alexander A. Cai, Yingyun Chandran, Kartik Davey, Robert A. Dolnik, Olga Dye, John M. Enterlein, Sven Gonzalez, Jean-Paul Formenty, Pierre Freiberg, Alexander N. Hensley, Lisa E. Honko, Anna N. Ignatyev, Georgy M. Jahrling, Peter B. Johnson, Karl M. Klenk, Hans-Dieter Kobinger, Gary Lackemeyer, Matthew G. Leroy, Eric M. Lever, Mark S. Lofts, Loreen L. Muehlberger, Elke Netesov, Sergey V. Olinger, Gene G. Palacios, Gustavo Patterson, Jean L. Paweska, Janusz T. Pitt, Louise Radoshitzky, Sheli R. Ryabchikova, Elena I. Saphire, Erica Ollmann Shestopalov, Aleksandr M. Smither, Sophie J. Sullivan, Nancy J. Swanepoel, Robert Takada, Ayato Towner, Jonathan S. van der Groen, Guido Volchkov, Viktor E. Wahl-Jensen, Victoria Warren, Travis K. Warfield, Kelly L. Weidmann, Manfred Nichol, Stuart T. TI Virus nomenclature below the species level: a standardized nomenclature for laboratory animal-adapted strains and variants of viruses assigned to the family Filoviridae SO ARCHIVES OF VIROLOGY LA English DT Article ID VERVET MONKEY DISEASE; MARBURG VIRUS; EBOLA-VIRUS; RHABDOVIRUS-SIMIAE; HEMORRHAGIC-FEVER; MOUSE MODEL; GUINEA-PIGS; VERO CELLS; INFECTION; AGENT AB The International Committee on Taxonomy of Viruses (ICTV) organizes the classification of viruses into taxa, but is not responsible for the nomenclature for taxa members. International experts groups, such as the ICTV Study Groups, recommend the classification and naming of viruses and their strains, variants, and isolates. The ICTV Filoviridae Study Group has recently introduced an updated classification and nomenclature for filoviruses. Subsequently, and together with numerous other filovirus experts, a consistent nomenclature for their natural genetic variants and isolates was developed that aims at simplifying the retrieval of sequence data from electronic databases. This is a first important step toward a viral genome annotation standard as sought by the US National Center for Biotechnology Information (NCBI). Here, this work is extended to include filoviruses obtained in the laboratory by artificial selection through passage in laboratory hosts. The previously developed template for natural filovirus genetic variant naming (< virus name > < isolation host-suffix >/< country of sampling >/< year of sampling >/< genetic variant designation >-< isolate designation >) is retained, but it is proposed to adapt the type of information added to each field for laboratory animal-adapted variants. For instance, the full-length designation of an Ebola virus Mayinga variant adapted at the State Research Center for Virology and Biotechnology "Vector" to cause disease in guinea pigs after seven passages would be akin to "Ebola virus VECTOR/C.porcellus-lab/COD/1976/Mayinga-GPA-P7". As was proposed for the names of natural filovirus variants, we suggest using the full-length designation in databases, as well as in the method section of publications. Shortened designations (such as "EBOV VECTOR/C.por/COD/76/May-GPA-P7") and abbreviations (such as "EBOV/May-GPA-P7") could be used in the remainder of the text depending on how critical it is to convey information contained in the full-length name. "EBOV" would suffice if only one EBOV strain/variant/isolate is addressed. C1 [Kuhn, Jens H.; Cai, Yingyun; Jahrling, Peter B.; Lackemeyer, Matthew G.; Wahl-Jensen, Victoria] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, Frederick, MD 21702 USA. [Bao, Yiming; Brister, J. Rodney] Natl Lib Med, Informat Engn Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Bavari, Sina; Dye, John M.; Honko, Anna N.; Lofts, Loreen L.; Olinger, Gene G.; Palacios, Gustavo; Pitt, Louise; Radoshitzky, Sheli R.; Warren, Travis K.] USA, Med Res Inst Infect Dis, Frederick, MD USA. [Becker, Stephan; Dolnik, Olga; Klenk, Hans-Dieter] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [Bradfute, Steven] Univ New Mexico, Albuquerque, NM 87131 USA. [Bukreyev, Alexander A.; Freiberg, Alexander N.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Bukreyev, Alexander A.; Freiberg, Alexander N.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Chandran, Kartik] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Davey, Robert A.; Patterson, Jean L.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Enterlein, Sven; Warfield, Kelly L.] Integrated BioTherapeut Inc, Gaithersburg, MD USA. [Gonzalez, Jean-Paul] Inst Rech Dev, Dept Hlth, Marseille, France. [Gonzalez, Jean-Paul] Metabiota Inc, San Francisco, CA USA. [Formenty, Pierre] World Hlth Org, Geneva, Switzerland. [Hensley, Lisa E.] US FDA, Med Countermeasure Initiat, Silver Spring, MD USA. [Ignatyev, Georgy M.] Fed State Unitary Co Microgen Sci Ind Co Immunobi, Minist Hlth & Social Dept Russian Federat, Moscow, Russia. [Kobinger, Gary] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Leroy, Eric M.] Ctr Int Rech Med Franceville, Franceville, Gabon. [Lever, Mark S.; Smither, Sophie J.] Dstl, Dept Biomed Sci, Salisbury, Wilts, England. [Muehlberger, Elke] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Muehlberger, Elke] Boston Univ, Sch Med, Natl Emerging Infect Dis Lab, Boston, MA 02118 USA. [Netesov, Sergey V.; Shestopalov, Aleksandr M.] Novosibirsk State Univ, Novosibirsk, Novosibirsk Obl, Russia. [Paweska, Janusz T.] Natl Hlth Lab Serv, Ctr Emerging & Zoonot Dis, Natl Inst Communicable Dis, Sandringham Johannesburg, Gauteng, South Africa. [Ryabchikova, Elena I.] Russian Acad Sci, Inst Chem Biol & Fundamental Med, Siberian Branch, Novosibirsk, Novosibirsk Obl, Russia. [Saphire, Erica Ollmann] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Saphire, Erica Ollmann] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Shestopalov, Aleksandr M.] State Res Ctr Virol & Biotechnol Vector, Koltsov, Novosibirsk Obl, Russia. [Sullivan, Nancy J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Swanepoel, Robert] Univ Pretoria, Zoonoses Res Unit, ZA-0002 Pretoria, South Africa. [Takada, Ayato] Hokkaido Univ, Div Global Epidemiol, Res Ctr Zoonosis Control, Sapporo, Hokkaido, Japan. [Towner, Jonathan S.; Nichol, Stuart T.] Ctr Dis Control & Prevent CDC, VSPB, DHCPP, NCEZID, Atlanta, GA 30333 USA. [van der Groen, Guido] Prins Leopold Inst Trop Geneeskunde, Antwerp, Belgium. [Volchkov, Viktor E.] Univ Lyon, Lab Filovirus, Inserm U758, UCB Lyon 1,Ecole Normale Super Lyon, Lyon, France. [Weidmann, Manfred] Univ Med Gottingen, Abt Virol, Gottingen, Germany. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov; stn1@cdc.gov RI Ryabchikova, Elena /G-3089-2013; Netesov, Sergey/A-3751-2013; Volchkov, Viktor/M-7846-2014; Kuhn, Jens H./B-7615-2011; Becker, Stephan/A-1065-2010; Palacios, Gustavo/I-7773-2015; Weidmann, Manfred/G-1817-2015; LEROY, Eric/I-4347-2016; OI Olinger, Gene/0000-0001-7338-0292; Shestopalov, Alexander/0000-0002-9734-0620; Ryabchikova, Elena /0000-0003-4714-1524; Netesov, Sergey/0000-0002-7786-2464; Volchkov, Viktor/0000-0001-7896-8706; Kuhn, Jens H./0000-0002-7800-6045; Becker, Stephan/0000-0002-2794-5659; Palacios, Gustavo/0000-0001-5062-1938; Weidmann, Manfred/0000-0002-7063-7491; LEROY, Eric/0000-0003-0022-0890; Gonzalez, Jean-Paul/0000-0003-3063-1770; Muhlberger, Elke/0000-0003-3547-9376; Honko, Anna/0000-0001-9165-148X FU Joint Science and Technology Office for Chem Bio Defense [TMTI0048_09_RD_T]; NIAID [HHSN272200200016I]; Intramural Research Program of the NIH, National Library of Medicine FX The content of this publication does not necessarily reflect the views or policies of the US Department of the Army, the US Department of Defense or the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. This work was funded in part by the Joint Science and Technology Office for Chem Bio Defense (proposal #TMTI0048_09_RD_T to SB). YC, JHK, and VWJ performed this work as employees of Tunnell Consulting, Inc., and MGL as an employee of Lovelace Respiratory Research Institute, both subcontractors to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200200016I. This research was also supported in part by the Intramural Research Program of the NIH, National Library of Medicine (YB and JRB). NR 42 TC 21 Z9 22 U1 1 U2 24 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 JUN PY 2013 VL 158 IS 6 BP 1425 EP 1432 DI 10.1007/s00705-012-1594-2 PG 8 WC Virology SC Virology GA 155QK UT WOS:000319762800035 PM 23358612 ER PT J AU Yazdanyar, A Wasko, MC Scalzi, LV Kraemer, KL Ward, MM AF Yazdanyar, Ali Wasko, Mary Chester Scalzi, Lisabeth V. Kraemer, Kevin L. Ward, Michael M. TI Short-Term Perioperative All-Cause Mortality and Cardiovascular Events in Women With Systemic Lupus Erythematosus SO ARTHRITIS CARE & RESEARCH LA English DT Article ID CORONARY-ARTERY DISEASE; NONCARDIAC SURGERY; RISK-FACTORS; MYOCARDIAL-INFARCTION; DEFINED POPULATION; CARDIAC RISK; DEATH; MORBIDITY; INDEX; GUIDELINE AB Objective Persons with systemic lupus erythematosus (SLE) are at an increased risk of cardiovascular disease (CVD) events, but this excess CVD burden in the perioperative setting is yet to be determined. We aimed to determine the risk of perioperative short-term all-cause mortality and CVD events among women with SLE compared to those without SLE. Methods We conducted a cross-sectional analysis of pooled hospital discharge data of the Nationwide Inpatient Sample from 1998-2002. We abstracted diseases and procedures using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The principal procedure was categorized into either a low, intermediate, or high risk level. Survey logistic regression adjusting for potential confounders provided estimates for stratum-specific odds of adverse events in women with SLE relative to those without SLE for each procedure risk level. Results All-cause mortality was significantly greater among women with SLE having a low- (odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.00-2.37) or a high-risk principal procedure (OR 2.52, 95% CI 1.34-4.75) relative to women without SLE, but did not differ significantly among persons with intermediate-risk procedures. Women with SLE with a low-risk procedure were also more likely to experience a composite CVD event relative to women without SLE (OR 1.40, 95% CI 1.04-1.87). Conclusion Women with SLE are at an increased risk for short-term perioperative adverse events. These results highlight a need for greater scrutiny during perioperative evaluation and management of women with SLE. C1 [Yazdanyar, Ali] Reading Hosp Med Ctr, W Reading, PA 19611 USA. [Wasko, Mary Chester] West Penn Allegheny Hlth Syst, Pittsburgh, PA USA. [Scalzi, Lisabeth V.] Penn State Univ, Hershey Med Ctr, Hershey, PA USA. [Kraemer, Kevin L.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Yazdanyar, A (reprint author), Reading Hosp Med Ctr, Dept Med, Sect Hosp Med, 6th Ave & Spruce St, W Reading, PA 19611 USA. EM a.yazzzd@gmail.com FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported in part by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 30 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUN PY 2013 VL 65 IS 6 BP 986 EP 991 DI 10.1002/acr.21915 PG 6 WC Rheumatology SC Rheumatology GA 155OY UT WOS:000319758900020 PM 23213026 ER PT J AU Brooks, SA Blackshear, PJ AF Brooks, Seth A. Blackshear, Perry J. TI Tristetraprolin (TTP): Interactions with mRNA and proteins, and current thoughts on mechanisms of action SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Tristetraprolin; Post-transcriptional regulation; mRNA stability; mRNA translation; AU-rich element ID TUMOR-NECROSIS-FACTOR; AU-RICH-ELEMENT; KINASE-ACTIVATED PROTEIN-KINASE-2; ZINC-FINGER PROTEINS; ENDOTHELIAL GROWTH-FACTOR; 3' UNTRANSLATED REGION; HUMAN COLON-CANCER; P-BODY FORMATION; HU ANTIGEN-R; TNF-ALPHA AB Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenosine and uridine (AU)-rich elements (ARE), often located in the 3' untranslated regions (3'UTR) of mRNAs, are known to target transcripts for rapid decay. They are also involved in the regulation of mRNA stability and translation in response to extracellular cues. This review focuses on one of the best characterized ARE binding proteins, tristetraprolin (UP), the founding member of a small family of CCCH tandem zinc finger proteins. In this survey, we have reviewed the current status of UP interactions with mRNA and proteins, and discussed current thinking about TTP's mechanism of action to promote mRNA decay. We also review the proposed regulation of TTP's functions by phosphorylation. Finally, we have discussed emerging evidence for UP operating as a translational regulator. This article is part of a Special Issue entitled: RNA Decay mechanisms. Published by Elsevier B.V. C1 [Brooks, Seth A.] Vet Affairs Med Ctr, White River Jct, VT USA. [Brooks, Seth A.] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU Intramural NIH HHS [ZIA ES090080-15] NR 199 TC 107 Z9 107 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD JUN-JUL PY 2013 VL 1829 IS 6-7 SI SI BP 666 EP 679 DI 10.1016/j.bbagrm.2013.02.003 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 164OP UT WOS:000320419700017 PM 23428348 ER PT J AU Pidala, J Chai, XY Martin, P Inamoto, Y Cutler, C Palmer, J Weisdorf, D Pavletic, S Arora, M Jagasia, M Jacobsohn, D Lee, SJ AF Pidala, Joseph Chai, Xiaoyu Martin, Paul Inamoto, Yoshihiro Cutler, Corey Palmer, Jeanne Weisdorf, Daniel Pavletic, Steven Arora, Mukta Jagasia, Madan Jacobsohn, David Lee, Stephanie J. TI Hand Grip Strength and 2-Minute Walk Test in Chronic Graft-versus-Host Disease Assessment: Analysis from the Chronic GVHD Consortium SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hand grip strength; Two minute walk test; Chronic graft vs. host disease ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; QUALITY-OF-LIFE; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; HUMAN ACTIVITY PROFILE; CLINICAL-TRIALS; PROGNOSTIC VALUE; PINCH STRENGTH; CRITERIA AB Hand grip strength (HGS) and the 2-minute walk test (2MWT) have been proposed as elements of chronic graft-versus-host disease (GVHD) assessment in clinical trials. Using all available data (n = 584 enrollment visits, 1689 follow-up visits, total of 2273 visits) from a prospective observational cohort study, we explored the relationship between HGS and 2MWT and patient-reported measures (Lee symptom scale, MOS 36-Item Short-Form Health Survey [SF-36], and Functional Assessment of Cancer Therapy [FACT]-Bone Marrow Transplantation quality of life instruments and Human Activity Profile [HAP]), chronic GVHD global severity (National Institutes of Health global score, clinician global score; and patient-reported global score), calculated and clinician-reported chronic GVHD response, and mortality (overall survival, nonrelapse mortality, and failure-free survival) in multivariable analyses adjusted for significant covariates. 2MWT was significantly associated with intuitive domains of the Lee Symptom Scale (overall, skin, lung, energy), SF-36 domain and summary scores, FACT summary and domain scores, and HAP scores (all P < .001). Fewer associations were detected with the HGS. The 2MWT and HGS both had significant association with global chronic GVHD severity. In multivariable analysis, 2MWT was significantly associated with overall survival, nonrelapse mortality, and failure-free survival, whereas no association was found for HGS. 2MWT and HGS were not sensitive to National Institutes of Health or clinician-reported response. Based on independent association with mortality, these data support the importance of the 2MWT for identification of high-risk chronic GVHD patients. However, change in 2MWT is not sensitive to chronic GVHD response, limiting its usefulness in clinical trials. (C) 2013 American Society for Blood and Marrow Transplantation. C1 [Pidala, Joseph] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Chai, Xiaoyu; Martin, Paul; Inamoto, Yoshihiro; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Palmer, Jeanne] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Weisdorf, Daniel; Arora, Mukta] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Pavletic, Steven] NCI, Bethesda, MD 20892 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Jacobsohn, David] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Pidala, J (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Joseph.pidala@moffitt.org FU NIAID [U54 AI 083028]; [CA 118953] FX Supported by grant CA 118953 (principle investigator, S.J.L.) and NIAID U54 AI 083028 (principle investigator, S.J.L.). NR 38 TC 12 Z9 12 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUN PY 2013 VL 19 IS 6 BP 967 EP 972 DI 10.1016/j.bbmt.2013.03.014 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 156TX UT WOS:000319847900020 PM 23542686 ER PT J AU Davidson-Moncada, JK Pittaluga, S Roth, M Dunleavy, K Duffy, A Pavletic, S AF Davidson-Moncada, J. K. Pittaluga, S. Roth, M. Dunleavy, K. Duffy, A. Pavletic, S. TI Second cancers early post allogeneic transplant: the case of 'unrestrained' malignancy? SO BONE MARROW TRANSPLANTATION LA English DT Letter ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; SOLID CANCERS; SECONDARY CANCERS; ROLES C1 [Davidson-Moncada, J. K.; Duffy, A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, S.; Roth, M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Dunleavy, K.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pavletic, S.] NCI, Expt Transplant & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Davidson-Moncada, JK (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 10 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JUN PY 2013 VL 48 IS 6 BP 872 EP 874 DI 10.1038/bmt.2012.238 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 158JW UT WOS:000319967200022 PM 23222376 ER PT J AU Wallace, GL Robustelli, B Dankner, N Kenworthy, L Giedd, JN Martin, A AF Wallace, Gregory L. Robustelli, Briana Dankner, Nathan Kenworthy, Lauren Giedd, Jay N. Martin, Alex TI Increased gyrification, but comparable surface area in adolescents with autism spectrum disorders SO BRAIN LA English DT Article DE autism; MRI; gyrification; cortical folding; surface area ID IN-VIVO MRI; DIAGNOSTIC INTERVIEW; CORTICAL DEVELOPMENT; MENTAL-RETARDATION; CORPUS-CALLOSUM; CEREBRAL-CORTEX; BRAIN; CONNECTIVITY; SCHIZOPHRENIA; AGE AB Autism spectrum disorders are associated with atypically excessive early brain growth. Recent studies suggest that later cortical development, specifically cortical thickness, during adolescence and young adulthood is also aberrant. Nevertheless, previous studies of other surface-based metrics (e.g. surface area and gyrification) at high-resolution in autism spectrum disorders are limited. Forty-one males with autism spectrum disorders and 39 typically developing males matched on age (mean similar to 17; range = 12-24 years) and IQ (mean similar to 113; range = 85-143) provided high-resolution 3 T anatomical magnetic resonance imaging scans. The FreeSurfer image analysis suite quantified vertex-level surface area and gyrification. There were gyrification increases in the autism spectrum disorders group (relative to typically developing subjects) localized to bilateral posterior cortices (cluster corrected P < 0.01). Furthermore, the association between vocabulary knowledge and gyrification in left inferior parietal cortex (typically developing group: positive correlation; autism spectrum disorders group: no association) differed between groups. Finally, there were no group differences in surface area, and there was no interaction between age and group for either surface area or gyrification (both groups showed decreasing gyrification with increasing age). The present study complements and extends previous work by providing the first evidence of increased gyrification (though no differences in surface area) at high resolution among adolescents and young adults with autism spectrum disorders and by showing a dissociation in the relationship between vocabulary and gyrification in autism spectrum disorders versus typically developing subjects. In contrast with previous findings of age-related cortical thinning in this same autism spectrum disorders sample, here we find that increases in gyrification are maintained across adolescence and young adulthood, implicating developmentally dissociable cortical atypicalities in autism spectrum disorders. C1 [Wallace, Gregory L.; Robustelli, Briana; Dankner, Nathan; Kenworthy, Lauren; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Wallace, GL (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 4C104,MSC 1366, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU Intramural Research Program of the NIH, National Institute of Mental Health FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health. NR 56 TC 39 Z9 39 U1 5 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2013 VL 136 BP 1956 EP 1967 DI 10.1093/brain/awt106 PN 6 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 160IZ UT WOS:000320114400024 PM 23715094 ER PT J AU Scherma, M Fattore, L Satta, V Businco, F Pigliacampo, B Goldberg, SR Dessi, C Fratta, W Fadda, P AF Scherma, M. Fattore, L. Satta, V. Businco, F. Pigliacampo, B. Goldberg, S. R. Dessi, C. Fratta, W. Fadda, P. TI Pharmacological modulation of the endocannabinoid signalling alters binge-type eating behaviour in female rats SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE binge eating; food intake; high-fat diet; weight loss; THC; URB597; rimonabant ID ACID-AMIDE-HYDROLASE; CB1 CANNABINOID RECEPTOR; NUCLEUS-ACCUMBENS SHELL; VENTRAL TEGMENTAL AREA; STIMULATES FOOD-INTAKE; PALATABLE FOOD; LIMITED ACCESS; ANANDAMIDE HYDROLYSIS; MISSENSE POLYMORPHISM; ANTAGONIST SR141716 AB Background and Purpose Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in the endocannabinoid signalling could be involved in the pathophysiology of BED. In this study, we investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED. Experimental Approach Binge-type eating was induced in female rats by providing limited access to an optional source of dietary fat (margarine). Rats were divided into three groups, all with ad libitum access to chow and water: control (C), with no access to margarine; low restriction (LR), with 2h margarine access 7 days a week; high restriction (HR), with 2h margarine access 3 days a week. Key Results Compared with the LR group, the HR group consumed more margarine and this was accompanied by an increase in body weight. The cannabinoid CB1/CB2 receptor agonist 9-tetrahydrocannabinol significantly increased margarine intake selectively in LR rats, while the fatty acid amide hydrolase inhibitor URB597 showed no effect. The CB1 receptor inverse agonist/antagonist rimonabant dose-dependently reduced margarine intake in HR rats. Notably, in HR rats, chronic treatment with a low dose of rimonabant induced a selective long-lasting reduction in margarine intake that did not develop tolerance, and a significant and persistent reduction in body weight. Conclusions and Implications Chronic pharmacological blockade of CB1 receptors reduces binge eating behaviour in female rats and may prove effective in treating BED, with an associated significant reduction in body weight. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8 C1 [Scherma, M.; Satta, V.; Businco, F.; Pigliacampo, B.; Dessi, C.; Fratta, W.; Fadda, P.] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, I-09042 Cagliari, Italy. [Fattore, L.; Fratta, W.; Fadda, P.] Ctr Excellence Neurobiol Addict, Cagliari, Italy. [Fattore, L.] CNR, Neurosci Inst Cagliari, Natl Res Council Italy, Cagliari, Italy. [Goldberg, S. R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Pigliacampo, B (reprint author), Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cittadella Univ Monserrato, I-09042 Cagliari, Italy. EM pfadda@unica.it OI FADDA, PAOLA/0000-0002-0642-6710 FU Italian Ministry of University and Scientific Research [FAR DM28141]; National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA FX This work was partially supported by grant from the Italian Ministry of University and Scientific Research (FAR DM28141 del 21/11/2005) and by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA. NR 96 TC 6 Z9 6 U1 3 U2 7 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 JUN PY 2013 VL 169 IS 4 BP 820 EP 833 DI 10.1111/bph.12014 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 151RF UT WOS:000319477200009 PM 23072421 ER PT J AU Kim, S Taylor, JA Milne, GL Sandler, DP AF Kim, Sangmi Taylor, Jack A. Milne, Ginger L. Sandler, Dale P. TI Association between Urinary Prostaglandin E-2 Metabolite and Breast Cancer Risk: A Prospective, Case-Cohort Study of Postmenopausal Women SO CANCER PREVENTION RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ELEVATED AROMATASE EXPRESSION; COLORECTAL ADENOMA; COX-2 EXPRESSION; ADIPOSE-TISSUE; OBESE WOMEN; FATTY-ACIDS; PGE-M; INFLAMMATION; BIOMARKER AB Overweight or obese women are at increased risk of developing and dying from breast cancer. Obesity-driven inflammation may stimulate prostaglandin E-2 (PGE(2))-mediated aromatase activation and estrogen biosynthesis in breast tissues. We hypothesized that increased production of PGE(2) would contribute to elevated breast cancer risk in postmenopausal women. We carried out a case-cohort study with 307 incident breast cancer cases and 300 subcohort members from the Sister Study cohort. HRs and 95% confidence intervals (CI) were estimated for the association between urinary levels of a major PGE(2) metabolite (PGE-M) and breast cancer risk using Prentice's pseudo-likelihood approach. Several lifestyle factors were associated with urinary levels of PGE-M: smoking, high-saturated fat diet, and obesity increased urinary PGE-M, and use of nonsteroidal antiinflammatory drugs (NSAID) decreased urinary PGE-M. Although there was no association between urinary PGE-M and postmenopausal breast cancer risk in the overall analysis or among regular users of NSAIDs, there was a positive association among postmenopausal women who did not regularly use NSAIDs with HRs of 2.1 [95% confidence interval (CI): 1.0-4.3]; 2.0(95% CI: 1.0-3.9); and 2.2 (95% CI: 1.1-4.3) for the second, third, and highest quartiles of PGE-M. Our findings suggest a link between systemic PGE(2) formation and postmenopausal breast cancer, and a possible modification of the association by lifestyle and pharmacologic interventions. If confirmed in larger studies, these results may have useful implications for the development of preventive strategies. (C) 2013 AACR. C1 [Kim, Sangmi] Georgia Regents Univ Canc Ctr, Med Coll Georgia, Sect Hematol Oncol, Dept Med, Augusta, GA 30912 USA. [Kim, Sangmi; Taylor, Jack A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Taylor, Jack A.] NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. [Milne, Ginger L.] Vanderbilt Univ, Eicosanoid Core Lab, Div Clin Pharmacol, Nashville, TN USA. RP Kim, S (reprint author), Georgia Regents Univ Canc Ctr, Med Coll Georgia, Sect Hematol Oncol, Dept Med, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. EM sankim@gru.edu RI Milne, Ginger/D-7648-2014; OI Milne, Ginger/0000-0003-3890-151X; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU Department of Defense [BC0923202]; NIH, National Institute of Environmental Health Sciences [Z01 ES044005] FX This work was supported by Department of Defense Breast Cancer Postdoctoral Fellowship BC0923202 (to S. Kim) and Intramural Program of the NIH, National Institute of Environmental Health Sciences Z01 ES044005 (to S. Kim, J.A. Taylor, D. P. Sandler). NR 48 TC 20 Z9 20 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUN PY 2013 VL 6 IS 6 BP 511 EP 518 DI 10.1158/1940-6207.CAPR-13-0040 PG 8 WC Oncology SC Oncology GA 156GR UT WOS:000319810400002 PM 23636050 ER PT J AU Kim, EK Kim, YS Milner, JA Wang, TTY AF Kim, Eun-Kyung Kim, Young S. Milner, John A. Wang, Thomas T. Y. TI Indole-3-Carbinol and 3 ',3 '-Diindolylmethane Modulate Androgen's Effect on C-C Chemokine Ligand 2 and Monocyte Attraction to Prostate Cancer Cells SO CANCER PREVENTION RESEARCH LA English DT Article ID HUMAN BREAST-CANCER; EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; TWIST; INFLAMMATION; EXPRESSION; RECEPTOR; CCL2; CHEMOATTRACTANT; CARCINOGENESIS AB Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of monocytes. Given the inhibitory effect of broccoli-derived compounds indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time-dependent (0-72 hours) and concentration-dependent (0-1 nmol/L) increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). This increase in CCL2 mRNA corresponded with increased secretion of CCL2 protein. The effect of dihydrotestosterone was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although dihydrotestosterone also induced TWIST1 mRNA, an epithelial-mesenchymal transition-related factor, and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit dihydrotestosterone induction of CCL2 mRNA. Moreover, conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of dihydrotestosterone on CCL2 and migration. These results show that androgen may regulate CCL2 and promote inflammatory microenvironment in prostate tumors and that this process can be blocked by broccoli-derived compounds. (C) 2013 AACR. C1 [Kim, Eun-Kyung; Kim, Young S.; Milner, John A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Kim, Eun-Kyung] Univ Maryland, Dept Nutr & Food Sci, College Pk, MD 20742 USA. [Kim, Eun-Kyung; Wang, Thomas T. Y.] ARS, Diet Gen & Immunol Lab, USDA, Beltsville, MD 20705 USA. [Milner, John A.] ARS, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. RP Wang, TTY (reprint author), USDA, Bldg 307C,Room 132,BARC EAST,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM tom.wang@ars.usda.gov FU U.S appropriated funds [1235-51530-053-00D]; National Cancer Institute FX This work was supported by U.S appropriated funds to USDA project number 1235-51530-053-00D (to T.T.Y. Wang) and the National Cancer Institute (to E.-K. Kim, Y.S. Kim, J.A. Milner). NR 49 TC 3 Z9 3 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUN PY 2013 VL 6 IS 6 BP 519 EP 529 DI 10.1158/1940-6207.CAPR-12-0419 PG 11 WC Oncology SC Oncology GA 156GR UT WOS:000319810400003 PM 23585426 ER PT J AU Cohen, SS Matthews, CE Bradshaw, PT Lipworth, L Buchowski, MS Signorello, LB Blot, WJ AF Cohen, Sarah S. Matthews, Charles E. Bradshaw, Patrick T. Lipworth, Loren Buchowski, Maciej S. Signorello, Lisa B. Blot, William J. TI Sedentary Behavior, Physical Activity, and Likelihood of Breast Cancer among Black and White Women: A Report from the Southern Community Cohort Study SO CANCER PREVENTION RESEARCH LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; AFRICAN-AMERICAN WOMEN; HEALTH DISPARITIES; RISK; OBESITY; ASSOCIATIONS; BIOMARKERS; INACTIVITY; TIME AB Increased physical activity has been shown to be protective for breast cancer although few studies have examined this association in Black women. In addition, limited evidence to date indicates that sedentary behavior may be an independent risk factor for breast cancer. We examined sedentary behavior and physical activity in relation to subsequent incident breast cancer in a nested case-control study within 546 cases (374 among Black women) and 2,184 matched controls enrolled in the Southern Community Cohort Study. Sedentary and physically active behaviors were assessed via self-report at study baseline (2002-2009) using a validated physical activity questionnaire. Conditional logistic regression was used to estimate mutually adjusted ORs and corresponding 95% confidence intervals (CI) for quartiles of sedentary and physical activity measures in relation to breast cancer risk. Being in the highest versus lowest quartile of total sedentary behavior (>= 12 vs. <5.5 h/d) was associated with increased odds of breast cancer among White women [OR, 1.94 (95% CI, 1.01-3.70); P-trend = 0.1] but not Black women [OR, 1.23 (95% CI, 0.82-1.83); P-trend = 0.6] after adjustment for physical activity. After adjustment for sedentary activity, greater physical activity was associated with reduced odds for breast cancer among White women (P-trend = 0.03) only. In conclusion, independent of one another, sedentary behavior and physical activity are risk factors for breast cancer among White women. Differences in these associations between Black and White women require further investigation. Reducing sedentary behavior and increasing physical activity are potentially independent targets for breast cancer prevention interventions. (C) 2013 AACR. C1 [Cohen, Sarah S.; Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Rockville, MD USA. [Bradshaw, Patrick T.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Lipworth, Loren; Buchowski, Maciej S.; Blot, William J.] Vanderbilt Univ, Dept Med, Div Epidemiol, Nashville, TN USA. [Buchowski, Maciej S.] Vanderbilt Univ, Dept Med, Div Gastroenterol Hepatol & Nutr, Nashville, TN USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Cohen, SS (reprint author), Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. EM sarahcohen@alumni.unc.edu RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Buchowski, Maciej/0000-0002-0566-1743 FU NIH [R01 CA092447, 3R01 CA092447-08S1] FX Funding for this research was provided by NIH grant R01 CA092447 and its American Reinvestment and Recovery Act Supplement 3R01 CA092447-08S1. NR 30 TC 17 Z9 17 U1 2 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUN PY 2013 VL 6 IS 6 BP 566 EP 576 DI 10.1158/1940-6207.CAPR-13-0045 PG 11 WC Oncology SC Oncology GA 156GR UT WOS:000319810400008 PM 23576427 ER PT J AU Swigris, JJ Lee, HS Cohen, M Inoue, Y Moss, J Singer, LG Young, LR McCormack, FX AF Swigris, Jeffrey J. Lee, Hye-Seung Cohen, Marsha Inoue, Yoshikazu Moss, Joel Singer, Lianne G. Young, Lisa R. McCormack, Francis X. CA Natl Inst Hlth Rare Lung Dis Multictr Int TI St. George's Respiratory Questionnaire Has Longitudinal Construct Validity in Lymphangioleiomyomatosis SO CHEST LA English DT Article ID QUALITY-OF-LIFE; HEALTH-STATUS; LUNG-FUNCTION; PROGESTERONE; DECLINE; DISEASE; COPD AB Background: Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that causes shortness of breath, hypoxemia, and impaired health-related quality of life (HRQL). Whether St. George's Respiratory Questionnaire (SGRQ), a respiratory-specific HRQL instrument, captures longitudinal changes in HRQL in patients with LAM is unknown. Methods: Using data from the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus trial, we performed analyses to examine associations between SGRQ scores and values for four external measures (anchors). Anchors included (1) FEV1, (2) diffusing capacity of the lung for carbon monoxide, (3) distance walked during the 6-min walk test, and (4) scrum vascular endothelial growth factor-D. Results: SGRQ scores correlated with the majority of anchor values at baseline, 6 months, and 12 months. Results from longitudinal analyses demonstrated that SGRQ change scores tracked changes over time in values for each of the four anchors. At 12 months, subjects with the greatest improvement from baseline in FEV1 experienced the greatest improvement in SGRQ scores (Symptoms domain, -13.4 +/- 14.6 points; Activity domain, -6.46 +/- 8.20 points; Impacts domain, -6.25 +/- 12.8 points; SGRQ total, -7.53 +/- 10.0 points). Plots of cumulative distribution functions further supported the longitudinal validity of the SGRQ in LAM. Conclusions: In LAM, SGRQ scores are associated with variables used to assess LAM severity. The SGRQ is sensitive to change in LAM severity, particularly when change is defined by FEV1, perhaps the most clinically relevant and prognostically important variable in LAM. The constellation of results here supports the validity of the SGRQ as capable of assessing longitudinal change in HRQL in LAM. C1 [Swigris, Jeffrey J.] Natl Jewish Hlth, Autoimmune Lung Ctr, Denver, CO 80206 USA. [Swigris, Jeffrey J.] Natl Jewish Hlth, Interstitial Lung Dis Program, Denver, CO 80206 USA. [Lee, Hye-Seung] Univ S Florida, Coll Med, Pediat Epidemiol Ctr, Tampa, FL USA. [Cohen, Marsha] Womens Coll Hosp, Womens Hlth Res Inst, Toronto, ON M5S 1B2, Canada. [Inoue, Yoshikazu] Natl Hosp Org, Kinki Chou Chest Med Ctr, Osaka, Japan. [Moss, Joel] NIH, Bethesda, MD 20892 USA. [Singer, Lianne G.] Univ Toronto, Lung Transplantat Program, Toronto, ON M5S 1A1, Canada. [Young, Lisa R.] Vanderbilt Univ, Sch Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37212 USA. [McCormack, Francis X.] Univ Cincinnati, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Cincinnati, OH USA. RP Swigris, JJ (reprint author), Natl Jewish Hlth, Autoimmune Lung Ctr, Southside Bldg,Off G011,1400 Jackson St, Denver, CO 80206 USA. EM swigrisj@njc.org OI McCormack, Francis/0000-0001-7168-9464; Singer, Lianne/0000-0002-2693-8676 FU National Institutes of Health (NIH) [K23 HL092227]; NIH, National Heart, Lung and Blood Institute; NIH Office of Rare Disease Research [RR019498]; US Food and Drug Administration [FD003362]; Japanese Ministry of Health, Labour, and Welfare; Canadian Institutes of Health Research; Pfizer Pharmaceuticals; LAM Foundation; Tuberous Sclerosis Alliance; Cincinnati Children's Hospital FX Dr Swigris is supported in part by a Career Development Award from the National Institutes of Health (NIH) [Grant K23 HL092227]. Dr Moss was supported by the Intramural Research Program, NIH, National Heart, Lung and Blood Institute. The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus Trial was supported by the NIH Office of Rare Disease Research [Grant RR019498]; the US Food and Drug Administration [Grant FD003362]; the Japanese Ministry of Health, Labour, and Welfare; the Canadian Institutes of Health Research; Pfizer Pharmaceuticals; The LAM Foundation; the Tuberous Sclerosis Alliance; and Cincinnati Children's Hospital. NR 23 TC 5 Z9 5 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2013 VL 143 IS 6 BP 1671 EP 1678 DI 10.1378/chest.12-0161 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 159UN UT WOS:000320072900027 PM 23328755 ER PT J AU El-Chemaly, S Malide, D Yao, JH Nathan, SD Rosas, IO Gahl, WA Moss, J Gochuico, BR AF El-Chemaly, Souheil Malide, Daniela Yao, Jianhua Nathan, Steven D. Rosas, Ivan O. Gahl, William A. Moss, Joel Gochuico, Bernadette R. TI Glucose Transporter-1 Distribution in Fibrotic Lung Disease Association With [F-18]-2-Fluoro-2-Deoxyglucose-PET Scan Uptake, Inflammation, and Neovascularization SO CHEST LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; HERMANSKY-PUDLAK-SYNDROME; HUMAN ERYTHROCYTES; F-18-FDG PET/CT; CARCINOMA; ANGIOGENESIS; MANAGEMENT; MUTATION AB Background: [F-18]-2-fluoro-2-deoxyglucose (FDG)-PET scan uptake is increased in areas of fibrosis and honeycombing in patients with idiopathic pulmonary fibrosis (IPF). Glucose transporter-1 (Glut-1) is known to be the main transporter for FDG. There is a paucity of data regarding the distribution of Glut-1 and the cells responsible for FDG binding in fibrotic lung diseases. Methods: We applied immunofluorescence to localize Glut-1 in normal, IPF, and Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis lung tissue specimens as well as an array of 19 different lung neoplasms. In addition, we investigated Glut-1 expression in inflammatory cells from BAL fluid (BALF) from healthy volunteers, subjects with IPF, and subjects with HPS pulmonary fibrosis. Results: In normal lung tissue, Glut-1 immunoreactivity was seen on the surface of erythrocytes. In tissue sections from fibrotic lung diseases (IPF and HPS pulmonary fibrosis), Glut-1 immunoreactivity was present on the surface of erythrocytes and inflammatory cells. BALF inflammatory cells from healthy control subjects showed no immunoreactivity; BALF cells from subjects with IPF and HPS pulmonary fibrosis showed Glut-1 immunoreactivity associated with neutrophils and alveolar macrophages. Conclusions: Glut-1 transporter expression in normal lung is limited to erythrocytes. In fibrotic lung, erythrocytes and inflammatory cells express Glut-1. Together, these data suggest that FDG-PET scan uptake in IPF could be explained by enhanced inflammatory and erythrocytes uptake due to neovascularization seen in IPF and not an upregulation of metabolic rate in pneumocytes. Thus, FDG-PET scan may detect inflammation and neovascularization in lung fibrosis. C1 [El-Chemaly, Souheil; Rosas, Ivan O.; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, Bethesda, MD 20892 USA. [Yao, Jianhua] NHGRI, Ctr Clin, Bethesda, MD 20892 USA. [Gahl, William A.; Gochuico, Bernadette R.] NIH, Med Genet Branch, NHGRI, Bethesda, MD 20892 USA. [El-Chemaly, Souheil; Rosas, Ivan O.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Nathan, Steven D.] Inova Fairfax Hosp, Falls Church, VA USA. RP El-Chemaly, S (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis Dr, Boston, MA 02115 USA. EM sel-chemaly@partners.org FU National Institutes of Health (National Heart, Lung, and Blood Institute); National Institutes of Health (National Human Genome Research Institute); National Institutes of Health [1K22HL092223] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Heart, Lung, and Blood Institute and National Human Genome Research Institute) and the National Institutes of Health [Grant 1K22HL092223, National Heart, Lung, and Blood Institute]. NR 30 TC 11 Z9 11 U1 2 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2013 VL 143 IS 6 BP 1685 EP 1691 DI 10.1378/chest.12-1359 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 159UN UT WOS:000320072900029 PM 23699745 ER PT J AU Wilson, WH Schenkein, DP Jernigan, CL Woodcock, J Schilsky, RL AF Wilson, Wyndham H. Schenkein, David P. Jernigan, Cheryl L. Woodcock, Janet Schilsky, Richard L. TI Reevaluating the Accelerated Approval Process for Oncology Drugs SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC BREAST-CANCER; HODGKIN-LYMPHOMA; TRASTUZUMAB; LAPATINIB; PROGRESS; PATIENT AB For a new therapy to qualify for the accelerated approval pathway, it must treat a serious disease for which there is "unmet medical need"-defined as providing a therapy where none exists or providing a therapy that may be potentially superior to existing therapy. The increasing number of available therapies, coupled with the lack of accepted endpoints considered "reasonably likely to predict clinical benefit" and the lack of clarity early in development about circumstances in which a new product will qualify for accelerated approval, is pushing developers to pursue accelerated approval in heavily pretreated patients to fulfill an unmet need. To optimize the accelerated approval pathway, we propose here a reevaluation of what constitutes "unmet medical need" and "available therapy" in oncology. We also discuss ways for new endpoints to become qualified for use in supporting accelerated approval, and propose a structured process for pursuing accelerated approval. (C) 2013 AACR. C1 [Wilson, Wyndham H.] NCI, Lymphoma Therapeut Sect, Bethesda, MD 20892 USA. [Woodcock, Janet] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Schenkein, David P.] Agios Pharmaceut, Cambridge, MA USA. [Jernigan, Cheryl L.] Susan G Komen Cure, Kansas City, MO USA. [Schilsky, Richard L.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. RP Schilsky, RL (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM Richard.Schilsky@asco.org NR 30 TC 8 Z9 8 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2013 VL 19 IS 11 BP 2804 EP 2809 DI 10.1158/1078-0432.CCR-13-0315 PG 6 WC Oncology SC Oncology GA 155FF UT WOS:000319732000004 PM 23553847 ER PT J AU DeMichele, A Berry, DA Zujewski, J Hunsberger, S Rubinstein, L Tomaszewski, JE Kelloff, G Perlmutter, J Buxton, M Lyandres, J Albain, KS Benz, C Chien, AJ Haluska, P Leyland-Jones, B Liu, MC Munster, P Olopade, O Park, JW Parker, BA Pusztai, L Tripathy, D Rugo, H Yee, D Esserman, L AF DeMichele, Angela Berry, Donald A. Zujewski, JoAnne Hunsberger, Sally Rubinstein, Larry Tomaszewski, Joseph E. Kelloff, Gary Perlmutter, Jane Buxton, Meredith Lyandres, Julia Albain, Kathy S. Benz, Chris Chien, A. Jo Haluska, Paul Leyland-Jones, Brian Liu, Minetta C. Munster, Pamela Olopade, Olufunmilayo Park, John W. Parker, Barbara A. Pusztai, Lajos Tripathy, Debu Rugo, Hope Yee, Douglas Esserman, Laura TI Developing Safety Criteria for Introducing New Agents into Neoadjuvant Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; PATHOLOGICAL COMPLETE RESPONSE; POSITIVE BREAST-CANCER; PHASE-III TRIAL; CLINICAL-TRIALS; CHEMOTHERAPY; COMBINATION; DRUG; GEMCITABINE; CARBOPLATIN AB New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U. S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. (C) 2013 AACR. C1 [DeMichele, Angela] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Zujewski, JoAnne; Hunsberger, Sally; Rubinstein, Larry; Tomaszewski, Joseph E.; Kelloff, Gary] NCI, Bethesda, MD 20892 USA. [Buxton, Meredith; Lyandres, Julia; Benz, Chris; Chien, A. Jo; Munster, Pamela; Park, John W.; Rugo, Hope; Esserman, Laura] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Parker, Barbara A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Tripathy, Debu] Univ So Calif, Los Angeles, CA USA. [Albain, Kathy S.] Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. [Olopade, Olufunmilayo] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Haluska, Paul; Liu, Minetta C.] Mayo Clin, Rochester, MN USA. [Yee, Douglas] Univ Minnesota, Minneapolis, MN USA. [Leyland-Jones, Brian] Sanford Hlth Syst, Sioux Falls, SD USA. [Pusztai, Lajos] Yale Univ, Sch Med, New Haven, CT USA. RP DeMichele, A (reprint author), Univ Penn, Sch Med, Abramson Canc Ctr, 3 West PCAM,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Angela.demichele@uphs.upenn.edu FU Biomarkers Consortium; Foundation for the NIH; FDA; NIH; GlaxoSmithKline; Sanofi-Aventis FX I-SPY 2 is sponsored by the Biomarkers Consortium, a unique partnership led by the Foundation for the NIH, which includes the FDA, the NIH, and a large number of partners from major pharmaceutical companies, leading academic medical centers, and nonprofit and patient advocacy groups. Funding for I-SPY 2 comes mostly from nonprofit foundations, including The Safeway Foundation and other philanthropic donors.; D.A. Berry is employed as a co-owner and statistical scientist; has ownership interest (including patents); and is a consultant/advisory board member of Berry Consultants, LLC. K.S. Albain is a consultant/advisory board member of Genentech, Roche, Pfizer, Novartis, Genomic Health, and Amgen. J.W. Park has received honoraria from the speakers' bureau from Genentech, Agendia, Novartis, and Bristol-Myers Squibb; has ownership interest (including patents) in Merrimack Pharmaceuticals; and is a consultant/ advisory board member of Merrimack Pharmaceuticals and Genentech. B.A. Parker has a commercial research grant from GlaxoSmithKline and Sanofi-Aventis and is a consultant/advisory board member of Roche. No potential conflicts of interest were disclosed by the other authors. NR 21 TC 10 Z9 10 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2013 VL 19 IS 11 BP 2817 EP 2823 DI 10.1158/1078-0432.CCR-12-2620 PG 7 WC Oncology SC Oncology GA 155FF UT WOS:000319732000006 PM 23470967 ER PT J AU Smith, MA Houghton, P AF Smith, Malcolm A. Houghton, Peter TI A Proposal Regarding Reporting of In Vitro Testing Results SO CLINICAL CANCER RESEARCH LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; MYELOID CELL LEUKEMIA-1; DOWN-REGULATION; ANTITUMOR-ACTIVITY; PHASE-I; ADVANCED CANCER; HEPATOCELLULAR-CARCINOMA; EOSINOPHILIC LEUKEMIA; PANCREATIC-CANCER AB The high rate of negative clinical trials and failed drug development programs calls into question the use of preclinical testing as currently practiced. An important issue for the in vitro testing of agents that have advanced into the clinic is the use of clinically irrelevant concentrations in reports making claims for anticancer activity, as illustrated by publications for sorafenib, vorinostat, and metformin. For sorafenib, high protein binding leads to a dichotomy between concentrations active in the 10% serum conditions commonly used for in vitro testing and concentrations active in plasma. Failure to recognize this distinction leads to inappropriate claims of activity for sorafenib based on the micromolar concentrations commonly used for in vitro testing in low serum conditions. For vorinostat and metformin, results using in vitro concentrations higher than those achievable in patients are reported despite the availability of publications describing human pharmacokinetic data for each agent. We encourage journal editors and reviewers to pay greater attention to clinically relevant concentrations when considering reports that include in vitro testing of agents for which human pharmacokinetic data are available. Steps taken to more carefully scrutinize activity claims based on in vitro results can help direct researchers away from clinically irrelevant lines of research and toward lines of research that are more likely to lead to positive clinical trials and to improved treatments for patients with cancer. (C) 2013 AACR. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Houghton, Peter] Nationwide Childrens Hosp, Columbus, OH USA. RP Smith, MA (reprint author), NCI, 9609 Med Ctr Dr,Room 5-W414,MSC 9737, Bethesda, MD 20892 USA. EM Malcolm.Smith@nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01 CM042216] NR 51 TC 24 Z9 25 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2013 VL 19 IS 11 BP 2828 EP 2833 DI 10.1158/1078-0432.CCR-13-0043 PG 6 WC Oncology SC Oncology GA 155FF UT WOS:000319732000008 PM 23580781 ER PT J AU Sharma, MR Karrison, TG Kell, B Wu, KH Turcich, M Geary, D Kang, SP Takebe, N Graham, RA Maitland, ML Schilsky, RL Ratain, MJ Cohen, EEW AF Sharma, Manish R. Karrison, Theodore G. Kell, Bethany Wu, Kehua Turcich, Michelle Geary, David Kang, Soonmo P. Takebe, Naoko Graham, Richard A. Maitland, Michael L. Schilsky, Richard L. Ratain, Mark J. Cohen, Ezra E. W. TI Evaluation of Food Effect on Pharmacokinetics of Vismodegib in Advanced Solid Tumor Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE-KINASE INHIBITOR; CLINICAL PHARMACOKINETICS; MASS-SPECTROMETRY; PHASE EXTRACTION; HUMAN PLASMA; ONCOLOGY; GDC-0449; PATHWAY; SAFETY; AGENTS AB Purpose: Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). Weconducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure. Experimental Design: In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C-max and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were Cmax and AUC(0-24). Results: Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C-max and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C-max or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups. Conclusions: A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing.(C) 2013 AACR. C1 [Sharma, Manish R.; Kell, Bethany; Wu, Kehua; Turcich, Michelle; Geary, David; Kang, Soonmo P.; Maitland, Michael L.; Schilsky, Richard L.; Ratain, Mark J.; Cohen, Ezra E. W.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Karrison, Theodore G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Sharma, Manish R.; Karrison, Theodore G.; Maitland, Michael L.; Schilsky, Richard L.; Ratain, Mark J.; Cohen, Ezra E. W.] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Sharma, Manish R.; Kang, Soonmo P.; Maitland, Michael L.; Ratain, Mark J.] Univ Chicago, Comm Clin Pharmacol & Pharmacogen, Chicago, IL 60637 USA. [Takebe, Naoko] NCI, Invest Drug Branch, Rockville, MD USA. [Graham, Richard A.] Genentech Inc, San Francisco, CA 94080 USA. RP Cohen, EEW (reprint author), Univ Chicago, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM ecohen@medicine.bsd.uchicago.edu FU Cancer Therapy Evaluation Program; NCI [5U01-CA69852-12]; National Cancer Institute [K12CA139160] FX The study was sponsored by the Cancer Therapy Evaluation Program and supported by NCI grant 5U01-CA69852-12 (Principal investigator: M.J. Ratain). M.R. Sharma was supported by award number K12CA139160 from the National Cancer Institute. NR 14 TC 9 Z9 9 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2013 VL 19 IS 11 BP 3059 EP 3067 DI 10.1158/1078-0432.CCR-12-3829 PG 9 WC Oncology SC Oncology GA 155FF UT WOS:000319732000030 PM 23553850 ER PT J AU Noonan, AM Eisch, RA Liewehr, DJ Sissung, TM Venzon, DJ Flagg, TP Haigney, MC Steinberg, SM Figg, WD Piekarz, RL Bates, SE AF Noonan, Anne M. Eisch, Robin A. Liewehr, David J. Sissung, Tristan M. Venzon, David J. Flagg, Thomas P. Haigney, Mark C. Steinberg, Seth M. Figg, William D. Piekarz, Richard L. Bates, Susan E. TI Electrocardiographic Studies of Romidepsin Demonstrate Its Safety and Identify a Potential Role for K-ATP Channel SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; T-CELL LYMPHOMA; ADVANCED SOLID TUMORS; SUDDEN CARDIAC DEATH; PHASE-I; MYOCARDIAL-ISCHEMIA; DEPSIPEPTIDE; ATRIAL; TRIAL; CHEMOTHERAPY AB Purpose: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted. Experimental Design: A phase II single-agent nonrandomized study of romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy. Results: Results for the first 42 patients enrolled on the NCI 1312 phase II study of romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met before 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of K-ATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes. Conclusions: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin. C1 [Noonan, Anne M.; Eisch, Robin A.; Sissung, Tristan M.; Figg, William D.; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Venzon, David J.; Steinberg, Seth M.] NCI, Biostat & Biometr Branch, NIH, Bethesda, MD 20892 USA. [Piekarz, Richard L.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Flagg, Thomas P.; Haigney, Mark C.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Bldg 10-12N226, Bethesda, MD 20892 USA. EM batess@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Celgene Pharmaceuticals through a Cooperative Research and Development Agreement; National Cancer Institute FX S.E. Bates received research funding from Celgene Pharmaceuticals through a Cooperative Research and Development Agreement with the National Cancer Institute. NR 50 TC 18 Z9 18 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 1 PY 2013 VL 19 IS 11 BP 3095 EP 3104 DI 10.1158/1078-0432.CCR-13-0109 PG 10 WC Oncology SC Oncology GA 155FF UT WOS:000319732000034 PM 23589175 ER PT J AU Bailey, EJ Duffield, AS Greenblatt, SM Aplan, PD Small, D AF Bailey, Emily J. Duffield, Amy S. Greenblatt, Sarah M. Aplan, Peter D. Small, Donald TI Effect of FLT3 Ligand on Survival and Disease Phenotype in Murine Models Harboring a FLT3 Internal Tandem Duplication Mutation SO COMPARATIVE MEDICINE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; SIGNAL-TRANSDUCTION; POOR-PROGNOSIS; SERUM-LEVELS; MOUSE MODEL; KNOCK-IN; ACTIVATION; CANCER; CELLS; MICE AB Many of the mutations contributing to leukemogenesis in acute myeloid leukemia have been identified. A common activating mutation is an internal tandem duplication (ITD) mutation in the FLT3 gene that is found in approximately 25% of patients and confers a poor prognosis. FLT3 inhibitors have been developed and have some efficacy, but patients often relapse. Levels of FLT3 ligand (FL) are significantly elevated in patients during chemotherapy and may be an important component contributing to relapse. We used a mouse model to investigate the possible effect of FL expression on leukemogenesis involving FLT3-ITD mutations in an in vivo system. FLT3(ITD/ITD) FL-/- (knockout) mice had a statistically significant increase in survival compared with FLT3(ITD/ITD) FL+/+ (wildtype) mice, most of which developed a fatal myeloproliferative neoplasm. These findings suggest that FL levels may have prognostic significance in human patients. We also studied the effect of FL expression on survival in a FLT3-ITD NUP98-HOX13 (NHD13) fusion mouse model. These mice develop an aggressive leukemia with short latency. We asked whether FL expression played a similar role in this context. The NUP98-HOX13 FLT3(ITD/wt) FL-/- mice did not have a survival advantage, compared with NUP98-HOX13 FLT3(ITD/wt) FL+/+ mice (normal FL levels). The loss of the survival advantage of the FL knockout group in the NUP98-HOX13 model suggests that adding a second mutation changes the effect of FL expression in the context of more aggressive disease. C1 [Bailey, Emily J.; Greenblatt, Sarah M.; Small, Donald] Johns Hopkins Univ, Sch Med, Dept Pediat Oncol, Baltimore, MD 21218 USA. [Duffield, Amy S.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Aplan, Peter D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Small, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat Oncol, Baltimore, MD 21218 USA. EM donsmall@jhmi.edu RI Aplan, Peter/K-9064-2016 FU National Cancer Institute [CA90668, CA70970]; Leukemia and Lymphoma Society; Giant Food Pediatric Cancer Research Fund; Intramural Research Program of the NIH National Cancer Institute FX This work was supported by the National Cancer Institute (CA90668, CA70970), Leukemia and Lymphoma Society, the Giant Food Pediatric Cancer Research Fund, and the Intramural Research Program of the NIH National Cancer Institute. NR 34 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2013 VL 63 IS 3 BP 218 EP 226 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 162WP UT WOS:000320297000005 PM 23759524 ER PT J AU Knowlen, GG Weller, RE Perry, RL Baer, JF Gozalo, AS AF Knowlen, Grant G. Weller, Richard E. Perry, Ruby L. Baer, Janet F. Gozalo, Alfonso S. TI Hypertrophic Cardiomyopathy in Owl Monkeys (Aotus spp.) SO COMPARATIVE MEDICINE LA English DT Article ID CROSS-SECTIONAL ECHOCARDIOGRAPHY; PLASMODIUM-FALCIPARUM; MATHEMATIC MODELS; LEFT-VENTRICLE; HEART-DISEASE; DENGUE VIRUS; HEPATITIS-A; TRIVIRGATUS; NANCYMAE; SAIMIRI AB Cardiac hypertrophy is a common postmortem finding in owl monkeys. In most cases the animals do not exhibit clinical signs until the disease is advanced, making antemortem diagnosis of subclinical disease difficult and treatment unrewarding. We obtained echocardiograms, electrocardiograms, and thoracic radiographs from members of a colony of owl monkeys that previously was identified as showing a 40% incidence of gross myocardial hypertrophy at necropsy, to assess the usefulness of these modalities for antemortem diagnosis. No single modality was sufficiently sensitive and specific to detect all monkeys with cardiac hypertrophy. Electrocardiography was the least sensitive method for detecting owl monkeys with hypertrophic cardiomyopathy. Thoracic radiographs were more sensitive than was electrocardiography in this context but cannot detect animals with concentric hypertrophy without an enlarged cardiac silhouette. Echocardiography was the most sensitive method for identifying cardiac hypertrophy in owl monkeys. The most useful parameters suggestive of left ventricular hypertrophy in our owl monkeys were an increased average left ventricular wall thickness to chamber radius ratio and an increased calculated left ventricular myocardial mass. Parameters suggestive of dilative cardiomyopathy were an increased average left ventricular myocardial mass and a decreased average ratio of left ventricular free wall thickness to left ventricular chamber radius. When all 4 noninvasive diagnostic modalities (physical examination, echocardiography, electrocardiography, and thoracic radiography) were used concurrently, the probability of detecting hypertrophic cardiomyopathy in owl monkeys was increased greatly. C1 [Knowlen, Grant G.] Washington State Univ, Dept Vet Clin Med & Surg, Pullman, WA 99164 USA. [Weller, Richard E.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Perry, Ruby L.] Tuskegee Univ, Dept Clin Sci, Tuskegee, AL 36088 USA. [Baer, Janet F.] CALTECH, Off Lab Anim Resources, Pasadena, CA 91125 USA. [Gozalo, Alfonso S.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Weller, RE (reprint author), Pacific NW Natl Lab, Richland, WA 99352 USA. EM dick.weller@pnl.gov FU US Agency for International Development [DPE-0453-C-00-6061-00]; National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID), Comparative Medicine Branch; Office of Research Support FX We extend a note of appreciation to Interspec Corporation for the loan of equipment used to obtain the echocardiograms reported in the current article. This study was supported by the US Agency for International Development (contract DPE-0453-C-00-6061-00) and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID), Comparative Medicine Branch, and the Office of Research Support. NR 45 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2013 VL 63 IS 3 BP 279 EP 287 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 162WP UT WOS:000320297000012 PM 23759531 ER PT J AU Sampselle, CM Knafl, KA Jacob, JD McCloskey, DJ AF Sampselle, Carolyn M. Knafl, Kathleen A. Jacob, Jacqueline Dunbar McCloskey, Donna Jo TI Nurse Engagement and Contributions to the Clinical and Translational Science Awards Initiative SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE multidisciplinary; nurse; engagement AB CTSAs are mandated to follow a multidisciplinary model. Requests for applications direct responsive applications to integrate clinical and translational science across multiple departments, schools, listing disciplines in addition to medicine such as engineering, nursing, and public health. This inventory of nurse engagement in CTSAs describes the extent of nursing's CTSA engagement from the perspective of participating nurse scientists within individual CTSAs, including institutional/national contributions and best practices that foster a multidisciplinary model. Of the 50 CTSAs affiliated with a nursing school, 44 responded (88% response rate). Of the ten CTSAs not affiliated with a nursing school, four responded (40% response rate). Overall funding success rates of nurse applicants are: TL1 fellowships 81%, KL2 fellowships 54%, and nurse-led pilots 58%. At most CTSAs nursing is contributing to the accomplishment of the CTSA mandate. The strongest categories of contribution are community engagement, implementation science, and training. Best practices to enhance multidisciplinary collaboration are: (1) inclusion of multiple disciplines on key committees who meet regularly to guide individual core and overall CTSA strategic planning and implementation; (2) required multidisciplinary co-mentors (ideally from different schools within the CTSA) on training grants and as co-investigators on pilot projects; and (3) documentation of multidisciplinary activity in annual reports. C1 [Sampselle, Carolyn M.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Knafl, Kathleen A.] Univ N Carolina, Sch Nursing, Chapel Hill, NC USA. [Jacob, Jacqueline Dunbar] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [McCloskey, Donna Jo] NINR, NIH, Bethesda, MD 20892 USA. RP Sampselle, CM (reprint author), Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. EM csampsll@umich.edu FU National Center for Research Resources; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA), part of the Roadmap Initiative, Re-Engineering the Clinical Research Enterprise; National Center for Research Resources [UL1RR024986, UL1RR025747, UL1 RR024153]; National Center for Advancing Translational Sciences [UL1TR000433, UL1TR000083, UL1TR000005] FX This project has been funded in whole or in part with Federal funds from the National Center for Research Resources and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA), part of the Roadmap Initiative, Re-Engineering the Clinical Research Enterprise. The manuscript was approved by the CTSA Consortium Publications Committee.; The project described was supported by the National Center for Research Resources, Grants UL1RR024986, UL1RR025747, and UL1 RR024153 and is now at the National Center for Advancing Translational Sciences, Grants UL1TR000433, UL1TR000083, and UL1TR000005. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 4 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD JUN PY 2013 VL 6 IS 3 BP 191 EP 195 DI 10.1111/cts.12020 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 160QV UT WOS:000320135300008 PM 23751023 ER PT J AU Hong, CW Libutti, SK Wood, BJ AF Hong, C. W. Libutti, S. K. Wood, B. J. TI Liposomal doxorubicin plus radiofrequency ablation for complete necrosis of a hepatocellular carcinoma SO CURRENT ONCOLOGY LA English DT Article DE RFA; ablation; hepatocellular carcinoma; doxorubicin; liposomes ID TEMPERATURE-SENSITIVE LIPOSOMES; MAGNETIC-RESONANCE; DRUG-DELIVERY; MODEL; CT AB Radiofrequency ablation (RFA) is a standard treatment for small, unresectable hepatocellular carcinomas (HCCS). However, rfa for larger tumours is less successful, and intravenous lyso-thermosensitive liposomal doxorubicin during rfa is one technique postulated to potentially address that limitation. This drug-plus-device combination therapy was used to completely treat a hcc in a patient who underwent liver transplantation 79 days later. C1 [Hong, C. W.; Wood, B. J.] NIH, Ctr Clin, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Hong, C. W.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Libutti, S. K.] Albert Einstein Coll Med, Montefiore Einstein Ctr Canc Care, Dept Surg, Bronx, NY 10467 USA. [Libutti, S. K.; Wood, B. J.] NCI, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bwood@cc.nih.gov FU U.S. Center for Interventional Oncology; U.S. National Cancer Institute; Intramural Research Program of the U.S. National Institutes of Health (NIH); NIH; Pfizer; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX The work discussed here is supported in part by the U.S. Center for Interventional Oncology, the U.S. National Cancer Institute, and the Intramural Research Program of the U.S. National Institutes of Health (NIH). The NIH and Celsion Corporation have a cooperative research and development agreement (search for NCT00093444 at http://clinicaltrials.gov/, grant no. ZIA BC 011242-03CCRO). The research was made possible through the nih Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and by generous contributions to the Foundation for the NIH from Pfizer, The Leona M. and Harry B. Helmsley Charitable Trust, the Howard Hughes Medical Institute, and other private donors. For more information, please visit the Foundation's Web site at http://www.fnih.org/work/programs-development/medical-researchscholars- program). NR 12 TC 9 Z9 10 U1 0 U2 13 PU MULTIMED INC PI TORONTO PA 66 MARTIN ST, TORONTO, ON L9T 2R2, CANADA SN 1198-0052 J9 CURR ONCOL JI Curr. Oncol. PD JUN PY 2013 VL 20 IS 3 BP E274 EP E277 DI 10.3747/co.20.1266 PG 4 WC Oncology SC Oncology GA 158KR UT WOS:000319969800012 PM 23737698 ER PT J AU Kleinman, A AF Kleinman, Arthur TI IMPLEMENTING GLOBAL MENTAL HEALTH SO DEPRESSION AND ANXIETY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; INDIA; INTERVENTION; DISORDERS; CHINA; CARE; GOA C1 [Kleinman, Arthur] Harvard Univ, PhD Program Med Anthropol, Cambridge, MA 02138 USA. [Kleinman, Arthur] Amer Psychiat Assoc, Washington, DC USA. [Kleinman, Arthur] NIH, Bethesda, MD 20892 USA. [Kleinman, Arthur] Harvard Univ, Dept Social Med, Sch Med, Cambridge, MA 02138 USA. [Kleinman, Arthur] Harvard Univ, Dept Global Hlth & Social Med, Sch Med, Cambridge, MA 02138 USA. [Kleinman, Arthur] Harvard Univ, Dept Anthropol FAS, Cambridge, MA 02138 USA. [Kleinman, Arthur] Harvard Univ, Asia Ctr, Cambridge, MA 02138 USA. [Kleinman, Arthur] Harvard Univ, Harvard Coll, Cambridge, MA 02138 USA. RP Kleinman, A (reprint author), Harvard Univ, PhD Program Med Anthropol, Cambridge, MA 02138 USA. EM kleinman@wjh.harvard.edu NR 14 TC 2 Z9 2 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUN PY 2013 VL 30 IS 6 BP 503 EP 505 DI 10.1002/da.22057 PG 3 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 157CC UT WOS:000319872200001 PM 23355444 ER PT J AU Kang, L Lantier, L Kennedy, A Bonner, JS Mayes, WH Bracy, DP Bookbinder, LH Hasty, AH Thompson, CB Wasserman, DH AF Kang, Li Lantier, Louise Kennedy, Arion Bonner, Jeffrey S. Mayes, Wesley H. Bracy, Deanna P. Bookbinder, Louis H. Hasty, Alyssa H. Thompson, Curtis B. Wasserman, David H. TI Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance SO DIABETES LA English DT Article ID SKELETAL-MUSCLE; EXTRACELLULAR-MATRIX; IN-VIVO; TUMOR MICROENVIRONMENT; ADIPOSE-TISSUE; PROTEIN-KINASE; WEIGHT-LOSS; CD44; MICE; INFLAMMATION AB Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance. C1 [Kang, Li; Lantier, Louise; Kennedy, Arion; Bonner, Jeffrey S.; Mayes, Wesley H.; Bracy, Deanna P.; Hasty, Alyssa H.; 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 USA. [Bookbinder, Louis H.; Thompson, Curtis B.] Halozyme Therapeut, San Diego, CA USA. RP Kang, L (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. EM li.kang@vanderbilt.edu OI Hasty, Alyssa/0000-0001-7302-8045 FU National Institutes of Health [DK-054902, DK-059637, DK-020593]; Halozyme Therapeutics, Inc. FX This work was supported by National Institutes of Health grants DK-054902 (D.H.W.), DK-059637 (Mouse Metabolic Phenotyping Center, D.H.W.), and DK-020593 (Vanderbilt Diabetes Research and Training Center).; This work was supported in part by a grant from Halozyme Therapeutics, Inc. L.H.B. was an employee of Halozyme Therapeutics, Inc. C.B.T. is an employee of Halozyme Therapeutics, Inc. No other potential conflicts of interest relevant to this article were reported. NR 48 TC 25 Z9 25 U1 1 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2013 VL 62 IS 6 BP 1888 EP 1896 DI 10.2337/db12-1502 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 156SU UT WOS:000319845000018 PM 23349492 ER PT J AU Cleary, PA Braffett, BH Orchard, T Lyons, TJ Maynard, J Cowie, C Gubitosi-Klug, RA Way, J Anderson, K Barnie, A Villavicencio, S AF Cleary, Patricia A. Braffett, Barbara H. Orchard, Trevor Lyons, Timothy J. Maynard, John Cowie, Catherine Gubitosi-Klug, Rose A. Way, Jeff Anderson, Karen Barnie, Annette Villavicencio, Stephan CA DCCT EDIC Res Grp TI Clinical and Technical Factors Associated with Skin Intrinsic Fluorescence in Subjects with Type 1 Diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID GLOMERULAR-FILTRATION-RATE; GLYCATION END-PRODUCTS; COLLAGEN; TRIAL; AUTOFLUORESCENCE; EPIDEMIOLOGY; MELLITUS; THERAPY; RISK; GLYCOXIDATION AB Background: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) studies have established multiyear mean hemoglobin A1c (HbA1c) as predictive of microvascular complications in persons with type 1 diabetes. However, multiyear mean HbA1c is not always available in the clinical setting. Skin advanced glycation end products (AGEs) are thought to partially reflect effects of hyperglycemia over time, and measurement of skin AGEs might be a surrogate for multiyear mean HbA1c. As certain AGEs fluoresce and skin fluorescence has been demonstrated to correlate with the concentration of skin AGEs, noninvasive measurement by skin intrinsic fluorescence (SIF) facilitates the exploration of the association of mean HbA1c and other clinical/technical factors with SIF using the detailed phenotypic database available in DCCT/EDIC. Subjects and Methods: Of the subjects, 1,185 (53% male) had measurements of SIF during years 16/17 of EDIC with mean age and diabetes duration of 51.5 and 29.8 years, respectively. SIF measurements were obtained on the underside of the forearm near the elbow using a skin fluorescence spectrometer. Demographic data and health history were self-reported, and an annual standardized examination measured clinical status. Linear regression models were constructed to identify significant clinical and technical factors associated with SIF, and the final models only used factors that were significant. Results: SIF ranged from 8.7 to 54.0 arbitrary units and was log-normally distributed. Log(SIF) correlated more with mean HbA1c as the time period increased. In multivariate analyses log(SIF) was significantly associated with mean HbA1c, age, estimated glomerular filtration rate <60mL/min/m(2), smoking status, skin tone, and clinic latitude <37 degrees N. Conclusions: SIF reflects age, mean HbA1c over time, smoking, and renal damage, which are known risk factors for diabetes complications. C1 [Cleary, Patricia A.; Braffett, Barbara H.; Anderson, Karen; Villavicencio, Stephan] George Washington Univ, Rockville, MD 20852 USA. [Orchard, Trevor] Univ Pittsburgh, Pittsburgh, PA USA. [Lyons, Timothy J.] Univ Oklahoma, Oklahoma City, OK USA. [Maynard, John; Way, Jeff] VeraLight Inc, Albuquerque, NM USA. [Cowie, Catherine] NIDDKD, Bethesda, MD 20892 USA. [Gubitosi-Klug, Rose A.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Barnie, Annette] Univ Toronto, Toronto, ON, Canada. RP Cleary, PA (reprint author), George Washington Univ, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM cleary@bsc.gwu.edu OI orchard, trevor/0000-0001-9552-3215 FU Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers Program; National Center for Research Resources; VeraLight; Genentech FX The authors would like to thank all members of the DCCT/EDIC Research Group. 22 The authors would also like to thank the contributors of free or discounted supplies and/or equipment: Abbott, Animas, Aventis, BD, Bayer, Can-AM, Eli Lilly, Lifescan, Medtronic Minimed, Omron, and Roche. In addition, the authors would like to acknowledge support from contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program and the Clinical and Translational Science Awards Program, National Center for Research Resources, and VeraLight and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. P. A. C. and J.M. researched the data, wrote significant portions of the manuscript, reviewed/edited the manuscript, and contributed to the discussion. B. H. B. researched the data, wrote a portion of the manuscript, reviewed/edited the manuscript, and contributed to the discussion. T.O., T.J.L., C. C., and R.A.G.-K. each wrote a portion of the manuscript, reviewed/edited the manuscript, and contributed to the discussion. J.W. and K. A. researched the data. A. B. reviewed/edited the manuscript and contributed to the discussion. S. V. reviewed/edited the manuscript. NR 34 TC 17 Z9 17 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 EI 1557-8593 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD JUN PY 2013 VL 15 IS 6 BP 466 EP 474 DI 10.1089/dia.2012.0316 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 156YN UT WOS:000319860900005 PM 23882708 ER PT J AU Tadokoro, T Rybanska-Spaeder, I Kulikowicz, T Dawut, L Oshima, J Croteau, DL Bohr, VA AF Tadokoro, Takashi Rybanska-Spaeder, Ivana Kulikowicz, Tomasz Dawut, Lale Oshima, Junko Croteau, Deborah L. Bohr, Vilhelm A. TI Functional deficit associated with a missense Werner syndrome mutation SO DNA REPAIR LA English DT Article DE Werner syndrome; Missense mutation; Loss of helicase; ATP binding defect ID PROTEIN-STRUCTURE ALIGNMENT; STRAND-ANNEALING ACTIVITIES; BLOOM-SYNDROME PROTEINS; SYNDROME GENE; RECQ HELICASES; DNA-REPAIR; SWISS-MODEL; HUMAN-CELLS; WRN; INTERACTS AB Werner syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WRN gene. WRN helicase, a member of the RecQ helicase family, is involved in various DNA metabolic pathways including DNA replication, recombination, DNA repair and telomere maintenance. In this study, we have characterized the G574R missense mutation, which was recently identified in a WS patient. Our biochemical experiments with purified mutant recombinant WRN protein showed that the G574R mutation inhibits ATP binding, and thereby leads to significant decrease in helicase activity. Exonuclease activity of the mutant protein was not significantly affected, whereas its single strand DNA annealing activity was higher than that of wild type. Deficiency in the helicase activity of the mutant may cause defects in replication and other DNA metabolic processes, which in turn could be responsible for the Werner syndrome phenotype in the patient. In contrast to the usual appearance of WS, the G574R patient has normal stature. Thus the short stature normally associated with WS may not be due to helicase deficiency. Published by Elsevier B.V. C1 [Tadokoro, Takashi; Rybanska-Spaeder, Ivana; Kulikowicz, Tomasz; Dawut, Lale; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Oshima, Junko] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100,Rm 06B133, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Research Program of the NIH, National Institute on Aging and NIH [CA078088, AG033313] FX We would like to thank Drs. Chandrika Canugovi and Huiming Lu for critically reading this manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging and NIH grants, CA078088 and AG033313 (J.O.). NR 56 TC 9 Z9 9 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JUN 1 PY 2013 VL 12 IS 6 BP 414 EP 421 DI 10.1016/j.dnarep.2013.03.004 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 162TV UT WOS:000320289800004 PM 23583337 ER PT J AU Ma, JZ Johnson, BA Yu, E Weiss, D McSherry, F Saadvandi, J Iturriaga, E Ait-Daoud, N Rawson, RA Hrymoc, M Campbell, J Gorodetzky, C Haning, W Carlton, B Mawhinney, J Weis, D McCann, M Pham, T Stock, C Dickinson, R Elkashef, A Li, MD AF Ma, Jennie Z. Johnson, Bankole A. Yu, Elmer Weiss, David McSherry, Frances Saadvandi, Jim Iturriaga, Erin Ait-Daoud, Nassima Rawson, Richard A. Hrymoc, Mark Campbell, Jan Gorodetzky, Charles Haning, William Carlton, Barry Mawhinney, Joseph Weis, Dennis McCann, Michael Pham, Tony Stock, Christopher Dickinson, Ruth Elkashef, Ahmed Li, Ming D. TI Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Addiction; Methamphetamine; Topiramate; Latent variable analysis ID RANDOMIZED CONTROLLED-TRIAL; ALCOHOL DEPENDENCE; ORAL TOPIRAMATE; CLINICAL-TRIALS; HETEROGENEITY; INTERVENTIONS; TRAJECTORIES; INSIGHTS AB Background: As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6-12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects. Methods: Latent variable analysis was used for the primary and secondary outcomes during weeks 6-12 and 1-12, adjusting for age, sex, and ethnicity. Results: Our analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6-12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio = 2.67; p = 0.019). Separate analyses of the outcomes during weeks 1-12 yielded similar results. Conclusions: Methamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Ma, Jennie Z.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Johnson, Bankole A.; Ait-Daoud, Nassima; Li, Ming D.] Univ Virginia, Dept Psychiat & Neurobehav Sci, Charlottesville, VA 22908 USA. [Yu, Elmer] Vet Adm Med Ctr, Philadelphia, PA 19104 USA. [Weiss, David; McSherry, Frances] Coordinating Ctr, Cooperat Studies Program, Dept Vet Affairs, Perry Point, MD 21902 USA. [Saadvandi, Jim] Informat Management Consultants, Reston, VA 22191 USA. [Iturriaga, Erin; Elkashef, Ahmed] NIDA, NIH, Bethesda, MD 20892 USA. [Rawson, Richard A.; Hrymoc, Mark] Univ Calif Los Angeles, Integrated Subst Abuse Programs, Los Angeles, CA 90025 USA. [Campbell, Jan; Gorodetzky, Charles] Univ Missouri, Dept Psychiat, Kansas City, MO 64131 USA. [Haning, William; Carlton, Barry] Pacific Addict Res Ctr, Honolulu, HI 96813 USA. [Mawhinney, Joseph] South Bay Treatment Ctr, San Diego, CA 92105 USA. [Weis, Dennis] Lutheran Hosp, Res Off, Des Moines, IA 50309 USA. [McCann, Michael; Pham, Tony] Matrix Inst Addict, West Los Angeles, CA 90025 USA. [Stock, Christopher; Dickinson, Ruth] Salt Lake City Hlth Care Syst, Dept Vet Affairs, Salt Lake City, UT 84148 USA. RP Ma, JZ (reprint author), Univ Virginia, Dept Publ Hlth Sci, POB 800717, Charlottesville, VA 22908 USA. EM jzm4h@virginia.edu FU National Institute on Drug Abuse (NIDA) through the Department of Veterans Affairs (VA) Cooperative Studies Program [Y1-DA4006] FX The National Institute on Drug Abuse (NIDA) provided support through the Department of Veterans Affairs (VA) Cooperative Studies Program (Interagency Agreement No. Y1-DA4006). Beyond the original study design and implementation, NIDA/VA had no further role in data analysis, the interpretation of results, the writing of the report, or the decision to submit the paper for publication. NR 35 TC 10 Z9 12 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2013 VL 130 IS 1-3 BP 45 EP 51 DI 10.1016/j.drugalcdep.2012.10.009 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 154ZK UT WOS:000319715000006 PM 23142494 ER PT J AU Lee, D Karschner, EL Milman, G Barnes, AJ Goodwin, RS Huestis, MA AF Lee, Dayong Karschner, Erin L. Milman, Garry Barnes, Allan J. Goodwin, Robert S. Huestis, Marilyn A. TI Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration? SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Oral fluid; Delta-9-tetrahydrocannabinol; Cannabis; Saliva; Sativex ID CHROMATOGRAPHY MASS-SPECTROMETRY; CHRONIC PAIN PATIENTS; REPORTED DRUG-USE; SMOKED CANNABIS; PHARMACOKINETIC PROPERTIES; PLANT CANNABINOIDS; MARIJUANA USE; DELTA(9)-TETRAHYDROCANNABINOL; PATTERNS; MEDICINE AB Objectives: We characterize cannabinoid disposition in oral fluid (OF) after dronabinol, synthetic oral Delta(9)-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. Methods: 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n =14). Oral fluid specimens were collected for 10.5 h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). Results: After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25-1 h. Median CBD/THC and CBN/THC ratios were 0.82-1.34 and 0.04-0.06, respectively, reflecting cannabinoids' composition in Sativex. THCCOOH/THC ratios within 4.5 h post Sativex were <= 1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. Conclusions: Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. Published by Elsevier Ireland Ltd. C1 [Lee, Dayong; Karschner, Erin L.; Milman, Garry; Barnes, Allan J.; Goodwin, Robert S.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Karschner, Erin L.] Aegis Sci Corp, Nashville, TN USA. RP Huestis, MA (reprint author), NIDA, IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH FX This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH. NR 47 TC 16 Z9 16 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2013 VL 130 IS 1-3 BP 68 EP 76 DI 10.1016/j.drugalcdep.2012.10.011 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 154ZK UT WOS:000319715000009 PM 23146820 ER PT J AU Kennedy, AP Phillips, KA Epstein, DH Reamer, DA Schmittner, J Preston, KL AF Kennedy, Ashley P. Phillips, Karran A. Epstein, David H. Reamer, David A. Schmittner, John Preston, Kenzie L. TI A randomized investigation of methadone doses at or over 100 mg/day, combined with contingency management SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Methadone maintenance; Methadone dose; Individualized dosing; Flexible dosing; Polydrug dependence; Contingency management ID SUBSTANCE USE DISORDERS; MAINTENANCE TREATMENT; OPIOID DEPENDENCE; CLINICAL-TRIALS; HEROIN USE; ABUSE TREATMENT; COCAINE USE; FOLLOW-UP; RETENTION; INTERVENTIONS AB Background: Methadone maintenance for heroin dependence reduces illicit drug use, crime, HIV risk, and death. Typical dosages have increased over the past few years, based on strong experimental and clinical evidence that dosages under 60 mg/day are inadequate and that dosages closer to 100 mg/day produce better outcomes. However, there is little experimental evidence for the benefits of exceeding 100 mg/day, or for individualizing methadone dosages. We sought to provide such evidence. Methods: We combined individualized methadone dosages over 100 mg/day with voucher-based cocaine-targeted contingency management (CM) in 58 heroin- and cocaine-dependent outpatients. Participants were randomly assigned to receive a fixed dose increase from 70 mg/day to 100 mg/day, or to be eligible for further dose increases (up to 190 mg/day, based on withdrawal symptoms, craving, and continued heroin use). All dosing was double-blind. The main outcome measure was simultaneous abstinence from heroin and cocaine. Results: We stopped the study early due to slow accrual. Cocaine-targeted CM worked as expected to reduce cocaine use. Polydrug use (effect-size h = .30) and heroin craving (effect-size d = .87) were significantly greater in the flexible/high-dose condition than in the fixed-dose condition, with no trend toward lower heroin use in the flexible/high-dose participants. Conclusions: Under double-blind conditions, dosages of methadone over 100 mg/day, even when prescribed based on specific signs and symptoms, were not better than 100 mg/day. This counterintuitive finding requires replication, but supports the need for additional controlled studies of high-dose methadone. Published by Elsevier Ireland Ltd. C1 [Kennedy, Ashley P.; Phillips, Karran A.; Epstein, David H.; Reamer, David A.; Schmittner, John; Preston, Kenzie L.] NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural Research Program of the NIH National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH National Institute on Drug Abuse. NR 49 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2013 VL 130 IS 1-3 BP 77 EP 84 DI 10.1016/j.drugalcdep.2012.10.025 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 154ZK UT WOS:000319715000010 PM 23195924 ER PT J AU Phillips, TM Wellner, E AF Phillips, Terry M. Wellner, Edward TI Detection of cerebral spinal fluid-associated chemokines in birth traumatized premature babies by chip-based immunoaffinity CE SO ELECTROPHORESIS LA English DT Article DE Chemokines; Chip-based immunoaffinity CE; Head trauma; Miniaturization; Preterm babies ID CEREBROSPINAL-FLUID; BRAIN-INJURY; CAPILLARY-ELECTROPHORESIS; MULTIPLE-SCLEROSIS; PRETERM INFANTS; CYTOKINES; NEUROINFLAMMATION; CHROMATOGRAPHY; BIOMARKERS; CXCL13 AB A major concern in treating premature infants with birth-associated head trauma is the rapid determination of reliable biomarkers of neuroinflammation. To this end a chip-based immunoaffinity CE device has been applied to determine the concentrations of inflammation-associated chemokines in samples of cerebral spinal fluid collected from such subjects. The chip utilizes replaceable immunoaffinity disks, to which reactive antibody fragments (FAb) of six antichemokine-specific antibodies were immobilized. Following injection of a sample into the device, the analytes were captured by the immobilized FAbs, labeled in situ with a red laser dye, chemically released and separated by CE. Each resolved peak was measured on-line by LIF detection and the results compared to standard curves produced by running known chemokine standards through the immunoaffinity system. The complete processing of a sample took 10 min with separation of all six analytes being achieved in less than 2 min. The system compared well to commercial ELISA, analysis of the results by linear regression demonstrating r2 values in the range of 0.903-0.978, and intra and interassay CV of the migration times and the measured peak areas being less than 2.3 and 5%, respectively. Application of the system to analysis of cerebrospinal fluid from head traumatized babies clearly indicated the group with mild trauma versus those with severe injury. Additionally, CE analysis demonstrated that the severe trauma group could be divided into individuals with good and poor prognosis, which correlated with the clinical finding for each patient. C1 [Phillips, Terry M.; Wellner, Edward] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Biophys, NIH, Bethesda, MD USA. RP Phillips, TM (reprint author), 4101 Albemarle St NW,Unit 508, Washington, DC 20016 USA. EM tmphil46@yahoo.com FU National Institutes of Health FX This work was supported by the intramural research program of the National Institutes of Health. NR 31 TC 7 Z9 7 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2013 VL 34 IS 11 SI SI BP 1530 EP 1538 DI 10.1002/elps.201200634 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 157ZW UT WOS:000319939300011 PM 23512340 ER PT J AU Lorenzo, MP Villasenor, A Ramamoorthy, A Garcia, A AF Paz Lorenzo, Ma Villasenor, Alma Ramamoorthy, Anuradha Garcia, Antonia TI Optimization and validation of a capillary electrophoresis laser-induced fluorescence method for amino acids determination in human plasma: Application to bipolar disorder study SO ELECTROPHORESIS LA English DT Article DE Amino acids; Biofluid; Bipolar disorder; Fluorescence; Plasma ID LIQUID-CHROMATOGRAPHIC ANALYSIS; TANDEM MASS-SPECTROMETRY; D-SERINE; CEREBROSPINAL-FLUID; BIOLOGICAL SAMPLES; DERIVATIZATION; DEPRESSION; CE; 4-FLUORO-7-NITRO-2,1,3-BENZOXADIAZOLE; QUANTIFICATION AB Quantitative and qualitative analysis of amino acids in biofluids offers relevant information in diagnosis of diseases, evaluation of nutritional state, and in elucidating metabolic influences on physiology. A simple, rapid, and robust procedure in terms of sample treatment, separation, and quantitation based on CE-LIF has been optimized for use in human plasma samples. Time required for derivatization was 15 min and analysis time was 35 min. 4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was the labeling agent used for obtaining fluorescent derivatives. Electrophoretic conditions were: 175 mM borate buffer at pH 10.25 prepared with 12.5 mM -cyclodextrin. The voltage applied was +21 kV. Fourteen amino acids could be quantified: l-proline, l-phenylalanine, l-leucine, l-isoleucine, l-ornithine, d-ornithine, l-glutamine, l-alanine, l-threonine, glycine, l-serine, d-serine, taurine and l-glutamate. With this chiral CE-LIF method, l- and d-amino acids are adequately separated. The method was validated for a representative group of amino acids in human plasma: l-proline, l-isoleucine, l-ornithine, l-glutamine, l-alanine l-threonine, glycine, l-serine, d-serine, and glutamate. The method has been successfully applied to human plasma from patients with bipolar disorder, all of whom were taking lithium as a mood stabilizer. Eleven amino acids were quantified in plasma from nine patients, aged 24-55 years. The results were in accordance to published values for the bipolar patients. The method is useful particularly in studies where plasma amino acid levels can be used as biomarkers for diagnosis of diseases, evaluating the disease progression, and monitoring response to drug therapy. C1 [Paz Lorenzo, Ma; Villasenor, Alma; Garcia, Antonia] Univ CEU San Pablo, Fac Farm, Ctr Metabol & Bioanal CEMBIO, Boadilla Del Monte 28668, Madrid, Spain. [Ramamoorthy, Anuradha] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Garcia, A (reprint author), Univ CEU San Pablo, Fac Farm, Ctr Metabol & Bioanal CEMBIO, Campus Monteprincipe, Boadilla Del Monte 28668, Madrid, Spain. EM antogar@ceu.es RI Garcia Fernandez, Antonia/C-4296-2008; Lorenzo, Maria /K-4497-2014 FU EADS-CASA; Ministry of Science and Innovation MICINN [CTQ2011-23562]; National Institute of Aging, National Institutes of Health (NIH); National Institute of Mental Health, NIH FX The authors thank Irving W. Wainer and Carlos A. Zarate, for the plasma samples and for their irreplaceable support and also Santiago Angulo for his scientific support. Alma Villasenor acknowledges EADS-CASA for her fellowship. The authors gratefully acknowledge the financial support from Ministry of Science and Innovation MICINN CTQ2011-23562. This work was supported in part by the Intramural Research Programs of the National Institute of Aging, National Institutes of Health (NIH), and the National Institute of Mental Health, NIH. NR 44 TC 18 Z9 19 U1 4 U2 86 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2013 VL 34 IS 11 SI SI BP 1701 EP 1709 DI 10.1002/elps.201200632 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 157ZW UT WOS:000319939300030 PM 23512402 ER PT J AU Ortiz, JGM Wallace, KA Leinisch, F Kadiiska, MB Mason, RP Kligerman, AD AF Ortiz, Jorge G. Muniz Wallace, Kathleen A. Leinisch, Fabian Kadiiska, Maria B. Mason, Ronald P. Kligerman, Andrew D. TI Catalase has a key role in protecting cells from the genotoxic effects of monomethylarsonous acid: A highly active metabolite of arsenic SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE arsenicals; mode of action; reactive oxygen species; DNA damage; Comet assay ID METHYLATED TRIVALENT ARSENICALS; DNA-DAMAGE; MALIGNANT-TRANSFORMATION; OXIDATIVE STRESS; MAMMALIAN-CELLS; DRINKING-WATER; EXPOSURE; REPAIR; MICE; TOXICITY AB Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic's exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The authors' studies are centered on identifying a reactive species involved in the genotoxicity of arsenic using a catalase (CAT) knockout mouse model that is impaired in its ability to breakdown hydrogen peroxide (H2O2). The authors assessed the induction of DNA damage using the Comet assay following exposure of mouse Cat+/+ and Cat-/- primary splenic lymphocytes to monomethylarsonous acid (MMAIII) to identify the potential role of H2O2 in mediating cellular effects of this metalloid. The results showed that the Cat-/- lymphocytes are more susceptible to MMAIII than the Cat+/+ lymphocytes by a small (1.5-fold) but statistically significant difference. CAT activity assays demonstrated that liver tissue has approximately three times more CAT activity than lymphocytes. Therefore, Comet assays were performed on primary Cat+/+, Cat+/-, and Cat-/- hepatocytes to determine if the Cat-/- cells were more susceptible to MMAIII than lymphocytes. The results showed that the Cat-/- hepatocytes exhibit higher levels of DNA strand breakage than the Cat+/+ (approximately fivefold) and Cat+/- (approximately twofold) hepatocytes exposed to MMAIII. Electron spin resonance using 5,5-dimethyl-1-pyrroline-N-oxide as the spin-trap agent detected the generation of center dot OH via MMAIII when H2O2 was present. These experiments suggest that CAT is involved in protecting cells against the genotoxic effects of the center dot OH generated by MMAIII. Environ. Mol. Mutagen. 54:317-326, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Ortiz, Jorge G. Muniz; Wallace, Kathleen A.; Kligerman, Andrew D.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Leinisch, Fabian; Kadiiska, Maria B.; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, Free Rad Metab Grp, Res Triangle Pk, NC USA. RP Kligerman, AD (reprint author), US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, B105-03, Res Triangle Pk, NC 27711 USA. EM kligerman.andrew@epa.gov FU U.S. Environmental Protection Agency; National Institutes of Health, National Institute of Environmental Health Sciences (Intramural Research Program) FX Grant sponsors: U.S. Environmental Protection Agency; National Institutes of Health, National Institute of Environmental Health Sciences (Intramural Research Program). NR 58 TC 1 Z9 1 U1 1 U2 9 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 JUN PY 2013 VL 54 IS 5 BP 317 EP 326 DI 10.1002/em.21780 PG 10 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 160OB UT WOS:000320127900003 ER PT J AU Baird, PN Wei, L AF Baird, Paul N. Wei, Lai TI Age-related macular degeneration and DNA methylation SO EPIGENOMICS LA English DT Editorial Material DE age-related macular degeneration; discordant twin; gene; genome-wide; immune; interleukin; methylation ID BEAVER DAM EYE; MACULOPATHY; PREVALENCE; SMOKING; TWINS; RISK C1 [Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic 3002, Australia. [Wei, Lai] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wei, Lai] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Wei, Lai] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Baird, PN (reprint author), Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, 32 Gisborne St, East Melbourne, Vic 3002, Australia. EM pnb@unimelb.edu.au RI Wei, Lai/D-1088-2014; OI Baird, Paul/0000-0002-1305-3502 NR 16 TC 2 Z9 2 U1 0 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 J9 EPIGENOMICS-UK JI Epigenomics PD JUN PY 2013 VL 5 IS 3 BP 239 EP 241 DI 10.2217/EPI.13.19 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 161CK UT WOS:000320168700001 PM 23750638 ER PT J AU Sacco, JE Dodd, KW Kirkpatrick, SI Tarasuk, V AF Sacco, J. E. Dodd, K. W. Kirkpatrick, S. I. Tarasuk, V. TI Voluntary food fortification in the United States: potential for excessive intakes SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE voluntary food fortification; NHANES; tolerable upper intake level ID MIXED-EFFECTS MODEL; DIETARY-SUPPLEMENTS; BREAKFAST CEREALS; IRISH ADULTS; NUTRIENTS; CHILDREN; VITAMIN; EAT; IMPACT; ZINC AB BACKGROUND: Historically, the voluntary addition of micronutrients to foods in the United States has been regarded as an important means to lessen problems of nutrient inadequacy. With expanding voluntary food fortification and widespread supplement use, it is important to understand how voluntary food fortification has an impact on the likelihood of excessive usual intakes. Our objective was to investigate whether individuals in the United States with greater frequency of exposure to micronutrients from voluntarily fortified foods (vFF) are more likely to have usual intakes approaching or exceeding the respective tolerable upper intake levels (UL). SUBJECTS/METHODS: The National Cancer Institute method was applied to data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) to estimate the joint distribution of usual intake from both vFF and non-vFF sources for 12 nutrients and determine the probability of consuming these nutrients from vFF on a given day. For each nutrient, we estimated the distribution of usual intake from all food sources by quintile of probability of consuming vFF and compared the distributions with ULs. RESULTS: An increased probability of consuming zinc, retinol, folic acid, selenium and copper from vFF was associated with a greater risk of intakes above the UL among children. Among adults, increased probability of consuming calcium and iron from vFF was associated with a greater risk of intakes above the UL among some age/sex groups. CONCLUSION: The high nutrient exposures associated with vFF consumption in some population subgroups suggest a need for more careful weighing of the risks and benefits of uncontrolled food fortification. C1 [Sacco, J. E.; Tarasuk, V.] Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. [Dodd, K. W.; Kirkpatrick, S. I.] NCI, Bethesda, MD 20892 USA. RP Tarasuk, V (reprint author), Univ Toronto, Fac Med, Dept Nutr Sci, Fitzgerald Bldg,150 Coll St, Toronto, ON M5S 3E2, Canada. EM valerie.tarasuk@utoronto.ca OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU Canadian Institutes of Health Research Doctoral Research Award FX JE Sacco is supported by a Canadian Institutes of Health Research Doctoral Research Award. NR 31 TC 11 Z9 12 U1 3 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2013 VL 67 IS 6 BP 592 EP 597 DI 10.1038/ejcn.2013.51 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 158KA UT WOS:000319967700005 PM 23462939 ER PT J AU Loverdo, C Lloyd-Smith, JO AF Loverdo, Claude Lloyd-Smith, James O. TI INTERGENERATIONAL PHENOTYPIC MIXING IN VIRAL EVOLUTION SO EVOLUTION LA English DT Article DE Adaptation; extinction; fitness; models; simulations; mutations ID RNA VIRUSES; MUTATION; REPLICATION; DYNAMICS; TRANSMISSION; EMERGENCE; DISEASES; ESCAPE; HIV-1 AB Viral particles (virions) are made of genomic material packaged with proteins, drawn from the pool of proteins in the parent cell. It is well known that when virion concentrations are high, cells can be coinfected with multiple viral strains that can complement each other. Viral genomes can then interact with proteins derived from different strains, in a phenomenon known as phenotypic mixing. But phenotypic mixing is actually far more common: viruses mutate very often, and each time a mutation occurs, the parent cell contains different types of viral genomes. Due to phenotypic mixing, changes in viral phenotypes can be shifted by a generation from the mutations that cause them. In the regime of evolutionary invasion and escape, when mutations are crucial for the virus to survive, this timing can have a large influence on the probability of emergence of an adapted strain. Modeling the dynamics of viral evolution in these contexts thus requires attention to the mutational mechanism and the determinants of fitness. C1 [Loverdo, Claude; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Loverdo, C (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM loverdo@ucla.edu RI Lloyd-Smith, James/K-4080-2012; OI Lloyd-Smith, James/0000-0001-7941-502X; Loverdo, Claude/0000-0002-0888-1717 FU National Science Foundation (NSF) [EF-0928690]; De Logi Chair in Biological Sciences; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The authors thank S. J. Schreiber and M. Park for providing useful comments on earlier drafts of this manuscript, and A. Siddiqui for providing valuable context over a breakfast table. Both authors are supported by the National Science Foundation (NSF) grant EF-0928690. JLS is grateful for the support of the De Logi Chair in Biological Sciences, and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 36 TC 3 Z9 3 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-3820 J9 EVOLUTION JI Evolution PD JUN PY 2013 VL 67 IS 6 BP 1815 EP 1822 DI 10.1111/evo.12048 PG 8 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 157DA UT WOS:000319874800024 PM 23730772 ER PT J AU Beachy, SH Onozawa, M Silverman, D Chung, YJ Rivera, MM Aplan, PD AF Beachy, Sarah H. Onozawa, Masahiro Silverman, Deborah Chung, Yang Jo Rivera, Mariela Martinez Aplan, Peter D. TI Isolated Hoxa9 overexpression predisposes to the development of lymphoid but not myeloid leukemia SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID BONE-MARROW-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; HEMATOPOIETIC PROGENITOR CELLS; T-ALL; DIFFERENTIAL EXPRESSION; NOTCH1 MUTATIONS; TRANSGENIC MICE; HOMEOBOX GENES; STEM-CELLS; MLL AB Hoxa9 is expressed in hematopoietic stem and progenitor cells, although this expression is usually diminished as these cells undergo differentiation. In addition, aberrant expression of Hoxa9 is strongly associated with both T cell and myeloid leukemia in mice and humans. Despite this strong association, enforced expression of Hoxa9 in murine bone marrow or thymus has only shown a modest ability to transform cells. To investigate this question, we used Vav regulatory elements to generate a transgenic mouse that targets Hoxa9 overexpression to all hematopoietic tissues. High-level expression of the Hoxa9 transgene in the hematopoietic compartment was associated with embryonic lethality, as no pups from founders that expressed high levels of the transgene were born live. However, offspring of an additional founder line, which expressed lower levels of Hoxa9, developed a precursor T cell lymphoblastic leukemia/lymphoma, accompanied by spontaneous Notch1 mutations. In contrast to most murine models of leukemia associated with Hoxa9 overexpression, the Vav-Hoxa9 mice did not overexpress other Hoxa cluster genes, mir196b (a microRNA that is embedded in the Hoxa locus), Meis1, or Pbx3. The Hoxa9 transgenic mouse reported in this study provides a suitable system for the study of Hoxa9 collaborators that drive myeloid and lymphoid malignant transformation. Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells. C1 [Beachy, Sarah H.; Onozawa, Masahiro; Silverman, Deborah; Chung, Yang Jo; Rivera, Mariela Martinez; Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 41 Ctr Dr, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016; OI Silverman, Deborah/0000-0003-2467-2445 FU Intramural Research Program of the National Institutes of Health National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute. The authors thank Jerry Adams for the gift of the Vav plasmid; Jan Linkenhoker and Maria Jorge for excellent veterinary care and animal husbandry; the National Cancer Institute transgenic and sequencing core facilities; and Chris Slape, Rachel Novak, Sheryl Gough, Zhenhua Zhang, and all the members of the Aplan lab for helpful discussions. NR 54 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2013 VL 41 IS 6 BP 518 EP 529 DI 10.1016/j.exphem.2013.02.006 PG 12 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 158ZM UT WOS:000320013800004 PM 23435313 ER PT J AU Ray, LA Sehl, M Bujarski, S Hutchison, K Blaine, S Enoch, MA AF Ray, L. A. Sehl, M. Bujarski, S. Hutchison, K. Blaine, S. Enoch, M. -A. TI The CRHR1 gene, trauma exposure, and alcoholism risk: a test of G x E effects SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Alcoholism; corticotropin-releasing hormone; CRHR1; genetics; stress ID CORTICOTROPIN-RELEASING-FACTOR; STRESSFUL LIFE EVENTS; HAPLOTYPE RECONSTRUCTION; CHILDHOOD TRAUMA; MALE TWINS; DEPENDENCE; ABUSE; DRINKING; ASSOCIATION; RELAPSE AB The corticotropin-releasing hormone type I receptor (CRHR1) gene has been implicated in the liability for neuropsychiatric disorders, particularly under conditions of stress. On the basis of the hypothesized effects of CRHR1 variation on stress reactivity, measures of adulthood traumatic stress exposure were analyzed for their interaction with CRHR1 haplotypes and single-nucleotide polymorphisms (SNPs) in predicting the risk for alcoholism. Phenotypic data on 2533 non-related Caucasian individuals (1167 alcoholics and 1366 controls) were culled from the publically available Study of Addiction: Genetics and Environment genome-wide association study. Genotypes were available for 19 tag SNPs. Logistic regression models examined the interaction between CRHR1 haplotypes/SNPs and adulthood traumatic stress exposure in predicting alcoholism risk. Two haplotype blocks spanned CRHR1. Haplotype analyses identified one haplotype in the proximal block 1 (P = 0.029) and two haplotypes in the distal block 2 (P = 0.026, 0.042) that showed nominally significant (corrected P < 0.025) genotype x traumatic stress interactive effects on the likelihood of developing alcoholism. The block 1 haplotype effect was driven by SNPs rs110402 (P = 0.019) and rs242924 (P = 0.019). In block 2, rs17689966 (P = 0.018) showed significant and rs173365 (P = 0.026) showed nominally significant, gene x environment (G x E) effects on alcoholism status. This study extends the literature on the interplay between CRHR1 variation and alcoholism, in the context of exposure to traumatic stress. These findings are consistent with the hypothesized role of the extra hypothalamic corticotropin-releasing factor system dysregulation in the initiation and maintenance of alcoholism. Molecular and experimental studies are needed to more fully understand the mechanisms of risk and protection conferred by genetic variation at the identified loci. C1 [Ray, L. A.; Bujarski, S.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Ray, L. A.] Univ Calif Los Angeles, Brain Res Inst, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Sehl, M.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Sehl, M.] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Hutchison, K.; Blaine, S.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Enoch, M. -A.] NIAAA, Neurogenet Lab, Bethesda, MD USA. RP Ray, LA (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. EM lararay@psych.ucla.edu FU Intramural NIH HHS [ZIA AA000306-08] NR 38 TC 8 Z9 8 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUN PY 2013 VL 12 IS 4 BP 361 EP 369 DI 10.1111/gbb.12032 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 156PM UT WOS:000319834800001 PM 23473364 ER PT J AU Proserpio, V Fittipaldi, R Ryall, JG Sartorelli, V Caretti, G AF Proserpio, Valentina Fittipaldi, Raffaella Ryall, James G. Sartorelli, Vittorio Caretti, Giuseppina TI The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy SO GENES & DEVELOPMENT LA English DT Article DE SMYD3; BRD4; muscle atrophy; myostatin ID RNA-POLYMERASE-II; DUCHENNE MUSCULAR-DYSTROPHY; CANCER CACHEXIA; MYOGENIC DIFFERENTIATION; MYOBLAST DIFFERENTIATION; CONDITIONAL ACTIVATION; PROPEPTIDE GENE; P-TEFB; GROWTH; INHIBITION AB Elucidating the epigenetic mechanisms underlying muscle mass determination and skeletal muscle wasting holds the potential of identifying molecular pathways that constitute possible drug targets. Here, we report that the methyltransferase SMYD3 modulates myostatin and c-Met transcription in primary skeletal muscle cells and C2C12 myogenic cells. SMYD3 targets the myostatin and c-Met genes and participates in the recruitment of the bromodomain protein BRD4 to their regulatory regions through protein-protein interaction. By recruiting BRD4, SMYD3 favors chromatin engagement of the pause-release factor p-TEFb (positive transcription elongation factor) and elongation of Ser2-phosphorylated RNA polymerase II (PolIISer2P). Reducing SMYD3 decreases myostatin and c-Met transcription, thus protecting from glucocorticoid-induced myotube atrophy. Supporting functional relevance of the SMYD3/BRD4 interaction, BRD4 pharmacological blockade by the small molecule JQ1 prevents dexamethasone-induced myostatin and atrogene up-regulation and spares myotube atrophy. Importantly, in a mouse model of dexamethasone-induced skeletal muscle atrophy, SMYD3 depletion prevents muscle loss and fiber size decrease. These findings reveal a mechanistic link between SMYD3/BRD4-dependent transcriptional regulation, muscle mass determination, and skeletal muscle atrophy and further encourage testing of small molecules targeting specific epigenetic regulators in animal models of muscle wasting. C1 [Proserpio, Valentina; Fittipaldi, Raffaella; Caretti, Giuseppina] Univ Milan, Dept Biosci, I-20133 Milan, Italy. [Ryall, James G.; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Caretti, G (reprint author), Univ Milan, Dept Biosci, I-20133 Milan, Italy. EM giuseppina.caretti@unimi.it OI Fittipaldi, Raffaella/0000-0001-9960-0249; Proserpio, Valentina/0000-0003-2071-4206; Ryall, James/0000-0003-4702-1143 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [MFAG 5386, PIRGES-224833]; Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health FX We thank A. Derfoul for help with satellite cell isolation protocol. The support of Associazione Italiana per la Ricerca sul Cancro (AIRC) MFAG 5386 and Marie Curie PIRGES-224833 to G.C. is kindly acknowledged. This work was supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health. NR 74 TC 18 Z9 19 U1 0 U2 17 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2013 VL 27 IS 11 BP 1299 EP 1312 DI 10.1101/gad.217240.113 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 160HP UT WOS:000320110000008 PM 23752591 ER PT J AU Au, WC Dawson, AR Rawson, DW Taylor, SB Baker, RE Basrai, MA AF Au, Wei Chun Dawson, Anthony R. Rawson, David W. Taylor, Sara B. Baker, Richard E. Basrai, Munira A. TI A Novel Role of the N Terminus of Budding Yeast Histone H3 Variant Cse4 in Ubiquitin-Mediated Proteolysis SO GENETICS LA English DT Article ID CELL-CYCLE PROGRESSION; SACCHAROMYCES-CEREVISIAE; CENTROMERIC CHROMATIN; TARGETING DOMAIN; CHROMOSOME LOSS; PROTEIN; DROSOPHILA; LOCALIZATION; GENE; MISLOCALIZATION AB Regulating levels of centromeric histone H3 (CenH3) variant is crucial for genome stability. Interaction of Psh1, an E3 ligase, with the C terminus of Cse4 has been shown to contribute to its proteolysis. Here, we demonstrate a role for ubiquitination of the N terminus of Cse4 in regulating Cse4 proteolysis for faithful chromosome segregation and a role for Doa1 in ubiquitination of Cse4. C1 [Au, Wei Chun; Dawson, Anthony R.; Rawson, David W.; Taylor, Sara B.; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20889 USA. [Baker, Richard E.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 41 Ctr Dr,Room C629B, Bethesda, MD 20892 USA. EM basraim@mail.nih.gov FU National Institutes of Health FX We thank Sue Biggins and Mitch Smith for strains, Charlie Boone and Michael Costanzo for strains and results of the SGA screen, Richard Gardner for advice on ubiquitin assays, and the Basrai laboratory members for discussions and comments on the manuscript. This work was supported by the National Institutes of Health Intramural Research Program. NR 29 TC 14 Z9 14 U1 0 U2 2 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 1943-2631 J9 GENETICS JI Genetics PD JUN PY 2013 VL 194 IS 2 BP 513 EP + DI 10.1534/genetics.113.149898 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 156IG UT WOS:000319814700019 PM 23525333 ER PT J AU Stumpf, JD Copeland, WC AF Stumpf, Jeffrey D. Copeland, William C. TI The Exonuclease Activity of the Yeast Mitochondrial DNA Polymerase gamma Suppresses Mitochondrial DNA Deletions Between Short Direct Repeats in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; MTDNA MUTATOR MICE; OXIDATIVE STRESS; MUTATIONS; DISEASE; POLG; QUANTIFICATION; REPLICATION; MUTAGENESIS; APOPTOSIS AB The importance of mitochondrial DNA (mtDNA) deletions in the progeroid phenotype of exonuclease-deficient DNA polymerase gamma mice has been intensely debated. We show that disruption of Mip1 exonuclease activity increases mtDNA deletions 160-fold, whereas disease-associated polymerase variants were mostly unaffected, suggesting that exonuclease activity is vital to avoid deletions during mtDNA replication. C1 [Stumpf, Jeffrey D.; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, 111 TW Alexander Dr,Bldg 101,Room E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU NIEHS; National Institutes of Health [ES-065078] FX We thank Elaine Sia for generously providing NPY75; Dmitry Gordenin for providing technical assistance; the National Institute of Environmental Health Sciences (NIEHS) Sequencing Core Facility for providing nucleotide sequences for the plasmids used; and Matthew Young, Matthew Longley, and Scott Lujan for critical reading of the manuscript. This work was supported by intramural funds from the NIEHS and National Institutes of Health (ES-065078). NR 37 TC 9 Z9 9 U1 0 U2 4 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUN PY 2013 VL 194 IS 2 BP 519 EP 522 DI 10.1534/genetics.113.150920 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 156IG UT WOS:000319814700020 PM 23589460 ER PT J AU Khoury, MJ Janssens, ACJW Ransohoff, DF AF Khoury, Muin J. Janssens, A. Cecile J. W. Ransohoff, David F. TI How can polygenic inheritance be used in population screening for common diseases? SO GENETICS IN MEDICINE LA English DT Article DE evidence-based medicine; genetics; genomics; polygenic model; public health; risk assessment; screening ID SERVICES TASK-FORCE; PERSONALIZED MEDICINE HOPE; EGAPP WORKING GROUP; BREAST-CANCER RISK; 5 GENETIC-VARIANTS; COLORECTAL-CANCER; PROSTATE-CANCER; RECOMMENDATION STATEMENT; FAMILY-HISTORY; COMPLEX DISEASES AB Advances in genomics have near-term impact on diagnosis and management of monogenic disorders. For common complex diseases, the use of genomic information from multiple loci (polygenic model) is generally not useful for diagnosis and individual prediction. In principle, the polygenic model could be used along with other risk factors in stratified population screening to target interventions. For example, compared to age-based criterion for breast, colorectal, and prostate cancer screening, adding polygenic risk and family history holds promise for more efficient screening with earlier start and/or increased frequency of screening for segments of the population at higher absolute risk than an established screening threshold; and later start and/or decreased frequency of screening for segments of the population at lower risks. This approach, while promising, faces formidable challenges for building its evidence base and for its implementation in practice. Currently, it is unclear whether or not polygenic risk can contribute enough discrimination to make stratified screening worthwhile. Empirical data are lacking on population-based age-specific absolute risks combining genetic and non-genetic factors, on impact of polygenic risk genes on disease natural history, as well as information on comparative balance of benefits and harms of stratified interventions. Implementation challenges include difficulties in integration of this information in the current health-care system in the United States, the setting of appropriate risk thresholds, and ethical, legal, and social issues. In an era of direct-to-consumer availability of personal genomic information, the public health and health-care systems need to prepare for an evidence-based integration of this information into population screening. C1 [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. [Janssens, A. Cecile J. W.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Ransohoff, David F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. EM mkhoury@cdc.gov OI Janssens, A Cecile/0000-0002-6153-4976 FU Intramural CDC HHS [CC999999] NR 57 TC 15 Z9 15 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUN PY 2013 VL 15 IS 6 BP 437 EP 443 DI 10.1038/gim.2012.182 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 158NV UT WOS:000319979800005 PM 23412608 ER PT J AU Yan, XW Lam, KH Li, X Chen, RM Ren, W Ren, XB Zhou, QF Shung, KK AF Yan, Xingwei Lam, Kwok Ho Li, Xiang Chen, Ruimin Ren, Wei Ren, Xiaobing Zhou, Qifa Shung, K. Kirk TI Lead-Free Intravascular Ultrasound Transducer Using BZT-50BCT Ceramics SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID PT SINGLE-CRYSTAL; HIGH-FREQUENCY; FABRICATION; FILMS AB This paper reports the fabrication and evaluation of a high-frequency ultrasonic transducer based on a new lead-free piezoelectric material for intravascular imaging application. Lead-free 0.5Ba(Zr0.2Ti0.8)O-3-0.5(Ba0.7Ca0.3)TiO3 (BZT-50BCT) ceramic with a high dielectric constant (similar to 2800) was employed to develop a high-frequency (similar to 30 MHz) needle-type ultrasonic transducer. With superior piezoelectric performance (piezoelectric coefficient d(33) similar to 600 pC/N), the lead-free transducer was found to exhibit a -6-dB bandwidth of 53% with an insertion loss of 18.7 dB. In vitro intravascular ultrasound (IVUS) imaging of a human cadaver coronary artery was performed to demonstrate the potential of the lead-free transducer for biomedical imaging applications. This is the first time that a lead-free transducer has been used for IVUS imaging application. The experimental results suggest that the BZT-50BCT ceramic is a promising lead-free piezoelectric material for high-frequency intravascular imaging applications. C1 [Yan, Xingwei; Ren, Wei] Xi An Jiao Tong Univ, Elect Mat Res Lab, Key Lab, Minist Educ, Xian 710049, Peoples R China. [Yan, Xingwei; Ren, Wei] Xi An Jiao Tong Univ, Int Ctr Dielect Res, Xian 710049, Peoples R China. [Lam, Kwok Ho; Li, Xiang; Chen, Ruimin; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lam, Kwok Ho; Li, Xiang; Chen, Ruimin; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA USA. [Ren, Xiaobing] Xi An Jiao Tong Univ, Multidisciplinary Mat Res Ctr, Frontier Inst Sci & Technol, Xian 710049, Peoples R China. RP Yan, XW (reprint author), Xi An Jiao Tong Univ, Elect Mat Res Lab, Key Lab, Minist Educ, Xian 710049, Peoples R China. EM wren@mail.xjtu.edu.cn; ren.xiaobing@nims.go.jp; qifazhou@usc.edu RI Lam, K.H./B-7765-2014; Ren, Xiaobing/B-6072-2009 OI Lam, K.H./0000-0003-1456-9049; Ren, Xiaobing/0000-0002-4973-2486 FU International Science and Technology Cooperation Program of China [2010DFB13640]; National Basic Research Program of China [2012CB619401]; Natural Science Foundation of China [90923001]; Shaanxi Province International Collaboration Program [2009KW-12, 2010KW-09]; National Institutes of Health (NIH) [P41-EB002182] FX This work was financially supported by the International Science and Technology Cooperation Program of China (grant number 2010DFB13640), National Basic Research Program of China (grant number 2012CB619401), Natural Science Foundation of China (grant number 90923001), the Shaanxi Province International Collaboration Program (grant numbers 2009KW-12 and 2010KW-09), and the National Institutes of Health (NIH; grant number P41-EB002182). NR 22 TC 9 Z9 9 U1 2 U2 49 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 JUN PY 2013 VL 60 IS 6 BP 1272 EP 1276 DI 10.1109/TUFFC.2013.2692 PG 5 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 158RR UT WOS:000319990800025 PM 25004492 ER PT J AU Lipshultz, SE Williams, PL Wilkinson, JD Leister, EC Van Dyke, RB Shearer, WT Rich, KC Hazra, R Kaltman, JR Jacobson, DL Dooley, LB Scott, GB Rabideau, N Colan, SD AF Lipshultz, Steven E. Williams, Paige L. Wilkinson, James D. Leister, Erin C. Van Dyke, Russell B. Shearer, William T. Rich, Kenneth C. Hazra, Rohan Kaltman, Jonathan R. Jacobson, Denise L. Dooley, Laurie B. Scott, Gwendolyn B. Rabideau, Nicole Colan, Steven D. CA Pediat HIV AIDS Cohort Study TI Cardiac Status of Children Infected With Human Immunodeficiency Virus Who Are Receiving Long-term Combination Antiretroviral Therapy Results From the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study SO JAMA PEDIATRICS LA English DT Article ID PROSPECTIVE (PCHIV)-C-2-H-2 MULTICENTER; CARDIOVASCULAR COMPLICATIONS; HIV-INFECTION; DIASTOLIC DYSFUNCTION; PERINATAL EXPOSURE; CD-1 MICE; MORTALITY; INFANTS; PULMONARY; HEART AB Importance: Prior to contemporary antiretroviral therapies (ARTs), children infected with human immunodeficiency virus (HIV) were more likely to have heart failure. This study suggests that highly active ART (HAART) does not appear to impair heart function. Objective: To determine the cardiac effects of prolonged exposure to HAART on HIV-infected children. Design: In the National Institutes of Health-funded Pediatric HIV/AIDS Cohort Study's Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiographic measures. Setting: A total of 14 US pediatric HIV clinics. Participants: Perinatally HIV-infected children receiving HAART (n=325), HIV-exposed but uninfected children (n=189), and HIV-infected (mostly HAART-unexposed) historical pediatric controls from the National Institutes of Health-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection ((PC2)-C-2-HIV) Study (n=70). Exposure: Long-term HAART. Main Outcomes and Measures: Echocardiographic measures of left ventricular (LV) function and structure. Results: The 325 AMP HIV-infected children had lower viral loads, higher CD4 counts, and longer durations of ART than did the 70 HIV-infected children from the (PC2)-C-2-HIV Study (all P<.001). The z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among HIV-infected children from the (PC2)-C-2-HIV Study than among the AMP HIV-infected group or the 189 AMP HIV-exposed but uninfected controls (P<.05). For HIV-infected children, a lower nadir CD4 percentage and a higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening z scores; all P=.001) and an increased LV end-systolic dimension z score (all P<.03). In an interaction analysis by HIV-infected cohort, the HIV-infected children from the (PC2)-C-2-HIV Study with a longer ART exposure or a lower nadir CD4 percentage had lower mean LV fractional shortening z scores, whereas the mean z scores were relatively constant among AMP HIV-infected children (P<.05 for all interactions). Conclusions and Relevance: Long-term HAART appears to be cardioprotective for HIV-infected children and adolescents. C1 [Lipshultz, Steven E.; Wilkinson, James D.; Scott, Gwendolyn B.] Univ Miami, Leonard M Miller Sch Med, Dept Pediat, Miami, FL 33101 USA. [Williams, Paige L.; Leister, Erin C.; Jacobson, Denise L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Rabideau, Nicole; Colan, Steven D.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Van Dyke, Russell B.] Tulane Univ, Dept Pediat, New Orleans, LA 70118 USA. [Shearer, William T.] Baylor Coll Med, Houston, TX 77030 USA. [Shearer, William T.] Texas Childrens Hosp, Houston, TX 77030 USA. [Rich, Kenneth C.] Univ Illinois, Dept Pediat, Chicago, IL USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Kaltman, Jonathan R.] NHLBI, Bethesda, MD 20892 USA. [Dooley, Laurie B.] Frontier Sci Technol & Res Fdn, Amherst, NY USA. RP Lipshultz, SE (reprint author), Univ Miami, Leonard M Miller Sch Med, Dept Pediat, POB 016820, Miami, FL 33101 USA. EM slipshultz@med.miami.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard School of Public Health [HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3]; Tulane University School of Medicine [HD052104, 3U01HD052104-06S1] FX The study and PHACS were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard School of Public Health (grants HD052102, 3 U01 HD052102-05S1, and 3 U01 HD052102-06S3) and the Tulane University School of Medicine (grants HD052104 and 3U01HD052104-06S1). Data management services were provided by the Frontier Science and Technology Research Foundation, and regulatory services and logistical support were provided by Westat, Inc. NR 35 TC 20 Z9 20 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD JUN PY 2013 VL 167 IS 6 BP 520 EP 527 DI 10.1001/jamapediatrics.2013.1206 PG 8 WC Pediatrics SC Pediatrics GA 156NR UT WOS:000319829700006 PM 23608879 ER PT J AU Hoberman, A Shaikh, N Bhatnagar, S Haralam, MA Kearney, DH Colborn, K Kienholz, ML Wang, L Bunker, CH Keren, R Carpenter, MA Greenfield, SP Pohl, HG Mathews, R Moxey-Mims, M Chesney, RW AF Hoberman, Alejandro Shaikh, Nader Bhatnagar, Sonika Haralam, Mary Ann Kearney, Diana H. Colborn, Kathleen Kienholz, Michelle L. Wang, Li Bunker, Clareann H. Keren, Ron Carpenter, Myra A. Greenfield, Saul P. Pohl, Hans G. Mathews, Ranjiv Moxey-Mims, Marva Chesney, Russell W. TI Factors That Influence Parental Decisions to Participate in Clinical Research Consenters vs Nonconsenters SO JAMA PEDIATRICS LA English DT Article ID CONTROLLED-TRIALS; CHILDREN; PERCEPTIONS AB Importance: A child's health, positive perceptions of the research team and consent process, and altruistic motives play significant roles in the decision-making process for parents who consent for their child to enroll in clinical research. This study identified that nonconsenting parents were better educated, had private insurance, showed lower levels of altruism, and less understanding of study design. Objective: To determine the factors associated with parental consent for their child's participation in a randomized, placebo-controlled trial. Design: Cross-sectional survey conducted from July 2008 to May 2011. The survey was an ancillary study to the Randomized Intervention for Children with VesicoUreteral Reflux Study. Setting: Seven children's hospitals participating in a randomized trial evaluating management of children with vesicoureteral reflux. Participants: Parents asked to provide consent for their child's participation in the randomized trial were invited to complete an anonymous online survey about factors influencing their decision. A total of 120 of the 271 (44%) invited completed the survey; 58 of 125 (46%) who had provided consent and 62 of 144 (43%) who had declined consent completed the survey. Main Outcomes and Measures: A 60-question survey examining child, parent, and study characteristics; parental perception of the study; understanding of the design; external influences; and decision-making process. Results: Having graduated from college and private health insurance were associated with a lower likelihood of providing consent. Parents who perceived the trial as having a low degree of risk, resulting in greater benefit to their child and other children, causing little interference with standard care, or exhibiting potential for enhanced care, or who perceived the researcher as professional were significantly more likely to consent to participate. Higher levels of understanding of the randomization process, blinding, and right to withdraw were significantly positively associated with consent to participate. Conclusions and Relevance: Parents who declined consent had a relatively higher socioeconomic status, had more anxiety about their decision, and found it harder to make their decision compared with consenting parents, who had higher levels of trust and altruism, perceived the potential for enhanced care, reflected better understanding of randomization, and exhibited low decisional uncertainty. Consideration of the factors included in the conceptual model should enhance the quality of the informed consent process and improve participation in pediatric clinical trials. C1 [Hoberman, Alejandro; Shaikh, Nader; Bhatnagar, Sonika; Haralam, Mary Ann; Kearney, Diana H.; Colborn, Kathleen; Kienholz, Michelle L.; Wang, Li; Bunker, Clareann H.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Keren, Ron] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Carpenter, Myra A.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Greenfield, Saul P.] SUNY Buffalo, Women & Childrens Hosp, New York, NY USA. [Pohl, Hans G.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Mathews, Ranjiv] Johns Hopkins Univ, Baltimore, MD USA. [Moxey-Mims, Marva] Natl Inst Diabet & Digest Kidney Dis, Bethesda, MD USA. [Chesney, Russell W.] Bonheur Childrens Med Ctr, Memphis, TN USA. RP Hoberman, A (reprint author), Childrens Hosp Pittsburgh, Gen Acad Pediat, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM hoberman@chp.edu FU National Institutes of Health through the University of Pittsburgh Clinical and Translational Science Award [UL1 RR024153]; National Center for Advancing Translational Sciences [UL1TR000005]; 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 [UL1TR000003] FX Funding/Support: This study was supported by the National Institutes of Health through the University of Pittsburgh Clinical and Translational Science Award UL1 RR024153 and grant UL1TR000005 from the National Center for Advancing Translational Sciences. The Randomized Intervention for Children with VesicoUreteral Reflux Study was supported by cooperative agreements U01 DK074059 (Dr Carpenter), U01 DK074053 (Dr Hoberman), U01 DK074082 (Dr Mathews), U01 DK074064 (Dr Keren), U01 DK074062 (Dr Tej Mattoo), and U01 DK074063 (Dr 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. NR 16 TC 26 Z9 26 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD JUN PY 2013 VL 167 IS 6 BP 561 EP 566 DI 10.1001/jamapediatrics.2013.1050 PG 6 WC Pediatrics SC Pediatrics GA 156NR UT WOS:000319829700013 PM 23546617 ER PT J AU Glasgow, RE Doria-Rose, VP Khoury, MJ Elzarrad, M Brown, ML Stange, KC AF Glasgow, Russell E. Doria-Rose, V. Paul Khoury, Muin J. Elzarrad, Mohammed Brown, Martin L. Stange, Kurt C. TI Comparative Effectiveness Research in Cancer: What Has Been Funded and What Knowledge Gaps Remain? SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PRACTICAL CLINICAL-TRIALS; MULTIMETHOD RESEARCH; HEALTH-CARE; UNINTENDED CONSEQUENCES; PARTICIPATORY RESEARCH; MULTISITE MULTIMETHOD; POPULATION HEALTH; DECISION-MAKING; PUBLIC-HEALTH; MEDICINE C1 [Glasgow, Russell E.; Doria-Rose, V. Paul; Khoury, Muin J.; Elzarrad, Mohammed; Brown, Martin L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Elzarrad, Mohammed] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Elzarrad, Mohammed] US FDA, Interagency Oncol Task Force Joint Fellowship Pro, Silver Spring, MD USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland Clin & Translat Sci Collaborat, Case Comprehens Canc Ctr, Dept Family Med & Community Hlth,Dept Epidemiol &, Cleveland, OH 44106 USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland Clin & Translat Sci Collaborat, Case Comprehens Canc Ctr, Dept Sociol, Cleveland, OH 44106 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 NR 64 TC 8 Z9 8 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUN PY 2013 VL 105 IS 11 BP 766 EP 773 DI 10.1093/jnci/djt066 PG 8 WC Oncology SC Oncology GA 160QK UT WOS:000320134100007 PM 23578853 ER PT J AU Ramirez, AS Rutten, LJF Oh, A Vengoechea, BL Moser, RP Vanderpool, RC Hesse, BW AF Ramirez, A. Susana Rutten, Lila J. Finney Oh, April Vengoechea, Bryan Leyva Moser, Richard P. Vanderpool, Robin C. Hesse, Bradford W. TI Perceptions of Cancer Controllability and Cancer Risk Knowledge: The Moderating Role of Race, Ethnicity, and Acculturation SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer fatalism; Health communication; Disparities; Communication inequalities ID OF-SPORTS-MEDICINE; PHYSICAL-ACTIVITY; PREVENTION BEHAVIORS; FATALISTIC BELIEFS; PUBLIC-HEALTH; RECOMMENDATIONS; ASSOCIATIONS; ADULTS AB Literature suggests racial/ethnic minorities, particularly those who are less-acculturated, have stronger fatalistic attitudes toward cancer than do non-Latino Whites. Knowledge of cancer prevention is also lower among racial/ethnic minorities. Moreover, low knowledge about cancer risk factors is often associated with fatalistic beliefs. Our study examined fatalism and cancer knowledge by race/ethnicity and explored whether race/ethnicity moderate the association of fatalism with knowledge of cancer prevention and risk factors. We analyzed data from the Health Information National Trends Survey (2008), a national probability survey, to calculate population estimates of the associations among race/ethnicity, fatalistic beliefs, and knowledge about cancer from multivariable logistic regression. Racial/ethnic minorities had higher odds of holding fatalistic beliefs and lower odds of having knowledge of cancer risk factors than non-Hispanic Whites, and important differences by acculturation among Latinos were observed. Limited evidence of the moderating effect of race/ethnicity on the relationship between fatalistic beliefs and cancer risk factor knowledge was observed. Knowledge of cancer risk factors is low among all race/ethnicities, while fatalistic beliefs about cancer are higher among racial/ethnic minorities compared with non-Hispanic Whites. Implications for cancer education efforts are discussed. C1 [Ramirez, A. Susana; Vengoechea, Bryan Leyva; Moser, Richard P.; Hesse, Bradford W.] NCI, Rockville, MD USA. [Rutten, Lila J. Finney] Mayo Clin, Rochester, MN USA. [Oh, April] SAIC Frederick Inc, Clin Res Program Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Vanderpool, Robin C.] Univ Kentucky, Coll Publ Hlth, Lexington, KY 40506 USA. RP Ramirez, AS (reprint author), NCI, 6130 Execut Blvd Suite 4051A,MSC 7150, Rockville, MD USA. EM ramirezas@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract No. HHSN261200800001E. The 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 26 TC 16 Z9 16 U1 1 U2 21 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 JUN PY 2013 VL 28 IS 2 BP 254 EP 261 DI 10.1007/s13187-013-0450-8 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 151PU UT WOS:000319473500008 PM 23355279 ER PT J AU Harman, J Walker, ER Charbonneau, V Akylbekova, EL Nelson, C Wyatt, SB AF Harman, Jane Walker, Evelyn R. Charbonneau, Vicki Akylbekova, Ermeg L. Nelson, Cheryl Wyatt, Sharon B. TI Treatment of Hypertension Among African Americans: The Jackson Heart Study SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID HIGH BLOOD-PRESSURE; CONVERTING-ENZYME-INHIBITOR; LIPID-LOWERING TREATMENT; CALCIUM-CHANNEL BLOCKER; UNITED-STATES; INTERNATIONAL SOCIETY; CONSENSUS STATEMENT; ATTACK TRIAL; MANAGEMENT; PREVALENCE AB Hypertension treatment regimens used by African American adults in the Jackson Heart Study were evaluated at the first two clinical examinations (2415 treated hypertensive persons at examination I [exam I], 2000-2004; 2577 at examination II [exam II], 2005-2008). Blood pressure (BP) was below 140/90mmHg for 66% and 70% of treated participants at exam I and exam II, respectively. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure treatment targets were met for 56% and 61% at exam I and exam II, respectively. Persons with diabetes or chronic kidney disease were less likely to have BP at target, as were men compared with women. Thiazide diuretics were the most commonly used antihypertensive medication, and persons taking a thiazide were more likely to have their BP controlled than persons not taking them; thiazides were used significantly less among men than women. Although calcium channel blockers are often considered to be effective monotherapy for African Americans, persons using calcium channel blocker monotherapy were significantly less likely to be at target BP than persons using thiazide monotherapy. (C) 2013 Wiley Periodicals, Inc. C1 [Harman, Jane; Charbonneau, Vicki; Nelson, Cheryl] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Walker, Evelyn R.] Mississippi Dept Hlth, Jackson, MS USA. [Akylbekova, Ermeg L.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Med, Jackson, MS 39216 USA. RP Harman, J (reprint author), NHLBI, 6701 Rockledge Dr,Mailstop 7936, Bethesda, MD 20892 USA. EM Jane.Harman@nih.gov FU National Institutes of Health from the National Heart, Lung, and Blood Institute [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Institute on Minority Health and Health Disparities FX The JHS is supported by National Institutes of Health contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. NR 37 TC 10 Z9 11 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD JUN PY 2013 VL 15 IS 6 BP 367 EP 374 DI 10.1111/jch.12088 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 157MA UT WOS:000319899000004 PM 23730984 ER PT J AU Myers, L Joedicke, JJ Carmody, AB Messer, RJ Kassiotis, G Dudley, JP Dittmer, U Hasenkrug, KJ AF Myers, Lara Joedicke, Jara J. Carmody, Aaron B. Messer, Ronald J. Kassiotis, George Dudley, Jaquelin P. Dittmer, Ulf Hasenkrug, Kim J. TI IL-2-Independent and TNF-alpha-Dependent Expansion of V beta 5(+) Natural Regulatory T Cells during Retrovirus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; C VIRUS-INFECTION; DEHYDROGENASE-ELEVATING VIRUS; IMMUNOLOGICAL SELF-TOLERANCE; IN-VITRO PROLIFERATION; MAMMARY-TUMOR VIRUS; TGF-BETA; AUTOIMMUNE-DISEASE; EFFECTOR FUNCTION; VIRAL-INFECTION AB Friend virus infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4(+) T cells that converted into induced Tregs. Analysis of Treg TCR V beta chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the V beta 5(+) Treg subset, which is known to be responsive to endogenous retrovirus-encoded superantigens. In contrast to the major population of Tregs, the V beta 5(+) subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8(+) T cell response rather than the level of Friend virus infection. Surprisingly, the expansion and accumulation of the V beta 5(+) Tregs was IL-2 independent but dependent on TNF-alpha. These experiments reveal a subset-specific Treg induction by a new pathway. C1 [Myers, Lara; Messer, Ronald J.; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Joedicke, Jara J.; Dittmer, Ulf] Univ Duisburg Essen, Inst Virol, Univ Hosp Essen, D-45122 Essen, Germany. [Carmody, Aaron B.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Kassiotis, George] Natl Inst Med Res, Med Res Council, Div Immunoregulat, London NW7 1AA, England. [Dudley, Jaquelin P.] Univ Texas Austin, Inst Cellular & Mol Biol, Sect Mol Genet & Microbiol, Austin, TX 78712 USA. RP Hasenkrug, KJ (reprint author), NIH, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases/National Institutes of Health; German Research Foundation [TRR60, GRK1045-2]; National Institutes of Health [R01 CA167053]; United Kingdom Medical Research Council [U117581330] FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases/National Institutes of Health, German Research Foundation Grants TRR60 Project B4 and GRK1045-2, National Institutes of Health Grant R01 CA167053 (to J.P.D.), and by United Kingdom Medical Research Council Grant U117581330. NR 81 TC 10 Z9 11 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2013 VL 190 IS 11 BP 5485 EP 5495 DI 10.4049/jimmunol.1202951 PG 11 WC Immunology SC Immunology GA 147XY UT WOS:000319205900019 PM 23645880 ER PT J AU Edwards, JP Fujii, H Zhou, AX Creemers, J Unutmaz, D Shevach, EM AF Edwards, Justin P. Fujii, Hodaka Zhou, Angela X. Creemers, John Unutmaz, Derya Shevach, Ethan M. TI Regulation of the Expression of GARP/Latent TGF-beta 1 Complexes on Mouse T Cells and Their Role in Regulatory T Cell and Th17 Differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROPROTEIN CONVERTASE FURIN; LATENT TGF-BETA; IN-VIVO; T(H)17 CELLS; GARP; INTERLEUKIN-2; TOLERANCE; SURFACE; ACTIVATION; INDUCTION AB GARP/LRRC32 was defined as a marker of activated human regulatory T cells (Tregs) that is responsible for surface localization of latent TGF-beta 1. We find that GARP and latent TGF-beta 1 are also found on mouse Tregs activated via TCR stimulation; however, in contrast to human Tregs, GARP is also expressed at a low level on resting Tregs. The expression of GARP can be upregulated on mouse Tregs by IL-2 or IL-4 exposure in the absence of TCR signaling. GARP is expressed at a low level on Tregs within the thymus, and Treg precursors from the thymus concomitantly express GARP and Foxp3 upon exposure to IL-2. The expression of GARP is independent of TGF-beta 1 and TGF-beta 1 loading into GARP and is independent of furin-mediated processing of pro-TGF-beta 1 to latent TGF-beta 1. Specific deletion of GARP in CD4(+) T cells results in lack of expression of latent TGF-beta 1 on activated Tregs. GARP-deficient Tregs develop normally, are present in normal numbers in peripheral tissues, and are fully competent suppressors of the activation of conventional T cells in vitro. Activated Tregs expressing GARP/latent TGF-beta 1 complexes are potent inducers of Th17 differentiation in the presence of exogenous IL-6 and inducers of Treg in the presence of IL-2. Induction of both Th17-producing cells and Tregs is caused preferentially by Tregs expressing the latent TGF-beta 1/GARP complex on their cell surface rather than by secreted latent TGF-beta 1. C1 [Edwards, Justin P.; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Fujii, Hodaka] Osaka Univ, Combined Program Microbiol & Immunol, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan. [Fujii, Hodaka] NYU, Dept Microbiol, Sch Med, New York, NY 10016 USA. [Creemers, John] Catholic Univ Louvain, Biochem Neuroendocrinol Lab, Ctr Human Genet, B-3000 Louvain, Belgium. RP Shevach, EM (reprint author), NIAID, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM ESHEVACH@niaid.nih.gov RI Fujii, Hodaka/A-2420-2008; OI Fujii, Hodaka/0000-0003-1296-4256; Edwards, Justin/0000-0001-8936-2136 FU National Institute of Allergy and Infectious Diseases; Ministry of Education, Culture, Sports, Science and Technology of Japan [23590569]; Osaka Clinical Immunology Foundation; Takeda Science Foundation; Senshin Medical Research Foundation; Japan Rheumatism Foundation; Itoh Chubei Foundation FX This work was supported by funds from the Intramural Program of the National Institute of Allergy and Infectious Diseases (to E.M.S), and Grant-in-Aid for Scientific Research C (#23590569) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Osaka Clinical Immunology Foundation, the Takeda Science Foundation, the Senshin Medical Research Foundation, the Japan Rheumatism Foundation, and the Itoh Chubei Foundation (all to H.F.). NR 24 TC 35 Z9 35 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2013 VL 190 IS 11 BP 5506 EP 5515 DI 10.4049/jimmunol.1300199 PG 10 WC Immunology SC Immunology GA 147XY UT WOS:000319205900021 PM 23645881 ER PT J AU Liu, J Lange, MD Hong, SY Xie, WQ Xu, KR Huang, L Yu, YS Ehrhardt, GRA Zemlin, M Burrows, PD Su, KH Carter, RH Zhang, ZX AF Liu, Jing Lange, Miles D. Hong, Sang Yong Xie, Wanqin Xu, Kerui Huang, Lin Yu, Yangsheng Ehrhardt, Goetz R. A. Zemlin, Michael Burrows, Peter D. Su, Kaihong Carter, Robert H. Zhang, Zhixin TI Regulation of V-H Replacement by B Cell Receptor-Mediated Signaling in Human Immature B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECOMBINATION-ACTIVATING GENES; HEAVY-CHAIN GENE; V(D)J RECOMBINATION; POSITIVE SELECTION; LYMPHOCYTE ACTIVATION; DEVELOPMENTAL ARREST; CLONAL SELECTION; PRO-B; ANTIGEN; MECHANISM AB V-H replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how V-H replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces V-H replacement in human EU12 mu HC+ cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling induced V-H replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that V-H replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments. C1 [Liu, Jing; Lange, Miles D.; Hong, Sang Yong; Xie, Wanqin; Xu, Kerui; Huang, Lin; Yu, Yangsheng; Su, Kaihong; Zhang, Zhixin] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Liu, Jing; Hong, Sang Yong; Burrows, Peter D.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Ehrhardt, Goetz R. A.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. [Zemlin, Michael] Univ Marburg, Dept Pediat, D-35032 Marburg, Germany. [Su, Kaihong] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE 68198 USA. [Su, Kaihong; Zhang, Zhixin] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Carter, Robert H.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zhang, ZX (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, LTC 11706A, Omaha, NE 68198 USA. EM zhangj@unmc.edu OI Zemlin, Michael/0000-0001-9528-7419 FU National Institutes of Health [AR048592, AI073174, AI074948, AI076475, AR059351] FX This work was supported in part by National Institutes of Health Grants AR048592, AI073174, AI074948, and AI076475 (to Z.Z.) and AR059351 (to KS). NR 46 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2013 VL 190 IS 11 BP 5559 EP 5566 DI 10.4049/jimmunol.1102503 PG 8 WC Immunology SC Immunology GA 147XY UT WOS:000319205900026 PM 23630348 ER PT J AU Boonnak, K Slike, BM Donofrio, GC Marovich, MA AF Boonnak, Kobporn Slike, Bonnie M. Donofrio, Gina C. Marovich, Mary A. TI Human Fc gamma RII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IGG-FC; DEPENDENT ENHANCEMENT; HEMORRHAGIC-FEVER; DENDRITIC CELLS; RECEPTORS; REGULATORS AB Ab-dependent enhancement (ADE) of dengue virus (DENY) infection is mediated through the interaction of viral immune complexes with Fc gamma Rs, with notable efficiency of Fc gamma RII. Most human dengue target cells coexpress activating (Fc gamma RIIa) and inhibitory (Fc gamma RIIb) isoforms, but their relative roles in ADE are not well understood. We studied the effects of Fc gamma RIIa and Fc gamma RIIb by transfecting cells to express each individual receptor isoform or through coexpression of both isoforms. We showed that although both isoforms similarly bind dengue-immune complexes, Fc gamma RIIa efficiently internalized virus leading to productive cellular infection, unlike Fc gamma RIIb. We next focused on the main discriminating feature of these isoforms: their distinct intra-cytoplasmic tails (Fcy gamma IIa with an immunoreceptor tyrosine-based activation motif [ITAM] and Fc gamma RIIb with an immunoreceptor tyrosine-based inhibitory motif [ITIM]). We engineered cells to express "swapped" versions of their Fc gamma RII by switching the cytoplasmic tails containing the ITAM/ITIM motifs, leaving the remainder of the receptor intact. Our data show that both Fc gamma RIIa and Fc gamma RIIb comparably bind dengue immune complexes. However, wild type Fc gamma RIIa facilitates DENY entry by virtue of the ITAM motif, whereas the swapped version Fc gamma RIIa-ITIM significantly inhibited ADE. Similarly, replacing the inhibitory motif in Fc gamma RIIb with an ITAM (Fc gamma RIIb-ITAM) reconstituted ADE capacity to levels of the wild type activating counterpart, Fc gamma RIIa. Our data suggest that Fc gamma RIIa and Fc gamma RIIb isoforms, as the most abundantly distributed class II Fc gamma receptors, differentially influence Ab-mediated DENY infection under ADE conditions both at the level of cellular infection and viral production. C1 [Boonnak, Kobporn; Slike, Bonnie M.; Donofrio, Gina C.; Marovich, Mary A.] Henry M Jackson Fdn Adv Mil Med, Walter Reed Army Inst Res, Rockville, MD 20850 USA. [Marovich, Mary A.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. RP Marovich, MA (reprint author), NIAID, Vaccine Res Program, Div AIDS, NIH, 6700-B Rockledge Room 5142, Bethesda, MD 20892 USA. EM mary.marovich@nih.gov FU Pediatric Dengue Vaccine Initiative; Henry M. Jackson Foundation for the Advancement of Military Medicine; U.S. Department of Defense [W81XWH-07-2-0067] FX This work was supported by the Pediatric Dengue Vaccine Initiative and in part by the cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the U.S. Department of Defense. NR 31 TC 24 Z9 26 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2013 VL 190 IS 11 BP 5659 EP 5665 DI 10.4049/j.immunol.1203052 PG 7 WC Immunology SC Immunology GA 147XY UT WOS:000319205900036 PM 23616574 ER PT J AU Shenderov, K Barber, DL Mayer-Barber, KD Gurcha, SS Jankovic, D Feng, CG Oland, S Hieny, S Caspar, P Yamasaki, S Lin, X Ting, JPY Trinchieri, G Besra, GS Cerundolo, V Sher, A AF Shenderov, Kevin Barber, Daniel L. Mayer-Barber, Katrin D. Gurcha, Sudagar S. Jankovic, Dragana Feng, Carl G. Oland, Sandy Hieny, Sara Caspar, Pat Yamasaki, Sho Lin, Xin Ting, Jenny P. -Y. Trinchieri, Giorgio Besra, Gurdyal S. Cerundolo, Vincenzo Sher, Alan TI Cord Factor and Peptidoglycan Recapitulate the Th17-Promoting Adjuvant Activity of Mycobacteria through Mincle/CARD9 Signaling and the Inflammasome SO JOURNAL OF IMMUNOLOGY LA English DT Article ID C-TYPE LECTIN; BACTERIAL MURAMYL DIPEPTIDE; INNATE IMMUNE-RESPONSES; AUTOIMMUNE ENCEPHALOMYELITIS; IL-1-BETA SECRETION; DENDRITIC CELLS; T-CELLS; TUBERCULOSIS; RECOGNITION; ACTIVATION AB Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4(+) T cell responses. We found that IL-17 secretion by CD4(+) T cells following CFA immunization requires MyD88 and IL-1 beta/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1 beta processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il lb transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1 beta expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1 and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators. C1 [Shenderov, Kevin; Mayer-Barber, Katrin D.; Jankovic, Dragana; Feng, Carl G.; Oland, Sandy; Hieny, Sara; Caspar, Pat; Sher, Alan] NIAID, NIH, Parasit Dis Lab, Immunobiol Sect, Bethesda, MD 20892 USA. [Shenderov, Kevin; Cerundolo, Vincenzo] John Radcliffe Hosp, Weatherall Inst Mol Med, MRC, Immunol Unit, Headington OX3 9DS, England. [Barber, Daniel L.] NIAID, NIH, Parasit Dis Lab, T Lymphocyte Biol Unit, Bethesda, MD 20892 USA. [Gurcha, Sudagar S.; Besra, Gurdyal S.] Univ Birmingham, Sch Biol Sci, Birmingham B15 2TT, W Midlands, England. [Yamasaki, Sho] Kyushu Univ, Med Inst Bioregulat, Div Mol Immunol, Fukuoka 8128582, Japan. [Lin, Xin] Univ Texas Houston, MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Ting, Jenny P. -Y.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Trinchieri, Giorgio] NCI, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Shenderov, K (reprint author), NIAID, NIH, Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM shenderovk@niaid.nih.gov; asher@niaid.nih.gov RI U-ID, Kyushu/C-5291-2016; OI Cerundolo, Vincenzo/0000-0003-0040-3793; Besra, Gurdyal/0000-0002-5605-0395 FU Intramural Research Program of the National Institute for Allergy and Infectious Diseases; UK Medical Research Council; Cancer Research UK [C399/A2291]; Rhodes Trust; Royal Society Wolfson Research Merit Award; Medical Research Council; Wellcome Trust [081569/Z/06/Z, 0849231B/08/Z] FX This work was supported by the Intramural Research Program of the National Institute for Allergy and Infectious Diseases, the UK Medical Research Council, and Cancer Research UK (C399/A2291). K.S. was supported by a scholarship from the Rhodes Trust. G.S.B. received support in the form of a Personal Research Chair from Mr. James Bardrick, a Royal Society Wolfson Research Merit Award, the Medical Research Council, and the Wellcome Trust (081569/Z/06/Z and 0849231B/08/Z). NR 49 TC 42 Z9 42 U1 0 U2 20 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2013 VL 190 IS 11 BP 5722 EP 5730 DI 10.4049/jimmunol.1203343 PG 9 WC Immunology SC Immunology GA 147XY UT WOS:000319205900042 PM 23630357 ER PT J AU Wang, LT Li, YJ Lin, A Choe, Y Gross, ME Kim, ES AF Wang, Lingtao Li, Yi-Jia Lin, Anderson Choe, Youngki Gross, Mitchell Eric Kim, Eun Sok TI A Self-Focusing Acoustic Transducer That Exploits Cytoskeletal Differences for Selective Cytolysis of Cancer Cells SO JOURNAL OF MICROELECTROMECHANICAL SYSTEMS LA English DT Article DE Cell lysis; cytoskeleton alteration; high-frequency focused ultrasound; microelectromechanical systems (MEMS); self-focusing acoustic transducer (SFAT) ID PROSTATE-CANCER; IN-VIVO; ULTRASOUND; MECHANICS; CAVITATION AB Biophysical effects of ultrasonic energy in tissue include changes induced by heat, cavitation, and body force (radiation energy). Conventional acoustic devices generate low-frequency (1-4 MHz) high-intensity acoustic waves (> 10(3) W/cm(2)), which cause tissue destruction primarily through thermal or cavitation effects. However, these effects may be difficult to precisely control and not specific for cancerous cells over normal tissue. Here, we describe the design, fabrication, and therapeutic potential of high-frequency (18-MHz) acoustic irradiation with a self-focusing acoustic transducer (SFAT). A surface micromachining technique was used on a piezoelectric substrate to produce a SFAT device capable of focusing acoustic energy within an area of 100 mu m in diameter at the 800-mu m focal length. As we sought to minimize potentially nonspecific heat or cavitation effects by acoustic irradiation, operational parameters were chosen to study bioeffects of the device in the absence of tissue heating or biological effects due to cavitation. By varying the acoustic energy, we identified an acoustic intensity threshold (AIT) of 0.15 W/cm(2) at 17.3 MHz, sufficient to cause this cytolysis effect in human prostate cancer cells 22RV1 without heat or cavitation. Next, we compared the AIT in various cell lines representative of benign and malignant prostate, breast, and skin cells and observed lower AITs in cancer cells over nonmalignant variants. As decreased stiffness (increased compliance) is a biomechanical characteristic, which differs between malignant and nonmalignant cell lines, we hypothesized that a less organized actin cytoskeletal pattern, which is known to be associated with decreased cell stiffness, would correlate with changes in the AIT. Actin staining of cytoskeletal structures confirmed an association between a pattern of diffuse and less organized actin filaments with decreased AIT. Moreover, the same trend of decreased actin organization and decreased AIT was observed following treatments that changed actin patterns in the MCF-10A breast epithelial cell line. These results suggest that biomechanical properties make malignant cells specifically sensitive to cytolysis caused by this form of acoustic energy. In summary, we describe a miniaturized acoustic transducer capable of producing a heatless and cavitation-free, cancer-specific focused cytolysis by direct body force (radiation pressure) effects alone. Ultimately, this device may lead to a miniaturized cancer-treatment system that can be used to focally and specifically ablate cancerous tissue with microscopic precision. C1 [Wang, Lingtao; Lin, Anderson; Choe, Youngki; Kim, Eun Sok] Univ So Calif, Dept Elect Engn Electrophys, Los Angeles, CA 90089 USA. [Li, Yi-Jia; Gross, Mitchell Eric] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Gross, Mitchell Eric] Univ So Calif, Keck Sch Med, Ctr Appl Mol Med, Los Angeles, CA 90033 USA. [Gross, Mitchell Eric] NCI, Bethesda, MD 20892 USA. RP Wang, LT (reprint author), Univ So Calif, Dept Elect Engn Electrophys, Los Angeles, CA 90089 USA. EM lingtao@usc.edu FU National Cancer Institute [P30CA014089]; Robert and May Wright Foundation; James H. Zumberge Research and Innovation Fund FX This work was supported in part by the National Cancer Institute under Award P30CA014089, in part by the Robert and May Wright Foundation Research Award, and in part by the James H. Zumberge Research and Innovation Fund. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Subject Editor X. Zhang. NR 26 TC 0 Z9 0 U1 0 U2 18 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1057-7157 J9 J MICROELECTROMECH S JI J. Microelectromech. Syst. PD JUN PY 2013 VL 22 IS 3 BP 542 EP 552 DI 10.1109/JMEMS.2012.2229696 PG 11 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Instruments & Instrumentation; Physics, Applied SC Engineering; Science & Technology - Other Topics; Instruments & Instrumentation; Physics GA 156MZ UT WOS:000319827700005 ER PT J AU Boucheron-Houston, C Canterel-Thouennon, L Lee, TL Baxendale, V Nagrani, S Chan, WY Rennert, OM AF Boucheron-Houston, Catherine Canterel-Thouennon, Lucile Lee, Tin-Lap Baxendale, Vanessa Nagrani, Sohan Chan, Wai-Yee Rennert, Owen M. TI Long-term vitamin A deficiency induces alteration of adult mouse spermatogenesis and spermatogonial differentiation: direct effect on spermatogonial gene expression and indirect effects via somatic cells SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Spermatogenesis; Vitamin A deficiency; Gene expression ID RETINOIC ACID RECEPTOR; MESSENGER-RNA LEVELS; BINDING-PROTEIN; THYROID-HORMONE; SERTOLI-CELLS; GERM-CELLS; TESTICULAR DEVELOPMENT; STAGE-SYNCHRONIZATION; SEMINIFEROUS TUBULES; SERUM RETINOL AB The objective of this study was to further understand the genetic mechanisms of vitamin A deficiency (VAD) induced arrest of spermatogonial stem-cell differentiation. Vitamin A and its derivatives (the retinoids) participate in many physiological processes including vision, cellular differentiation and reproduction. VAD affects spermatogenesis, the subject of our present study. Spermatogenesis is a highly regulated process of differentiation and complex morphologic alterations that leads to the formation of sperm in the seminiferous epithelium. VAD causes early cessation of spermatogenesis, characterized by degeneration of meiotic germ cells, leading to seminiferous tubules containing mostly type A spermatogonia and Sertoli cells. These observations led us to the hypothesis that VAD affects not only germ cells but also somatic cells. To investigate the effects of VAD on spermatogenesis in mice we used adult Balb/C mice fed with Control or VAD diet for an extended period of time (6-28 weeks). We first observed the chronology, then the extent of the effects of VAD on the testes. Using microarray analysis of isolated pure populations of spermatogonia, Leydig and Sertoli cells from control and VAD 18- and 25-week mice, we examined the effects of VAD on gene expression and identified target genes involved in the arrest of spermatogonial differentiation and spermatogenesis. Our results provide a more precise definition of the chronology and magnitude of the consequences of VAD on mouse testes than the previously available literature and highlight direct and indirect (via somatic cells) effects of VAD on germ cell differentiation. Published by Elsevier Inc. C1 [Boucheron-Houston, Catherine; Canterel-Thouennon, Lucile; Baxendale, Vanessa; Nagrani, Sohan; Chan, Wai-Yee; Rennert, Owen M.] NICHHD, Lab Clin Genom, Sect Dev Genom, NIH, Bethesda, MD 20892 USA. [Lee, Tin-Lap; Chan, Wai-Yee] CUHK, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RP Rennert, OM (reprint author), NICHHD, Lab Clin Genom, Sect Dev Genom, NIH, Bethesda, MD 20892 USA. EM rennerto@mail.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS [ZIA HD008726-11, ZIA HD008817-04, ZIA HD008817-06] NR 81 TC 5 Z9 5 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JUN PY 2013 VL 24 IS 6 BP 1123 EP 1135 DI 10.1016/j.jnutbio.2012.08.013 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 160DG UT WOS:000320096400024 PM 23253600 ER PT J AU Minniti, CP Lu, K Groninger, H AF Minniti, Caterina P. Lu, Kit Groninger, Hunter TI Pain in Sickle Cell Disease #270 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID VASOOCCLUSIVE CRISIS; MANAGEMENT; ADULTS; MORPHINE; CHILDREN C1 [Groninger, Hunter] NIH, Pain & Palliat Care Serv, Clin Res Ctr, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Pain & Palliat Care Serv, Clin Res Ctr, Bldg 10 Room 2-1733,10 Ctr Dr, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 19 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD JUN PY 2013 VL 16 IS 6 BP 697 EP 699 DI 10.1089/jpm.2013.9505 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 155GW UT WOS:000319736900022 PM 23614713 ER PT J AU Inagaki, S Ghirlando, R White, JF Gvozdenovic-Jeremic, J Northup, JK Grisshammer, R AF Inagaki, Sayaka Ghirlando, Rodolfo White, Jim F. Gvozdenovic-Jeremic, Jelena Northup, John K. Grisshammer, Reinhard TI LIPIDS MODULATE THE INTERACTION BETWEEN NEUROTENSIN RECEPTOR NTS1 AND G-PROTEIN: A NANODISC STUDY SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Meeting Abstract C1 [Inagaki, Sayaka; White, Jim F.; Gvozdenovic-Jeremic, Jelena; Grisshammer, Reinhard] Natl Inst Deafness & Other Commun Disorders, Membrane Prot Struct Funct Unit, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Ghirlando, Rodolfo] Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Northup, John K.] Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Dept Hlth & Human Serv, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 14 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD JUN PY 2013 VL 33 IS 3 BP 191 EP 191 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 155LI UT WOS:000319749200032 ER PT J AU Thomason, ME Tocco, MA Quednau, KA Bedway, AR Carre, JM AF Thomason, Moriah E. Tocco, Maria A. Quednau, Kelly A. Bedway, Andrea R. Carre, Justin M. TI Idle Behaviors of the Hippocampus Reflect Endogenous Cortisol Levels in Youth SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE cortisol; default mode; functional connectivity; hippocampus; resting state ID DEFAULT-MODE NETWORK; MAJOR DEPRESSIVE DISORDER; GLOBAL SIGNAL REGRESSION; RESTING-STATE NETWORKS; CEREBRAL BLOOD-FLOW; FUNCTIONAL CONNECTIVITY; SUBGENUAL CINGULATE; STRESS REACTIVITY; DENTATE GYRUS; SOCIAL PHOBIA AB Objective: Compelling evidence indicates that disruption in functional connectivity (PC) in brain networks underlies many psychiatric and developmental disorders. Current theory posits that biological (i.e., cortisol) and environmental (i.e., stress) experiences in early life are strong determinants in the development of functional brain systems and formative in the genesis of such disorders. The objective of this study was to examine the extent to which individual differences in cortisol concentrations during PC magnetic resonance imaging (MR[) would map onto variability in hippocampal to default mode network (DMN) connectivity in typically developing youth. Method: Salivary cortisol and FC MRI data were collected concurrently in 33 scan-naive 7- to 15-year-old participants. Twenty-nine of these participants previously completed the Trier Social Stress Test. Hippocampal to DMN FC and endogenous cortisol variability during MRI were examined. A possible association between MR[ cortisol and cortisol response to the Trier Social Stress Test during the preceding visit or a participant's ratings of anxiety during MRI was tested. Results: There were significant positive relations between MRI cortisol levels and measurements in the following 3 areas: hippocampal to DMN FC during the resting state, cortisol levels during the Trier Social Stress Test, and fear/anxiety ratings during MRI. Fear/anxiety ratings during MRI also related to self-reported anxiety on standardized measurements. Conclusions: This study shows for the first time that FC of the hippocampus is altered with changing cortisol responsivity in youth. Altered FC during the resting state may represent altered alertness or monitoring resulting from variation in glucocorticoid function in youth, which carries implications for the effect of stress on response monitoring and decision making. C1 [Thomason, Moriah E.; Tocco, Maria A.; Quednau, Kelly A.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [Bedway, Andrea R.] Michigan State Univ, Coll Human Med, E Lansing, MI 48824 USA. [Thomason, Moriah E.; Carre, Justin M.] Wayne State Univ, Dept Psychol, Detroit, MI 48202 USA. [Thomason, Moriah E.] Wayne State Univ, Dept Pediat, Sch Med, Detroit, MI 48202 USA. [Thomason, Moriah E.] NICHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. RP Thomason, ME (reprint author), Merrill Palmer Skillman Inst, 71 E Ferry St, Detroit, MI 48202 USA. FU Merrill Palmer Skillman Institute; Department of Pediatrics, WSU School of Medicine; National Alliance for Research on Schizophrenia and Depression (NARSAD) FX The project was supported in part by the Merrill Palmer Skillman Institute and the Department of Pediatrics, WSU School of Medicine and by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (M.E.T.). NR 74 TC 5 Z9 5 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 2013 VL 52 IS 6 BP 642 EP 652 DI 10.1016/j.jaac.2013.04.004 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 160UZ UT WOS:000320147300012 PM 23702453 ER PT J AU Jackson, WM Alexander, PG Bulken-Hoover, JD Vogler, JA Ji, YM Mckay, P Nesti, LJ Tuan, RS AF Jackson, Wesley M. Alexander, Peter G. Bulken-Hoover, Jamie D. Vogler, Jared A. Ji, Youngmi McKay, Patricia Nesti, Leon J. Tuan, Rocky S. TI Mesenchymal progenitor cells derived from traumatized muscle enhance neurite growth SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE mesenchymal stem cells; nerve regeneration; neurotrophic factors; dorsal root ganglia; brain-derived neurotrophic factor ID PERIPHERAL-NERVE REGENERATION; STEM-CELLS; STROMAL CELLS; NEUROTROPHIC FACTORS; CONDITIONED MEDIUM; NEURAL PROTEINS; TISSUE-REPAIR; IN-VITRO; DIFFERENTIATION; EXPRESS AB The success of peripheral nerve regeneration is governed by the rate and quality of axon bridging and myelination that occurs across the damaged region. Neurite growth and the migration of Schwann cells is regulated by neurotrophic factors produced as the nerve regenerates, and these processes can be enhanced by mesenchymal stem cells (MSCs), which also produce neurotrophic factors and other factors that improve functional tissue regeneration. Our laboratory has recently identified a population of mesenchymal progenitor cells (MPCs) that can be harvested from traumatized muscle tissue debrided and collected during orthopaedic reconstructive surgery. The objective of this study was to determine whether the traumatized muscle-derived MPCs exhibit neurotrophic function equivalent to that of bone marrow-derived MSCs. Similar gene- and protein-level expression of specific neurotrophic factors was observed for both cell types, and we localized neurogenic intracellular cell markers (brain-derived neurotrophic factor and nestin) to a subpopulation of both MPCs and MSCs. Furthermore, we demonstrated that the MPC-secreted factors were sufficient to enhance in vitro axon growth and cell migration in a chick embryonic dorsal root ganglia (DRG) model. Finally, DRGs in co-culture with the MPCs appeared to increase their neurotrophic function via soluble factor communication. Our findings suggest that the neurotrophic function of traumatized muscle-derived MPCs is substantially equivalent to that of the well-characterized population